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Keywords:

  • human obesity gene map;
  • association;
  • linkages;
  • Mendelian disorders;
  • quantitative trait loci

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

This is the tenth update of the human obesity gene map, incorporating published results up to the end of October 2003 and continuing the previous format. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) from human genome-wide scans and animal crossbreeding experiments, and association and linkage studies with candidate genes and other markers is reviewed. Transgenic and knockout murine models relevant to obesity are also incorporated (N = 55). As of October 2003, 41 Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. QTLs reported from animal models currently number 183. There are 208 human QTLs for obesity phenotypes from genome-wide scans and candidate regions in targeted studies. A total of 35 genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 272 studies reporting positive associations with 90 candidate genes. Fifteen such candidate genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, more than 430 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful sites can be found at http:obesitygene.pbrc.edu.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

The interest for the compendium of putative human obesity genes continues to be very strong. This paper is the tenth in a series (1, 2, 3, 4, 5, 6, 7, 8, 9) on the status of the human obesity gene map; this is the ninth report published in Obesity Research. As in previous versions of the map, the current publication incorporates material published up to the end of October 2003. The review includes publications that have dealt with a variety of phenotypes pertaining to obesity; such phenotypes include BMI, body-fat mass, percentage of body fat, abdominal fat, fat-free mass, skinfolds, resting metabolic rates, plasma leptin levels, and other components of fat distribution and energy balance. As in previous updates, negative findings are not systematically reviewed but are briefly introduced when such data were available to us. The interested reader will notice that a good number of genes and genomic positions are now supported by multiple studies and, at times, more than one line of evidence.

The present synthesis includes sections dealing with single-gene and digenic human obesity cases, Mendelian disorders exhibiting a phenotype of relevance to human obesity, quantitative trait loci (QTLs)1 from rodent and other animal model studies, human linkage studies including genome scans performed to identify QTLs of obesity or obesity-related phenotypes, association studies in humans with specific genes and polymorphisms, and a comprehensivepictogram of the 2003 human obesity gene map. A section deals with transgenic (Tg) and knockout (KO) mice, the phenotypes of which include alterations in adiposity levels or a trait relevant to obesity. The references to each entry in the current human obesity gene map are provided for convenience. We are using gene symbols and chromosomal locations given in the Locus Link website (http:www.ncbi.nlm.nih.govLocusLink) available from the National Center for Biotechnology Information (NCBI). The Appendix provides a complete list of genes and map locations cited in this paper.

The search for the relevant genetic literature is undertaken through a variety of sources: PubMed searches using a combination of key words, authors, and journals; continuous reviews of obesity and genetics journals; personal collection of reprints; and papers made available to us by colleagues from around the world. Each collaborating author is assigned an area of the report for closer scrutiny of the material available and for preparing the summary of studies relevant to that area. The electronic version of the human obesity gene map with numerous useful links is available at http:obesitygene.pbrc.edu.

Bioinformatics Issues

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

The data management requirements for this review have increased significantly since the Obesity Gene Map was first published in 1996. The online Obesity Gene Map Database (OGMDB) was created in 2000 to give users additional querying and browsing capability and to facilitate the accurate creation of the map figure. This is the first year in which full capabilities of the database were exploited, enabling us to create the map and tables in an automated fashion. The online OGMDB (http:obesitygene.pbrc.edu) contains HTML (hypertext markup language) versions of the tables (created on demand), complete with hypertext links to the corresponding OGMDB data objects.

The OGM database and website were made possible by three key software components. ACeDB (10, 11) (A C. elegans DataBase) is an object-oriented database environment initially built to support the Caenorhabditis elegans genome sequencing project (12) but has become a bioinformatics workhorse for a variety of projects including the SNP Consortium database (13). The database's web interface was deployed using AceBrowser (14), a collection of common gateway interface scripts that connect to the ACeDB server to generate generic database query forms and display documents. The tables were created using the application programming interface known as AcePerl (14). This code library allows a Perl script to retrieve data from the database and manipulate it programmatically. AcePerl also greatly reduced the time required to update the cytogenetic and sequence map positions of loci in the database.

The browsing and querying capabilities of OGMDB have brought to light even more acutely that our ability to draw conclusions from a large-scale analysis of the obesity literature is limited. One major problem is the poor standardization in the description of polymorphisms such as those reported in Table 1. The use of a standard nomenclature [such as that proposed by Antonarakis et al. (15)] for the representation of polymorphisms at the amino acid and nucleotide level could prevent confusion and loss of information. Furthermore, it would be helpful if all residue numbering were done with reference to a standard sequence such as those available in GenBank or European Molecular Biology Laboratory. In addition, as new mutations and polymorphisms are identified, they should be deposited in the Database of Single Nucleotide Polymorphism (dbSNP), particularly when population frequency information is available (for submission information see http:www.ncbi.nlm.nih.govSNP).

Table 1. . Monogenic and digenic nonsyndromic human obesity cases
GeneLocationMutationNAge (years)BMI (SDS)References
  1. Status as of October 2003.

  2. N represents the number of published cases.

  3. SDS stands for standard deviation BMI scores and are shown in parentheses.

LEPR1p31.3IVS16 + 1G > A313 to 1953 to 72(192)
POMC2p24.1R236G613(2.9)(26)
  7133delC13 (193)
  7013G > T    
  3804C > A17 (193)
PCSK15q15G483R13 (194)
  IVS5 + 4A > C    
LEP7q32.2G398del22 to 837 to 46(195)
  R105W46 to 3433 to 56(196, 197)
MC4R18q21.32V50M26 to 39(2.8 to 5.4)(21, 24, 198)
  S58C213 to 39(2.1 to 4.2)(21, 24, 198)
  I102S116(4.1)(24, 198)
  I170V213 to 45(3.8 to 4.4)(21, 23, 198)
  279–280insGT78 to 36 (17, 24, 199)
  C271Y98 to 40 (17, 22, 23, 199)
  3′UTR + 28delC1  (199)
  T112M2  (23, 199, 200)
  R165Q1  (19, 23, 199)
  V253I1  (19, 22, 23, 199)
  335–336insA1  (17)
  I125K2  (17, 22)
  A175T2  (17, 22)
  I316S11  (17, 22)
  Deletion6  (17)
  N97D5  (17, 22)
  N62S9  (17, 21, 22)
  I137T14357(23, 201)
  P78L1  (19, 23, 24)
  V95I1  (19)
  I121T1  (19)
  G181D1  (19)
  A244E1  (19)
  750–751delGA1  (19)
  S94R1  (19)
  960delT1  (19)
  Y35X118 to 6426 to 57(18, 19, 202, 203)
  -65-(-64)delTG14040(204)
  171delC14140(204)
  G98R14062(21, 205)
  S127L28 to 3427 to 45(24, 206)
     (3.2 to 5.3) 
  A244G38 to 5024 to 32(24, 206)
     (1.8 to 4.1) 
  P299H26 to 2728 to 34(24, 206)
     (2.7 to 6.3) 
  47–48insG12042(207)
  T150I15250(207)
  I170V22030 (3.8)(23, 207)
  L250Q16068 (8.5)(207)
  I301T230 to 3554 to 57(207)
     (10 to 10.4) 
  R165W540 to 7533 to 62(207)
     (2.1 to 10) 
  732–733insGATT511 to 5830 to 57(208)
  Y287X1  (22)
  L106P1  (22)
  631–634delCTCT104 to 8128 to 41(17, 19, 24, 202, 203, 209)
PPARG3p25.2553–555delAAAinsT521 to 4926 to 31.4(27)
PPP1R3A7q31.21984–1985delAG    

Another critical issue has to do with the lack of standardized vocabularies for describing obesity phenotypes and the populations in which they are studied. We currently index 125 distinct study traits, which reduce to ∼100 after merging trivial variants. The latter subset shares many common features that could probably be represented by a series of hierarchical relationships. The same is true of the 83 study populations and demographic characteristics (age, sex, ethnic origin, etc.) that have been identified in this year's inventory. Much work into defining gene function relationships has been done under the auspices of the Gene Ontology Consortium (16). However, there are no widely accepted ontologies for describing human phenotypic data or populations. A move to create structured vocabularies appropriate for obesity research reporting would facilitate communication and data mining activities in the future.

Single-Gene and Digenic Obesity Cases

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

In the past year, no novel single-gene obesity syndromes have been described. However, there has been more activity on the melanocortin-4 receptor (MC4R) gene with several papers on the functional impact of previously and newly reported mutations (17, 18, 19, 20, 21, 22, 23, 24). The number of sequence variants discovered so far is quite large (well over 50). However, there is often insufficient information in the published reports on pedigrees and trait transmission. The mutations retained in Table 1 are those that have been shown to be functional through in vitro studies or would be strongly suspected to affect receptor structure (deletions, frameshift and nonsense mutations). A total of 42 different mutations in 130 individuals fit these criteria, making MC4R mutations the most prevalent genetic cause of obesity identified to date. These mutations are typically associated with early onset and rather severe obesity. However, not surprisingly, the variation in phenotypic expression of obesity related to the MC4R gene points to variable penetrance and other genetic factors. One possible mechanism through which these mutations affect body weight is loss of normal regulation of food intake (17). Two studies have reported an association with bulimia (18, 25).

As for the other genes, one group described 2 unrelated children with obesity (2.9 and 3.4 SD scores for BMI), both carrying a missense R236G mutation in the POMC gene, not found in a control population (26). This mutation disrupted the dibasic cleavage site between β-melanocyte stimulating hormone and β-endorphin, causing the formation of a fusion protein that only weakly activates the receptor. The mutation co-segregated with early-onset obesity over three generations in one family.

One report pertained to a family in which all affected members with overweight or obesity (and insulin resistance) were double heterozygotes for a premature stop mutation 553–555delAAAinsT (creating a frameshift at codon 185 and a stop codon at 186) in PPARG and a frameshift/premature stop mutation 1984–1985delAG (creating a frameshift at codon 662 and a stop codon at 668) in PPP1R3A, a gene that encodes protein phosphatase 1, muscle-specific regulatory subunit 3, involved in carbohydrate metabolism (27). Two affected members of another family were carriers of the PPP1R3A mutation, suggesting that other genes could be involved as well. The oligogenic obesity cases identified thus far could all be ascribed to a single-gene defect. The previous paper appears to be the first to report on cases in which two hits in different genes were necessary for the patients to be obese. We have high-lighted this report because we feel that it will be followed by many others as the oligogenic nature of many obesity cases is progressively revealed.

Mendelian Disorders

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

Updated references for all Mendelian disorders exhibiting obesity as one of their clinical features and new additions are described in Table 2. Among the autosomal dominant syndromes, several dozen new mutations in the GNAS1 gene have been discovered by different groups in patients with Albright Hereditary Osteodystrophy (AHO) (28, 29, 30, 31, 32). These mutations were confirmed to affect function. Exclusive maternal transmission of mutations was reported by one group, suggesting a role of parental imprinting of the GNAS1 gene (30). There exists a form of AHO with no resistance to parathyroid hormone. In this condition called pseudopseudohypoparathyroidism, the classical features of AHO such as obesity are present. The STK25 gene, coding for a kinase involved in heterotrimeric G protein signaling, is absent as a result of micro-deletions at 2q27 described in these patients and, thus, is a strong candidate gene for this condition (33, 34, 35). Among the lipodystrophy syndromes, several patients with either generalized or partial lipodystrophy combined with other clinical features have been reported (36, 37, 38, 39). All carried mutations in the lamin A (LMNA) gene.

Table 2. . Obesity-related Mendelian disorders with known map locations
OMIM no.SyndromeLocusCandidate gene*References
Autosomal recessive
  • Status as of October 2003.

  • OMIM, Online Mendelian Inheritance of Man.

  • *

    Symbols with asterisks are the National Center for Biotechnology Information LocusLink symbols for the traits rather than for the genes and are used when no candidate genes are known.

203800Alstrom syndrome2p13.1ALMS1(210, 211, 212, 213)
209901Bardet-Biedl syndrome 111q13.1BBS1(50, 51, 214, 215, 216, 217)
209900Bardet-Biedl syndrome 216q13BBS2(217, 218, 219)
600151Bardet-Biedl syndrome 33p13-p12BBS3*(220, 221, 222)
600374Bardet-Biedl syndrome 415q22.33BBS4(217, 223, 224, 225, 226)
603650Bardet-Biedl syndrome 52q31BBS5*(227, 228)
209900Bardet-Biedl syndrome 620p12.2MKKS(229, 230, 231)
607590Bardet-Biedl syndrome 74q27BBS7(49)
269700Berardinelli-Seip congenital lipodystrophy 19q34.3AGPAT2(52, 232, 233)
606158Berardinelli-Seip congenital lipodystrophy 211q13BSCL2(52, 234, 235, 236)
212065Carbohydrate-deficient glycoprotein type 1a16p13.2PMM2(237)
216550Cohen syndrome8q22.2COH1(53, 238, 239)
601538Combined pituitary hormone deficiency5q35.3PROP1(240, 241)
227810Fanconi-Bickel syndrome3q26.31SLC2A2(54, 55, 242, 243, 244, 245, 246, 247)
139191Isolated growth hormone deficiency7p14GHRHR(248, 249)
Autosomal dominant
100800Achondroplasia4p16.3FGFR3(250, 251, 252, 253)
103580Albright hereditary osteodystrophy20q13.32GNAS1(254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267)
103580Albright hereditary osteodystrophy (PPHP)2q37.3STK25(33, 34, 35)
103581Albright hereditary osteodystrophy 215q11-q13AHO2*(268)
105830Angelman syndrome with obesity15q11-q12ANCR*(269)
605746Anisomastia16q13-q21ANMA*(270)
151660Familial partial lipodystrophy, Dunnigan1q23.1LMNA(36, 37, 38, 39, 271, 272, 273, 274, 275, 276)
604517Familial partial lipodystrophy, non-Dunnigan4p15.31PPARGC1(40, 41, 277)
147670Insulin resistance syndromes19p13.3INSR(278, 279, 280, 281, 282, 283, 284, 285)
122000Posterior polymorphous corneal dystrophy (Chr 1)1p34.3COL8A2(286)
605020Posterior polymorphous corneal dystrophy (Chr 20)20p11.21VSX1(42, 287)
176270Prader-Willi syndrome15q11.2IPW(288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305)
  15q11.2PWCR1 
  15q12SNRPN 
  15q11.2MAGEL2 
  15q11.2NDN 
  15q11.2MKRN3 
603128Prader-Willi-like syndrome (chr 6q)6q16.3SIM1(291, 301, 302, 305, 306, 307, 308, 309)
188830Primary pigmented nodular adrenocortical disease17q24.3PRKAR1A(48)
181450Schinzel syndrome12q24.21TBX3(310)
190160Thyroid hormone resistance syndrome3p24.1THRB(311)
181450Ulnar-mammary syndrome12q24.21TBX3(43, 310, 312)
194072WAGR syndrome11p13WT1(44, 45, 313, 314, 315)
  11p13PAX6 
X-linked
301900Borjeson-Forssman-Lehmann syndromeXq26.3PHF6(56, 316, 317, 318)
303110Choroideremia with deafnessXq21.1DFN3(319, 320)
  Xq21.2CHM 
309550Fragile X syndrome with Prader-Willi-like phenotypeXq28FMR1(60, 61, 62, 63)
300148MEHMO syndromeXp22.13-p21.1MEHMO*(321, 322, 323)
300218Mental retardation X-linked, syndromic 7Xp11.3-q22.1MRXS7*(324)
300238Mental retardation, X-linked, syndromic 11X26-q27MRXS11(57, 325)
176270Prader-Willi-like syndrome, X-linkedXq23-q25 (308, 326)
312870Simpson-Golabi-Behmel 1Xq26.2GPC3(327, 328, 329, 330, 331, 332, 333)
  XGPC4 
300209Simpson-Golabi-Behmel 2Xp22SGBS2*(334)
309585Wilson-Turner syndromeXq21.2-q22WTS*(335, 336)

As for non-Dunnigan familial partial lipodystrophy (FPLD), another family was reported with a mutation in the PPARG gene (40). All five affected members carried an F388L mutation that affected transcriptional activity and receptor activity. Another group described severe insulin resistance with partial lipodystrophy in carriers of a P467L mutation in PPARG (41).

In cases of posterior polymorphous corneal dystrophy, a corneal endothelial dystrophy in which obesity has been observed, two loci seem to be involved. Mutations in the COL8A2 gene at 1p34.2-p32.3 and the VSX1 gene (at 20q11), which encodes a homeodomain transcription factor (42), have been reported. The Prader-Willi-like syndrome linked to 6q16.2-q14 and the SIM1 gene are now reported here with the Mendelian syndromes. New mutations have been reported for ulnar-mammary (Schinzel) syndrome (43). For the Wilms’ tumor-aniridia-genital anomalies-mental retardation (WAGR) syndrome, a further case of obesity with hyperphagia has been described (44). One recent report described several mutations in the PAX6 gene in patients with aniridia, a condition of iris hypoplasia. One patient had WAGR syndrome, in which PAX6 was deleted, making PAX6 a possible candidate gene (45).

One of the classical forms of central obesity is Cushing's syndrome, in which obesity, insulin resistance, glucose abnormalities, hypertension, and other features are invariably found, all of which are caused by pathologically elevated levels of cortisol. The causal gene for the only known inherited form of this disease has recently been reported by 2 groups (46, 47). Primary pigmented nodular adrenocortical disease with Cushing's syndrome is caused by mutations in the regulatory subunit R1A of the protein kinase A gene (PRKAR1A), encoding a key mediator of cyclic adenosine 3′, 5′-monophosphate signaling in mammals. This disease is part of the multiple neoplasia syndrome, the Carney complex (48).

In the autosomal recessive syndrome category, another Bardet-Biedl syndrome (BBS) locus has been found, BBS7. The gene causing the corresponding syndrome codes for a protein of unknown function (49). Two groups reported on the complex inheritance in BBS (50, 51).

An exploration of the heterogeneity of congenital generalized lipodystrophy (Berardinelli-Seip Congenital Lipodystrophy) led to the identification of 12 different mutations in AGPAT2 in 27 pedigrees and 9 mutations in BSCL2 in 11 other pedigrees (52). Two other studies described patients with the syndrome who did not carry any mutations in these genes, suggesting a possible additional BSCL locus. The causal gene, COH1, in Cohen syndrome, in which obesity is a minor component, was recently identified by a Finnish group (53). Affected individuals carried mutations encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Finally, several new mutations have been described in the GLUT2 or SLC2A2 gene that causes the Fanconi-Bickel syndrome (54, 55).

As for the X-linked syndromes, a novel D333del mutation in the candidate gene for Borjeson-Forssman-Lehmann syndrome has been reported (56). A second family with Shashi X-linked mental retardation syndrome with prominent obesity has been described (57). In Simpson-Golabi-Behmel 1 syndrome patients with overgrowth, two studies expanded on the phenotypic and genotypic spectrum of the disease (58, 59). Finally, we have added to this year's list a fragile X syndrome with Prader-Willi-like phenotype. Fragile-X syndrome is a common cause of mental retardation. However, a subtype with Prader-Willi-like phenotype has been described in which mutations in the FMR-1 gene are present, with no deletions at the PWS locus at 15q11-q12 (60, 61, 62, 63). Patients with this syndrome often present with severe obesity.

Single-Gene Mutations in Mice

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

Table 3 summarizes the mouse models of obesity caused by a defect in a single gene. There is only one addition this year. The Mahoganoid (MGRN1) gene has been cloned from the mouse coat color mutant Mahoganoid (md) (64). MGRN1 encodes a 494-amino acid protein containing a C3HC4 RING domain. The human homologue is 81% identical at the amino acid level. Three mutations have been observed (md, md2J, and md5J). They are all due to large (5- to 8-kb) retroviral insertions (exon 2, intron 2, intron 11, respectively), resulting in a 10- to 20-fold lower expression level of the normal transcript. Mahoganoid diminishes the obesity of AY mice (65), but does not suppress obesity caused by a high-fat diet (64).

Table 3. . Natural single-gene mutation in mouse models of obesity
 MouseHuman homolog 
Mutations*ChrGenesInheritanceChrGenesGene productReferences
  • Status as of October 2003.

  • Chr, chromosome.

  • *

    The strain carrying the Adult (ad) dominant mutation on chromosome 7 is now extinct.

  • Homologous to rat fat (fa)/corpulent (cp).

Diabetes (db)4LeprRecessive1p31LEPRLeptin receptor(337, 338)
Fatty liver dystrophy (fld)12Lpin1Recessive2p21LPIN1Lipin(339)
Fat (fat)8CpeRecessive4q32CPECarboxypeptidase E(340)
OLETF5CckarRecessive4p15.2-p15.1CCKARCholecystokinin receptor A(341, 342)
Little11GhRecessive8q12.3GHGrowth hormone(343)
Obese (ob)6LepRecessive7q31.3LEPLeptin(344)
Tubby (tub)7TubRecessive11p15.5TUBInsulin signaling protein(345, 346, 347)
Mahogany (mg)2AtrnRecessive20p13ATRNAttractin(348, 349)
Mahoganoid (md)16Mgm1Recessive16p13.3MGRN1Mahogunin, ring finger 1(64)
Agouti yellow (Ay)2AyDominant20q1.2-q12ASIPAgouti signaling protein(350)

Knockout and Transgenic Models

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

New KO and Tg mice have evidenced that other genes have the potential to impact obesity-related phenotypes. We have retained only those models in which the gene has a human equivalent (Table 4). Five new KO or Tg gene models and one transgenic model for a chromosomal duplication/deletion have been added to the compendium. Two hormonal genes (luteinizing hormone or LH and androgen receptor or AR) have been related to obesity-related phenotypes. Tg female mice overexpressing a chimeric bovine LH β-subunit/human chorionic gonadotropin β-subunit COOH-terminal extension (bLHb-CTP) became obese with a 32% increase in body weight at 5 months of age (66). Food intake was increased and thermogenic activity reduced (66). Using a conditional targeting technique based on the Cre-loxP system, AR knockout male mice showed late-onset obesity at 30 weeks of age (67). Food intake remained normal whereas white adipose tissue accumulated, which suggests that ARs act as a negative regulator of adipocyte development (67).

Table 4. . Knockout and transgenic rodent models relevant to obesity
RodentHuman 
ChrGeneMutationsChrGeneProductReferences
  • Status as of October 2003.

  • Chr, chromosome.

  • *

    Dp(11)(17) and Df(11)(17) represent an engineered chromosomal duplication or deletion, respectively, of the Smith-Magenis syndrome region on mouse chromosome 11. Similarly, del(17)(p11.2) and dup(17)(p11.2)(p11.2) refer to the deletion and duplication, respectively, of the corresponding human chromosomal regions.

5Acc2Knockout12q24.1ACACBAcetyl CoA carboxylase 2(351)
7ApoC1Transgenic19q13.2APOC1Apolipoprotein C1(352)
XArKnockoutXq11.2-q12ARAndrogen receptor(67)
2AtrnNaturally occurring20p13ATRNMahogany(348, 349)
2AyNaturally occurring20q11.2-q12ASIPAgouti yellow(350)
12Batf(A-ZIP/F)Transgenic14q24.3BATFRegulator of transcription factor B-ZIP(353)
XBrs3KnockoutXq26-q28BRS3Bombesin receptor 3(354)
17C3Knockout19p13.3C3Acylation-stimulating protein(355)
5CckarNaturally occurring4p15.2-p15.1CCKAROLETF(341, 342)
7CebpKnockout20q12-q13.1CEBPACCAAT enhancer binding protein(356)
7CebpKnockout20q13.13CEBPBCCAAT/enhancer binding protein (C/EBP), beta(357)
13Chrm3Knockout1q41-q44CHRM3Muscarinic receptor M3(358)
8CpeNaturally occurring4q32CPEFat(340)
9Cyp19Knockout15q21CYP19A1Transferase Aromatase(359)
11Df(11)(17)* SmcrTransgenic17p11.2del(17)(p11.2)* SMCRSmith-Magenis syndrome(72)
15DgatKnockout8q-terDGAT1Acyl CoA: diacylglycerol acyl transferase(360)
11Dp(11)(17)* SmcrTransgenic17p11.2dup(17)(p11.2)(p11.2)* SMCRSmith-Magenis syndrome(72)
13Drd1aKnockout5q34-q35DRD1Dopamine receptor D1(361)
8Eif4ebp1Knockout8p12EIF4EBP1Eukaryotic translation initiation factor 4E binding protein 1(362)
3Fabp4 (aP2)Knockout8q21FABP4Fatty acid binding protein 4(363)
17FshrKnockout2p21FSHRFollicular stimulating hormone receptor(364)
3GabtITransgenic3p25-p24SLC6A1Gamma-aminobutyric acid transporter I(365)
15Gdc1Transgenic12q13.2GPD1alpha-glycerol phosphate dehydrogenase(366)
2GhrhTransgenic20q11.2GHRHGrowth hormone releasing hormone(367)
6GhrhrNaturally occurring7p14GHRHRLittle(343)
15Gpr24Knockout22q13.3GPR24G protein-coupled receptor 24(368)
6H1rKnockout3p25HRH1Histamine receptor H1(369)
11HcrtKnockout17q21HCRTHypocretin (Orexin)(370)
5HdhTransgenic4p16.3HDHuntingtin(371)
10Hmga2Knockout12q15HMGA2Component enhancesome Hmgic(372)
1Hsd11b1Transgenic1q32-q41HSD11B1Hydroxysteroid (11-beta) dehydrogenase 1(373)
9Icam1Knockout19p13.2ICAM1Intercellular adhesion molecule 1(374)
2Il1rn(Il-1ra)Knockout2q14.2IL1RNinterleukin 1 receptor antagonist(375)
5Il-6Knockout7p15.3IL6Interleukin 6(69)
6LepNaturally occurring7q32.2LEPObese(344)
4LeprNaturally occurring1p31.3LEPRDiabetes(337, 338)
7LhbTransgenic19q13.32LHBLuteinizing hormone beta polypeptide(66)
12Lpin1Naturally occurring2p21LPIN1Fatty liver dystrophy(339)
2Mapk8ipKnockout11p11.2MAPK8IP1Mitogen-activated protein kinase 8 interacting protein 1(71)
8MtKnockout16q13MT1AMetallothionein I and II(376)
3Nhlh2Knockout1p12-p11NHLH2Neural transcription factor 2(377)
3Pkar2bKnockout1q12PRKAB2Protein kinase A RIIb(378)
7PlinKnockout15q26PLINPerilipin(379, 380)
10PmchTransgenic12q23.3PMCHMelanin concentrating hormone(381, 382)
11PpyTransgenic17q21PPYPancreatic polypeptide(383)
2PrkcqTransgenic10p15.1PRKCQProtein kinase C, theta(70)
2Ptpn1Knockout20q13.1-q13.2PTPN1Protein tyrosine phosphatase, non-receptor type 1(384)
5PtprbKnockout12q15-q21PTPRBProtein tyrosine phosphatase 1 B(384)
12Sdc1Transgenic2p24.1SDC1Syndecan 1(385)
11SparcKnockout5q33.1SPARCSecreted protein, acidic, cysteine-rich (osteonectin)(68)
8Srebf1/Srebf2Transgenic17p11.2SREBF1Sterol regulatory element binding protein(386, 387)
11Stat5Knockout17q11.2STAT5ASignal transducer and activator of transcription 5(388)
7Tgfb1Transgenic19q13.31TGFB1Transforming growth factor, beta 1(389)
7TubNaturally occurring11p15.5TUBTubby(345, 346, 347)
5VgfKnockout7q22VGFNeural expressed protein(390)

Secreted protein acidic and rich in cysteine/osteonectin/BM-40 (SPARC) is a matrix-associated protein that elicits changes in cell shape. SPARC-null mice have a greater deposit of subcutaneous fat arising from an increase in size and number of adipocytes (68). The immune-modulating cytokine interleukin-6 is expressed both in adipose tissue and hypothalamic nuclei that regulate body composition. Interleukin-6 KO mice showed disturbed carbohydrate and lipid metabolism resulting in mature-onset obesity (69). In a Tg model overexpressing a mutated form of protein kinase C theta (PKC-theta), a dominant negative mutation that acted specifically in skeletal muscle to invalidate kinase activity, mice were obese and insulin resistant at 4 months of age (70), whereas the inactivation of the c-Jun amino-terminal kinase 1 (JNK1) decreased adiposity and improved insulin sensitivity (71).

Finally, Tg mice carrying a deletion on chromosome 11 [Df(11)17] homologous to the human Smith-Magenis syndrome region at 17p11.2 exhibited marked obesity. In contrast, Tg mice carrying the reciprocal duplication of the same chromosomal region [Dp(11)17] were underweight (72). carrying the reciprocal duplication of the same chromosomal region [Dp(11)17] were underweight (72). Examination of the Df(11)17/Dp(11)17 animals suggests that the phenotype results from a gene dosage effect (72).

QTLs from Crossbreeding Experiments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

A total of 183 animal QTLs are now included in our inventory (Table 5) with equivalent human syntenic regions determined from the Mouse Genome Database of the Jackson Laboratory (73) and the NCBI Mouse/Human homology maps (74). Only mice crosses have been added to this year's review. In previous years, maps described by Yamada et al. (75) and Jacob et al. (76) were used for the rat, and maps from the Animal Genome Database in Japan (77) and from the U.S. Livestock Genome Mapping Projects (78) for the pig.

Table 5. . QTLs for obesity phenotypes from animal crosses with putative syntenic locations in the human genome
     Chromosome 
CrossQTLStatisticsVariance (%)PhenotypesAnimalHumanReferences
  • Status as of October 2003.

  • Adip, adiposity; Afp, abdominal fat percent; Afpq, abdominal fat QTL; Afw, abdominal fat weight; Batq, brown adipose tissue QTL; BFM4, backfat QTL on chromosome 4; Bl, body length; BTA17LW, bovine chromosome 17 live weight; Bw, body weight; bw/gk, body weight/Goto-Kakizaki; Bw6, body weight at 6 weeks; Bw8q, QTL for body weight at 8 weeks of age; Bwq, body weight QTL; C10bw, castaneus 10-week body weight QTL; Carfhg1 (Q5Ucd1-fp): carcass fat in high growth mice 1; DAHL3, Dahl rat body weight QTL on chromosome 3; Dmo, diabetic mouse; Dob, dietary obese; FAT 1, pig QTL with major effect on fitness; Fatq, fat QTL; Fob, fat obesity; Hlq, heat loss QTL; IGF2q, QTL located near the gene for insulin-like growth factor 2; Imfq1, intramuscular fat QTL 1; Kcal, cumulative kilocalorie intake; KK7, KK mouse chromosome 7 region; Lepq, leptin receptor QTL; m, maternal effect; Minc, macronutrient intake, carbohydrate; Mnif, macronutrient intake, fat; Mob, multigenic obesity; na, Not available; Nidd, non-insulin dependent diabetes mellitus; Nidd3n (Nidd3nsy), non-insulin-dependent diabetes mellitus 3 in NSY; Niddm, non-insulin dependent diabetes mellitus; Nob1, New Zealand obese QTL 1; Nzoq, New Zealand obese contributed QTL; Obq, obesity QTL; Obs, Obesity QTL; p, paternal effect; Pfat, polygenic fatness; Pfatp, predicted fat percent; PigQTL2, Pig backfat thickness QTL; PIT1, POU-domain transcriptional regulator; Q1 ms1, metabolic syndrome QTL on chromosome 1; Q5 ms1, metabolic syndrome QTL on chromosome 5; Qbw, QTL body weight; Qfa, QTL LEPRfa; Nidd/gk, non-insulin dependent diabetes/Goto-Kakizaki; Qlep, QTL for leptin; Qlw, QTL late weight gain (6 to 10 weeks); Qsbw, Quackenbush-Swiss body weight; SHR, salt hypertensive rat; SSC, swine chromosome; WEIGHT1, body weight QTL 1; WOKW, Wistar Ottawa Karlsburg Rt1uW.

  • *

    Also observed in the cross (C3H/He × A/J) × M. spretus (391).

  • Also observed in the CAST/Ei × C57B1/6J F2 intercross (451).

  • Also observed in the cross CAST/Ei × C57BL/6J (396).

  • §

    Replicated.

  • Yu T, Wang L, Tuttle C, Rothschild M. Mapping genes for fatness and growth on pig chromosome 13: a search in the region close to the pig PIT1 gene. J Anim Breed Genet. 1999;116:269–80.

  • Synteny relationships established according to the following references: (74, 75, 77, 78, 452).

Mus musculus (A/J × M. spretus) × C57BL/6JBw1*Lod = 3.424Body weightXXp11-q26(391)
 Bw2*Lod = 6.6 Body weightXXq11-q13 
 Bw3Lod = 4.3 Body weightXXp22-q27 
Mus musculus 129/Sv × Le/SuzObq2Lod = 5.56.3Adiposity76q12-q14(392)
 Obq1Lod = 812.3Adiposity719q13.2-q13.3 
Mus musculus 129S6 × C57BL/6JD12Mit38Lod = 3.733Leptin, increased711q13(82)
Mus musculus A/J × (C57BL/6J × A/J)Bw8q2Lod = 3.34Body weight, 8 weeks46p22.2-p22.3(80)
Mus musculus AKR/J × C57L/JObq4Lod = 4.66.1Adiposity176q27(393)
 Obq3Lod = 5.17Adiposity211p11.2 
Mus musculus AKR/J × SWR/JDob1Lod = 4.87Adiposity41p33-p32(394, 395)
 Dob2Lod = 3.94Adiposity93p21 
 Dob3   158q24.1 
Mus musculus C3H/HeJXDBA/2J × (BALB/cJ × C57BL/6J)D3Mit127p = 0.00117Leptin, 4 months34q23-q25(83)
Mus musculus C57BL/6J × 129P3/JAdip5Lod = 4.04.7Adiposity911q23.1-q24.3(81)
 Bwq5Lod = 4.44.8Body weight220q11.2-q12 
 Bwq6Lod = 4.04.3Body weight93p21.33-q21 
 Adip9Lod = 3.34.4Adiposity1621q22.11-q22.2 
Mus musculus C57BL/6J × A/JBw8q1Lod = 4.42Body weight, 8 weeks11q21(80)
Mus musculus CAST/Ei × C57BL/6JMob7Lod = 5.7 Subcutaneous fat23p21.3(396)
 Mob8Lod = 4.7 Body fat, percentage96p12.1 
 QlepLod = 5.2 Leptin level (no obesity)49p22 
 Mob6Lod = 7.3 Subcutaneous fat211p11.2 
 BlLod = 4.3 Body length15  
 BwLod = 2.5 Body weight15  
Mus musculus CAST/Ei × M16iPfat1  Adiposity22q11-q14(397)
 Pfat3  Adiposity135q23-q31 
 Pfat4  Adiposity158q22-q23 
 Pfat5  Adiposity158q24 
 Pfat2  Adiposity220q13.11-q13.13 
Mus musculus CAST/EiJ × C57BL/6JMnif1Lod = 8.07.1Fat, intake88p22-p21.3(79)
 Mnif2Lod = 6.05.4Fat, intake185q22-q23 
 Mnif3Lod = 4.03.6Fat, intakeXXq26-q26.3 
 Mnic1Lod = 6.76Carbohydrate intake176p21 
 Mnic2Lod = 3.43.1Carbohydrate intake63p26-p24 
 Mnic3Lod = 4.13.7Carbohydrate intakeXXq13.1 
 Kcal1Lod = 7.76.8Kilocalorie intake175q31 
 Kcal2Lod = 4.94.4Kilocalorie intake186p21.3-p21.1 
Mus musculus CAST/EiJ × C57BL/6J-hg/hgCarfhg1Lod = 2.56.2Fat content54p15.1(398)
 Carfhg2Lod = 5.812.5Fat content911q25 
Mus musculus DBA/2J × C57BL/6JBw6aLod = 3.336-week weight11q31-q33(399, 400)
 Bw6eLod = 446-week weight62p12 
 Pfatp6Lod = 4.920Predicted fat, percent63p14.1-p12 
 Bw6cLod = 3.246-week weight54q12-q13 
 Pfatp13Lod = 5.320Predicted fat, percent135q22-q31 
 Bw6gLod = 4.456-week weight96q12-q16 
 Bw6kLod = 4.976-week weight176p21 
 Bw6jLod = 336-week weight148p23.1-p22 
 Pfatp15Lod = 8.620Predicted fat, percent158q24-qter 
 Bw6bLod = 3.346-week weight49p24-p23 
 Pfatp4Lod = 520Predicted fat, percent49p24 
 Bw6dLod = 4.356-week weight512q24 
 Bw6iLod = 4.146-week weight1315q23-q25 
 Bw6hLod = 5.766-week weight1117p13 
 Bw6fLod = 6.996-week weight719q13.3 
Mus musculus Du6 × DuKAfw3F = 4.77.7Abdominal fat131q43(401, 402)
 Afw1F = 4.8910–13Abdominal fat41p34-p33 
 Afp2F = 4.898.3Abdominal fat, percentage33q25 
 Qbw1Lod = 2.76.9Abdominal fat34q23-q27 
 Afw2F = 4.798.3Abdominal fat117p13-p11.2 
 Qbw2Lod = 7.617Body mass1117q12-q22 
 Bw4F = 4.7923.1Body weight1117q21-q22 
 Afp1F = 4.8910–13Abdominal fat4  
Mus musculus Du6i × DBA/2Bw5F = 10.45.4Body weight12q34(403)
 Bw16F = 7.523.9Body weight112p13.3 
 Bw13F = 11.76Body weight57p22 
 Bw15F = 7.363.8Body weight137p14-p13 
 Afpq10F = 7.483.9Abdominal fat, percentage127p15 
 Lepq1F = 7.584.4Leptin148p21-p12 
 Bw14F = 25.912.3Body weight715q11-12 
 Afpq6F = 8.924.6Abdominal fat, percentage1719p13.3-p13.2 
 Afpq9F = 18.59.1Abdominal fat, percentage719q13.3 
 Afw10F = 8.564.5Abdominal fat, percentage12  
 Afw9F = 24.912Abdominal fat, percentage7  
Mus musculus F × LFob1Lod > 3.34.914-weeks fat, percent22q21-q37(404)
 Fob2Lod = 3.319.514-weeks fat, percent (female)127p22-q22 
 Fob3Lod = 11.314.414-weeks fat, percent158q24.2-q24.3 
 Fob4Lod = 3.37.314-weeks fat, percentXXq12-q21.2 
Mus musculus JU/CBA × CFLP (P6)Bw19Lod = 24.417–2010-week weightXXq28(404)
 QbwXLod = 24.417–2010-week weightX  
Mus musculus KK-A(y) × C57BL/6JBwq2Lod = 4.126Adiposity63p26-p25(405)
 Bwq1Lod = 3.115Body weight46q16 
Mus musculus KK/H1Lt × C57BL/6JObq5Lod = 6.317Adiposity (females)911q23-q24(406)
 KK7Lod = 4.411.7Inguinal fat711q21 
 Obq6Lod = 5 Adiposity (males)XXq26-q28 
Mus musculus MH × C57BL/6JHlq1Lod = 5.64.7Heat loss11q21-q41(407)
 Batq1Lod = 43.3Brown fat11q41-q42.1 
 Hlq2Lod = 3.73.1Heat loss22p13-q13 
 Hlq3Lod = 3.83.1Heat loss33q25 
 Batq2Lod = 3.52.8Brown fat34q28-q31 
 Hlq4Lod = 4.73.9Heat loss38q21.3-q22.1 
 Hlq5Lod = 4.063.4Heat loss716p12-p11.2 
 Fatq1Lod = 85.9Gonadal fat118q21.3 
Mus musculus Mus spretus × C57BL/6JMob4Lod = 3.45.9Mesenteric fat155p14-p13(408)
 Mob2Lod = 4.87.1Femoral fat67q31.2-q31.3 
 Mob3Lod = 4.87Body fat, percentage1214q32.1-q32 
 Mob1Lod = 4.26.5Body fat, percentage716p12.1-p11.2 
Mus musculus NSY × C3H/HeNidd3nsyLod = 6.8 Epididymal fat62p14-p12(409)
Mus musculus NZB/B1NJ × SM/JMob5Lod = 3.636Body fat220q13.1-q13.3(410)
Mus musculus NZO × SJLNob1Lod = 3.816.8BMI54p15(411)
Mus musculus NZO × SMObq8Lod = 6.4 Retroperitoneal fat, percentage11q31(412)
 Obq9Lod = 6.7 Percent mesenteric fat (females11q22-q23 
 Obq7Lod = 6 Mesenteric fat, percentage (males)12q33.1 
 Obq14Lod = 9.2 Mesenteric fat, percentage63p26 
 Obq12Lod = 4.5 Gonadal fat, percentage 4p15 
 Obq4Lod = 6.3 Inguinal fat, percentage (males)176q27 
 Obq11Lod = 4.1 Gonadal fat, percentage57q22-q36 
 Obq13Lod = 9.3 Mesenteric fat, percentage67p14 
 Obq10Lod = 6.4 Gonadal fat, percentage (males)211p13 
 Obq15Lod = 6.6 Gonadal fat, percentage (males)711p15.5 
Mus musculus NZO/H1Lt × NON/LtNzoq1Lod = 3.8–9.416Body weight16p12-p11(413)
 Nzoq2Lod = 4 BMI1214q31-q32 
Mus musculus Quackenbush-Swiss × C57BL/6JQsbwp = 0.00940Body weight1012q22-q23(414)
Mus musculus SM/J × A/JBwq4Lod = 4.86Body weight at 10 weeks185q32-q35(415)
 Bwq3Lod = 4.66Body weight at 10 weeks816q22-q23 
Mus musculus SM/J × LG/JQlw13Lod = 1.92.4Adiposity131q43(409, 416, 417, 418)
 Qlw12Lod = 2.31.9Late weight gain122p24-p23 
 Qlw1Lod = 2.38.4Late weight gain12q35-q36 
 Qlw3Lod = 2.33.4Late weight gain33q25-q26 
 Qlw5Lod = 2.8§2.4Late weight gain63p26-p24 
 Qlw18Lod = 2.8§2Adiposity185q31 
 Qlw9Lod = 1.82.6Adiposity96p12.1 
 Qlw4§Lod = 2.42.4Late weight gain49q31-q32 
 Qlw7§Lod = 2 Late weight gain711p15 
 Qlw10§Lod = 4.9 Weight1012q21 
 Qlw14Lod = 2.1 Weight1414q11.2 
 Qlw2Lod = 2.9 Late weight gain215q11.2-q22.2 
 Qlw11Lod = 2.6 Late weight gain1122q12 
 Adip2Lod = 3.5–6.2 Adiposity/weight (females)6  
 Adip3Lod = 9.7 Adiposity (males)/weight7  
Mus musculus TSOD × BALB/cANidd6Lod = 4.659.2Body weight11q25(419)
 Nidd5Lod = 5.9110.9Body weight22q22-q23 
Mus musculus Wild Mus musculus castaneus × C57BL/6JC10bw1Lod = 10.7 1.4-g body weight22q24.2(420)
 C10bw4Lod = 3.7 0.9-g body weight (females)135q13 
 C10bw5Lod = 3.4 0.8-g body weight (males)135q14.3 
 C10bw7p = 0.00001 Body weight (males; epistatic)1214q23-q24.2 
 C10bw2Lod = 3.3 1.1-g body weight (females)915q21-q22 
 C10bw3Lod = 3.7 1.3-g body weight (males)1117q24-q25 
 C10bw6Lod = 4.3 1.4-g body weight (females)XXp22.2-p21.2 
Rattus norvegicus (OLETF × BN) × OLETFDmo9Lod = 3.5 Adiposity index113q26.1-q28(421)
 Dmo1Lod = 8.2–14 Body weight110q23-q24 
 Dmo4Lod = 4.4–5.5 Adiposity index111p15.5-p15.4 
 Dmo7pLod = 4.9–5.4 Adiposity index712q22-q23 
 Dmo6pLod = 3.5–3.6 Adiposity index614q32 
 Dmo5Lod = 3.5–3.6 Adiposity index319p13.2-q13.3 
 Dmo10Lod = 3.5–3.6 Body weight1121q22.1 
Rattus norvegicus Dahl × MNSDAHL3p = 0.0000313Body weight310q25(422)
Rattus norvegicus GK × BNNidd/gk6  Body weight171q41-q44(423)
 Nidd/gk1  Adiposity13p21 
 bw/gk1  Body weight78q21-q24 
 Nidd/gk5  Body weight811q22-q23 
Rattus norvegicus GK × F344Niddm1Lod = 3.223.5Body weight110q24-q26(424)
 Weight1   712q22-q23 
 Niddm3   1017pter-q23 
Rattus norvegicus Lepr(fa)/Lepr(fa) 13M × WKYQfa12Lod = 38.3BMI, female127q22(425)
 Qfa1Lod = 2.26.9BMI, female116q13 
Rattus norvegicus OLETF × BNDmo1Lod = 611.6Body weight110q23-q24(426)
Rattus norvegicus OLETF × F344Obs5Lod = 5.412.4Retroperitoneal fat144q12-q13(427, 428)
 Obs1Lod = 5.113.8Mesenteric fat25p13-p12 
 Obs3Lod = 5.913.4Mesenteric fat86q12-q13 
 Obs4Lod = 5.316.5Retroperitoneal fat96p21 
 Obs2Lod = 4.211.3Retroperitoneal fat47q11.2-q36 
 Obs6Lod = 4.513.8Retroperitoneal fat147p13-p12 
 Imfq1Lod = 3.45Intramuscular fat19q12 
Rattus norvegicus SHR × BB/OKSHR4Lod = 3.114Body weight (females)47p15.3(429)
 SHR1Lod = 3.332Body weight (males)111p15.5 
Rattus norvegicus SHR × WildSHR10Lod = 3.5 Body weight (males)1017pter-q23(430)
Rattus norvegicus WOKW × DA/KWOKW1/Q5 ms1Lod = 4.516BMI51p36-p31(404, 431)
 WOKW1/Q1 ms1Lod = 4.93130-week body weight13p21 
Sus scrofa Berkshire × YorkshireSSC7F = 13.86.9Back fat76p21.3(432)
 SSC1F = 11.34.8Back fat19q32-q34.1 
 SSC4F = 11.86Weight4  
 SSC5F = 9.54.8Back fat5  
Sus scrofa European wild boar × Large WhiteFAT1p = 0.00019.7Body fat, percentage41q21-q25(433, 434, 435)
Sus scrofa Iberian × LandraceFAT1F = 11.1 Back fat depth41q21-q25(436)
Sus scrofa Meishan × (Dutch Landrace × Large White)SSC7F = 18§ Back fat thickness76p21.3(437, 438)
 SSC2F = 2.7 Back fat thickness211p15 
Sus scrofa Meishan × Duroc, Hampshire, LandracePigQTL2F = 7.9 Average backfat76p21(439, 440)
Sus scrofa Meishan × DutchSSC6qF = 14.70.1–0.2Intramuscular fat6q1p33-p32(441, 442)
 SSC7F = 49.4 Back fat thickness76p21.3 
 SSC2F = 24.1 Back fat thickness211p15 
 SSC6pF = 14.5 Intramuscular fat6p16q22-qter 
 SSCXF = 12.8 Intramuscular fatXXq11.2-q22 
Sus scrofa Meishan × GottingenSSC7F = 19.518Back fat thickness76p21.3(443)
Sus scrofa Meishan × Large WhiteBFM4  Mid-back fat depth41q21-q25(444)
Sus scrofa Meishan × WhiteSSC7F = 10.4–20.53–4Back fat depth76p21.3(445, 446)
 SSC1F = 39.4–94.91–2Weight19q32-q34.1 
 SSCXF = 37.4–71.82–5Back fat depthXXq11.2-q22 
 SSC4F = 14.9–15.31–2Back fat thickness4  
 SSC8F = 9.5 Back fat thickness8  
 SSC5F = 13.4–15.1 Back fat thickness5  
 SSC6F = 11.9 Back fat thickness6  
Sus scrofa Meishan × White compositeSSC7F = 14.7 Back fat thickness76p21.3(447)
 SSC1F = 15.4 Back fat thickness19q32-q34.1 
 SSCXF = 32.3 Back fat thicknessXXq11.2-q22 
Sus scrofa Minghu × Hampshire, LandracePIT1F = 3.34 42-day weight133p11
Sus scrofa Wild Boar × Large WhiteIGF2qF = 7.110.4Back fat depth2p11p15.5(448, 449)
Bos bovis Hereford × CGCBTA17LWF = 8 −24 kg live weight174(450)

A cross between fat-preferring C57BL/6J and carbohydrate-preferring CAST/EiJ mice was studied for macronutrient intake (79). Three QTLs for intake of fat (Mnif1 to 3), three for carbohydrate (Mnic1 to 3), and two for total caloric intake (Kcal1 and 2) were uncovered (79). A total of 16.4%, 12.8%, and 9% of the variance was explained by these QTLs for the three phenotypes, respectively. Similarly, A/J and C57BL/6J strains differ markedly in a number of behavioral traits with A/J mice showing a significantly inhibited exploratory behavior. In an intercross between A/J and C57BL/6J, a QTL for body weight at 8 weeks (Bw8q1) was detected and a second one (Bw8q2) in the backcross (C57BL/6J × A/J) × A/J, accounting for 2% and 4% of the phenotypic variance in body weight, respectively (80). In a new cross between the heavier and fatter inbred strain C57BL/6ByJ and strain 129P3/J, two QTLs for body weight (Bwq5 and Bwq6) and two for adiposity (Adip5 and Adip9) were observed. They explained 9.1% of each of the variance in weight and adiposity (81). Double heterozygotes for insulin receptor and insulin receptor substrate-1 (DH) mice exhibited a reduction in size and body weight, but showed a marked hyperinsulinemia and diabetes on a C57BL/6J background, and only a mild elevation of insulin and with no diabetes on a 129S6 background. The cross DH-C57BL/6J× DH-129S6 uncovered a QTL for hyperleptinemia on chromosome 7 in the vicinity of the uncoupling protein 2/3 gene cluster (82). Finally, a QTL for leptin has been found on chromosome 3 in the UM-HET3 mice obtained from the cross [BALB/cJ × C57BL/6J] × [C3H/HeJXDBA/2J]. These mice showed an average difference of 0.9 ng/mL from mean leptin levels (5.3 and 5.0 ng/mL for females and males, respectively) (83).

Association Studies

The evidence for associations between candidate genes and obesity-related phenotypes is summarized in Table 6. A total of 272 studies covering 90 candidate genes have reported significant associations. Of these, 58 studies (43 candidate genes) were published during the past year. This year's update includes 23 new candidate gene entries. These new reports indicate that body weight, BMI, overweight, and obesity were associated with DNA sequence variation in ACE (84), ADRB2 (85), ADRB3 (86), AGRP (87), APM1 (88, 89), APOA1 (90), APOA4 (91), ATP1A2 (92), CAPN10 (93), ESR1 (94), FABP2 (95), FOXC2 (96), GNB3 (97), HSD11B1 (98), IL6 (99), IL6R (100), IRS2 (101), LIPC (102), LIPE (103), MACS2 (104), MC4R (19), NCOA3 (105), NR0B2 (106), NR3C1 (107, 108), PGR (105), PPARA (109), PPARG (110, 111, 112, 113, 114), SCARB1 (112), SLC6A3 (115), TCF1 (116), and TGFB1 (117).

Table 6. . Evidence for association between markers of candidate genes with obesity-related phenotypes
GeneLocationCases (N)PhenotypepReferences
  1. Status as of October 2003.

ABCC811p15.1232Obesity, morbid0.02(453)
ACE17q24.1959Overweight0.014(84)
ACP12p2575BMI (in children)0.02(454)
  265BMI (in NIDDM subjects)0.002(455)
ADA20q13.12273BMI (in NIDDM subjects)0.0004(456)
ADRA2A10q25.3213Skinfolds, trunk to extremity ratio (in blacks)0.04(457)
  72Skinfolds, trunk to extremity ratio (in women)0.002(458)
ADRA2B2q11.2166Basal metabolic rate (in obese nondiabetics)0.01(459)
  126Body weight, change, 5-year (in nondiabetics)0.04(460)
ADRB110q26.11931Body weight, BMI, fat mass0.05(461)
ADRB25q31-q32239Waist-to-hip ratio0.05(462)
  180BMI0.003(463)
  494Body weight, increase (in men)0.01(464)
  247Change in BMI (in women)0.04(141)
  247Change in fat mass (in women)0.0008(141)
  247Change in percent body fat (in women)0.0003(141)
  230Change in sum of 8 skinfolds (in men)0.03(141)
  236Lipolysis0.02(465)
  508BMI (in Japanese)0.001(466)
  140BMI, fat mass, fat cell volume0.001(467)
  826Obesity, BMI, waist-to-hip ratio, waist circumference, hip circumference0.05(468)
  366BMI (in women)0.01(469)
  836Body weight, BMI, waist-to-hip ratio, waist circumference, hip circumference (in French men)0.002(470)
  63BMI, fat mass0.05(471)
  277BMI (in Japanese men)0.004(472)
  1576BMI0.02(85)
  284Leptin0.03(473)
  224BMI, abdominal total fat, abdominal subcutaneous fat (in men)0.01(474)
  24Leptin, body weight, increase, skinfolds, sum of 80.03(475)
  286Body weight, increase0.04(476)
  574BMI (in Japanese)0.009(477)
ADRB38p12-p11.2185Body weight, increase over 20 years, weight, current0.007(478)
  313Obesity (in those 20 to 35 years old)0.05(462)
  476BMI (in men)0.05(479)
  553Obesity (in Japanese children)0.02(480)
  179BMI0.006(481)
  295BMI0.05(482)
  83BMI (in CAD patients)0.05(483)
  211Obesity, moderate0.02(484)
  53Obesity0.05(485)
  350BMI0.009(486)
  398BMI, abdominal subcutaneous fat, abdominal visceral fat0.02(487)
  154Obesity (in sedentary individuals)0.05(488)
  586BMI, hip circumference (in women)0.03(489)
  56BMI, fat mass, waist circumference0.05(490)
  128Body weight, increase over 25 years0.01(491)
  1675Obesity, BMI, percent body fat0.05(492)
  254Obesity, early onset0.002(493)
  76Fat mass (in Thai males)0.05(494)
  131Fat mass, abdominal visceral fat0.01(495)
  261BMI0.05(496)
  979Waist-to-hip ratio, overweight (in men >53 years old)0.05(497)
  802BMI0.02(498)
  49BMI0.03(499)
  335Waist-to-hip ratio (in women)0.02(500)
  47Body weight (in obese children)0.05(501)
AGRP16q22.1183BMI, percent body fat, fat mass (in whites)0.003(502)
  253BMI0.015(87)
  212Fat mass0.028(87)
  212Percent body fat0.013(87)
AGT1q42.2135Body weight, change0.006(503)
  316Waist-to-hip ratio0.007(504)
  94Fat mass (in women >42 years old)0.008(505)
APM13q28413Body weight, waist circumference (in Japanese, in whites)0.03(506)
  371BMI0.02(507)
  95BMI (in obese women)0.014(508)
  95Sagittal diameter (in obese women)0.032(508)
  245BMI0.05(88)
APOA111q23.3482BMI (in type 2 diabetics)0.048(90)
  482Waist-to-height ratio (in type 2 diabetics)0.023(90)
APOA21q23.1624Waist circumference0.03(509)
APOA411q23.3369BMI0.003(91)
  375BMI, waist-to-hip ratio (in young men)0.004(510)
  613BMI, percent body fat0.004(511)
APOB2p24.256Abdominal fat, percent body fat0.04(512)
  232BMI0.005(513)
  181BMI0.05(514)
APOD3q26.2-qter114BMI0.006(515)
APOE19q13.32164Waist circumference (in women with a family history of diabetes)0.05(516)
ARXq12113Waist circumference (in women)0.002(122)
  106Percent body fat0.01(118)
ATP1A21q23.1122Percent body fat, respiratory quotient0.05(517)
  156Respiratory quotient (in young adults)0.0001(518)
  12Fat mass0.01(508)
  12Body weight0.05(508)
CAPN102q37.3148ADRB3 activity in adipocytes (in overweight individuals)0.004(519)
  286BMI0.003(93)
CART5q13.2612Waist-to-hip ratio (in men)0.002(520)
  528Obesity, BMI0.008(521)
CBFA2T18q21.3281BMI, percent body fat, waist circumference, hip circumference0.0002(522)
CCKAR4p15.2-p15.11296Leptin, percent body fat0.003(523)
CNTFR9p13.2465Fat-free mass0.011(119)
CYP19A115q21125Sagittal diameter (in women)0.049(123)
CYP7A18q12.11102BMI0.05(524)
DF19p13.324Abdominal fat (in MZ twins)0.05(124)
DRD211q23.2392Body weight0.002(525)
  176Obesity0.002(526)
  320Energy expenditure, 24-hour, sleeping metabolic rate0.03(527)
  383Skinfolds, iliac, skinfolds, triceps0.002(528)
  990Obesity0.03(529)
ENPP16q23.1293Leptin0.01(132)
ESR16q25.1108BMI (in postmenopausal women)0.04(530)
  551BMI (in middle-aged women)0.05(94)
  551Percent body fat (in middle-aged women)0.05(94)
  551Waist circumference (in middle-aged women)0.05(94)
  216Obesity, android type0.0002(531)
FABP24q27507BMI, percent body fat0.01(532)
  395Abdominal fat0.008(533)
FABP48q21714BMI0.042(95)
FOXC216q24.1644BMI0.03(96)
  215Percent body fat0.02(96)
GCGR17pter950Waist-to-hip ratio, waist girth, sagittal abdominal diameter0.001(534)
GCK7p1358Body weight at birth (in males)0.002(535)
GHRL3p25.365BMI (in tall obese children)0.001(536)
  192Obesity (in women)0.05(537)
GNB312p13.31737Obesity (in men)0.01(97)
  294Weight gain during pregnancy0.006(137)
  230BMI (in primiparous women)0.01(538)
  20Lipolysis0.01(539)
  111Weight loss with sibutramine0.0013(138)
  213BMI, waist circumference, hip circumference, skinfolds (in Nunavut Inuit)0.05(540)
  181Body weight at birth0.02(541)
  130BMI0.001(542)
  250Fat mass, change, body fat, percent change0.006(543)
  114Lipolysis (subcutaneous, adrenoreceptor-mediated)0.004(544)
  197BMI (in hypertensives)0.02(545)
  1950Body weight, BMI (in males, white, Chinese and African)0.001(546)
GYS119q13.33130Obesity0.03(547)
HSD11B11q32-41263BMI (in children)0.005(98)
  263Waist circumference (in children)0.05(98)
  263Waist-to-hip ratio (in children)0.05(98)
HSD3B11p11.2132Skinfolds, sum of six, 12-year change in0.04(548)
HSPA1B6p21.31517Obesity0.0002(549)
HTR1B6q14.198BMI (in women with bulimia nervosa)0.001(550)
HTR2A13q14.11276dietary energy, carbohydrate and alcohol intake (in obese subjects)0.028(551)
  264BMI, abdominal sagittal diameter, waist-to-hip ratio0.015(552)
HTR2CXq24117Body weight, gain, antipsychotic-induced0.0003(553)
  148Body weight, loss (in teenage women)0.0001(554)
  589BMI0.009(555)
IGF112q23.3502Percent body fat, fat-free mass, fat mass, fat-free mass, change in0.05(556)
IGF211p15.51474BMI0.02(557)
  427Fat mass0.05(558)
IL67p15.3271BMI (in men)0.007(99)
  271Waist circumference (in men)0.01(99)
  124Fasting energy expenditure0.012(127)
  124Energy expenditure during hyperinsulinemic clamp0.007(127)
IL6R1q22184Obesity (in women)0.05(100)
INS11p15.5758Body weight0.009(559)
  2734Body weight0.001(560)
  238Obesity0.05(561)
  1152BMI0.0002(562)
  52Waist-to-hip ratio (in obese women)0.005(563)
INSR19p13.375Obesity (in hypertensives)0.05(564)
IRS12q36.3156Leptin (in obese subjects)0.03(565)
  1748BMI (in African Americans)0.04(566)
IRS213q33.3233BMI0.02(101)
  233Percent body fat0.01(101)
  233Waist circumference0.004(101)
LDLR19p13.283BMI (in normotensives)0.008(567)
  131BMI, skinfolds, subscapular, skinfolds, triceps, arm fat index0.001(568)
  270Obesity0.02(569)
  84BMI (in hypertensives)0.004(570)
  112BMI (in hypertensives)0.04(571)
LEP7q32.2103Body weight, BMI0.005(572)
  395Leptin0.02(573)
  unknownLeptin secretion0.05(574)
  233Leptin (in obese women)0.02(575)
  211Obesity (in women)0.05(576)
  117Leptin0.04(577)
  168Body weight, decrease0.006(578)
  84Body weight0.05(579)
LEPR1p31.3502BMI, fat mass0.005(580)
  308Fat-free mass0.03(581)
  335Body weight, BMI, fat mass (in women)0.01(582)
  179BMI, fat mass, body weight, loss (in overweight women)0.006(583)
  336Overweight/obesity0.009(584)
  220Leptin, BMI, fat mass (in postmenopausal women)0.0001(585)
  267BMI, abdominal sagittal diameter0.04(586)
  130Obesity, extreme (in children)0.02(587)
  26824-hour energy expenditure0.02(128)
  184Subcutaneous abdominal adipocyte size0.02(128)
  20Percent body fat0.003(588)
  62Abdominal total fat, abdominal subcutaneous fat0.03(589)
  118BMI0.01(590)
LIPC15q21.3230BMI0.002(102)
  234Waist circumference0.002(102)
  231Abdominal visceral fat0.03(102)
LIPE19q13.31257BMI, percent body fat, fat mass, skinfolds, sum of 8 (in white women, in black women)0.005(591)
  117Waist-to-hip ratio, lipolysis0.02(592)
  405Obesity (in women)0.05(593)
  405Percent body fat (in women)0.05(593)
  380Obesity0.002(594)
  110BMI (in women)0.012(595)
LMNA1q23.148Ilpodystrophy, leptin, leptin: BMI ratio0.05(596)
  306Leptin, BMI, waist-to-hip ratio (in Canadian Oji-Cree)0.05(597)
  47Familial partial lipodystrophy0.0001(598)
  186Body weight, BMI, waist circumference, skinfolds, subscapular0.002(599)
LPL8p21.3587BMI (in women)0.02(479)
  249Percent body fat, fat mass, BMI, change (in white women)0.01(600)
  236BMI0.05(601)
MACS216p12.31976BMI0.009(104)
  1976Waist-to-hip ratio0.0011(104)
MC3R20q13.2314BMI, percent body fat, fat-free mass, fat mass, respiratory quotient (in normal-weight individuals, in overweight individuals)0.0005(602)
  244Leptin (in morbidly obese subjects)0.05(133)
MC4R18q21.32156BMI, percent body fat, fat-free mass, fat mass (in females)0.003(603)
  1135Obesity (in children and adolescents)0.006(19)
  268BMI, waist-to-hip ratio0.023(604)
NCOA320q13.13301BMI (in postmenopausal women with breast cancer)0.01(105)
NPY7p15.3595BMI, waist-to-hip ratio0.03(605)
  369Body weight at birth0.03(606)
NPY5R4q32.274Obesity (in Pima Indians)0.05(607)
NR0B21p35.3294Birth weight0.05(106)
  809BMI (in 7-year-olds)0.05(106)
  809Waist circumference (in 7-year-olds)0.01(106)
  305BMI (in women)0.05(106)
  217Obesity, early-onset0.009(608)
NR3C15q3151Abdominal visceral fat (in lean subjects)0.003(609)
  279BMI (in obese subjects)0.04(107)
  135Waist-to-hip ratio (in males)0.01(610)
  262Leptin, BMI, waist-to-hip ratio, waist circumference0.001(611)
  369Overweight (in type 2 diabetics)0.003(108)
  83Increase in sum of skinfolds (in girls)0.01(136)
  480Abdominal visceral fat0.001(612)
  12Body weight, gain0.01(613)
PGR11q22.2301BMI (in postmenopausal women with breast cancer)0.005(105)
PLIN15q26117Lipolysis in adipocytes (in obese women)0.0008(131)
PNMT17q21.2149Weight loss (in women)0.006(139)
POMC2p24.175Leptin (in obese children)0.03(614)
  337Leptin (in Mexican Americans)0.001(615)
  118Leptin (in lean subjects)0.003(134)
PON27q21.3100Body weight at birth (in Trinidadian neonates and South Asians)0.05(616)
PPARA22q13.31698BMI0.023(109)
  570Percent body fat0.028(109)
  154BMI (in type 2 diabetics)0.02(617)
PPARG3p25.2921Leptin, BMI, waist circumference (in Mexican Americans)0.02(618)
  333BMI (in the middle-aged)0.03(619)
  973BMI (in the elderly)0.02(619)
  422BMI0.03(111)
  752BMI, change (in obese men)0.002(620)
  869BMI, change (in lean men)0.008(620)
  464Obesity, BMI0.01(621)
  619BMI0.04(622)
  451BMI (in overweight blacks)0.02(114)
  451Waist-to-hip ratio (in overweight blacks)0.01(114)
  451Waist circumference (in overweight blacks)0.004(114)
  228Morbid obesity0.02(112)
  119Weight, increase, 10-year0.009(623)
  225Weight, decrease, 3-year0.04(624)
  838Body weight, BMI, waist circumference, height0.002(625)
  820Leptin (in obese subjects)0.001(626)
  18324-hour lipid oxidation0.03(129)
  18324-hour lipid balance0.02(129)
  70Weight, increase0.01(627)
  121BMI0.03(628)
  714BMI0.04(113)
  596Fat mass0.009(113)
  685Waist circumference0.03(113)
  501Abdominal visceral fat0.01(113)
  501Abdominal subcutaneous fat0.001(113)
  268BMI0.022(110)
  375Obesity, severe, with early onset0.05(629)
  141Body weight, BMI, fat mass, waist circumference, lean body bass, hip circumference0.002(630)
PPARGC14p15.31467Fat mass (in Austrian women)0.005(631)
  467BMI (in Austrian women)0.006(631)
  467Waist circumference (in Austrian women)0.01(631)
  467Hip circumference (in Austrian women)0.03(631)
  201Adipocyte size (in Pima Indians)0.04(117)
  16524-hour lipid oxidation (in Pima Indians)0.03(117)
  16524-hour lipid balance (in Pima Indians)0.004(117)
RETN19p13.3411Obesity, BMI0.0097(632)
SAH16p13.114059BMI0.0066(633)
SCARB112q24.31288BMI (in healthy lean women)0.004(634)
  228Morbid obesity0.002(112)
SERPINE17q22.1505Obesity0.002(635)
SLC6A35p15.3390Obesity (in black smokers)0.006(115)
SORBS110q24.1770Obesity0.05(636)
TCF112q24.31203BMI (in young early onset diabetics)0.0024(116)
TGFB119q13.31284BMI (in Swedish men)0.05(117)
  284Abdominal sagittal diameter (in Swedish men)0.05(117)
TNF6p21.3176BMI0.01(637)
  136Waist circumference (in women)0.04(638)
  38Percent body fat0.02(639)
  1351BMI0.004(640)
  378BMI, percent body fat (in women)0.02(641)
  1047Obesity0.04(642)
  363BMI0.01(643)
  110Obesity0.02(644)
TNFRSF1B1p36.21217Leptin, BMI0.05(645)
TNRC11Xq13.168Obesity0.001(646)
UCP14q31.1163Body weight, decrease, BMI, decrease0.05(647)
  526BMI (in overweight women)0.02(648)
  162Waist-to-hip ratio0.003(125)
  113Body weight (in Japanese women)0.001(649)
  99Change in body weight (in premenopausal women)0.048(135)
  123Fat, increase (in high weight gainers)0.05(650)
  24Body weight, resting metabolic rate0.05(651)
UCP211q13.360Energy expenditure, 24-hour, spontaneous physical activity, 24-hour, sleeping spontaneous physical activity, respiratory quotient, 24-hour non-protein, fat oxidation, 24-hour0.005(652)
  220BMI (in South Indian women)0.02(653)
  791BMI0.03(654)
  596Obesity0.007(654)
  813Obesity0.002(655)
  949Obesity0.006(656)
  41Body weight, increase, fat mass, increase (in peritoneal dialysis patients)0.05(657)
  82BMI, metabolic rate, 24-hour sleeping (in those >45 years old)0.007(658)
  105Body weight, BMI, percent body fat, fat mass, overweight, percentage, skinfolds, sum of 40.001(659)
UCP311q13.3120BMI, respiratory quotient, lean body bass, non-protein respiratory quotient, fat oxidation (in African Americans)0.008(660)
  116Waist-to-hip ratio (in South Indian women, in European women)0.03(661)
  419BMI0.004(662)
  73Resting energy expenditure (in black women)0.01(663)
  734leptin, BMI, percent body fat, fat mass, skinfolds, sum of 60.0005(664)
  393skinfolds, sum of 80.01(665)
  401BMI (in morbidly obese subjects)0.0037(666)
  382Body weight, BMI, current, BMI, maximum0.02(667)
  64Leptin, percent body fat (in women)0.03(668)

Body fatness-related phenotypes (fat mass, percentage of body fat, sum of skinfolds) showed associations with markers in AGRP (87), AR (118), ATP1A2 (92), CNTFR (119), ESR1 (94), FOXC2 (96), IRS2 (101), LIPE (103), PPARA (109), and PPARG (113). Phenotypes reflecting body fat distribution (abdominal visceral fat, waist circumference, waist-to-hip girth ratio, sagittal diameter) were associated with ADRB2 (120, 121), APM1 (89), APOA1 (90), AR (122), CYP19A1 (123), DF (124), ESR1 (94), HSD11B1 (98), IL6 (99), IRS2 (101), LIPC (102), MACS2 (104), PPARG (113, 114), TGFB1 (117), and UCP1 (125). Resting energy expenditure, thermic effect of feeding, and 24-hour lipid oxidation phenotypes were associated with ADRB3 (126), IL6 (127), LEPR (128), PPARG (129), and PPARGC1 (130) markers, whereas adipocyte size and lipolysis showed associations with polymorphisms in LEPR (128), PLIN (131), and PPARGC1 (130). Three candidate genes (ENPP1, MC3R, POMC) were reported to be associated with plasma leptin levels (132, 133, 134).

Seven studies reported associations between candidate genes and changes in body weight and body composition (132). The UCP1 (135) and NR3C1 (136) loci showed associations with spontaneous changes in body weight and adiposity over time, whereas weight gain during pregnancy was associated with the GNB3 polymorphism (137). Markers in the GNB3 (138) and PNMT (139) loci were reported to be predictive of sibutramine-induced weight loss. Response to a lifestyle based weight-loss program was associated with a marker in the ADRB3 locus (140) and endurance training-induced changes in body composition showed associations with the ADRB2 polymorphisms (141)

In addition to the positive studies summarized above, we identified 40 studies dealing with 27 candidate genes in which there were no associations between DNA sequence variations and obesity-related phenotypes. Among these studies, the most frequent were those pertaining to markers of UCP2 (142, 143, 144, 145) (four studies), ADRA2B (146, 147, 148), ADRB2 (149, 150, 151), PPARG (86, 152, 153), and RETN (154, 155, 156) (three studies each). Other markers yielding negative findings were those related to ACE (157), ADRB3 (158), APOE (159, 160), CAPN10 (161), CYP27B1 (162), DGAT1 (163), DRD2 (164), EDN1 (165, 166), ESR1 (167), F7 (168), FABP2 (169), GNB3 (170), GPR10 (171), IL6 (172, 173), IRS1 (174), IRS2 (174), LEPR (175), LPL (176), NOS3 (177), NR0B2 (178), SORBS1 (179), and TNF (180).

Linkage Studies

A total of nine linkage studies with obesity-related phenotypes were reported over the last 12 months, including five new genome-wide scans (53, 181, 182, 183, 184). The other four studies were attempts to replicate previous linkages reported on chromosomes 3q27 (185), 7q22-q35 (186), 2p and 10p (103), and 10p and 20q (187). Results from these studies are described below, and the new QTLs have been added to Table 7.

Table 7. . Evidence for the presence of linkage with obesity-related phenotypes in human studies
Gene/MarkerLocationPopulationPhenotypesp or Lod scoreReferences
  1. Status as of October 2003.

  2. HDL, high-density lipoprotein; ln-TG, natural log-transformed triglycerides; MLS, multipoint Lod score; NPL, nonparametric linkage score.

  3. Computer programs used: 1) SEGPATH [Province MA, Rao DC. General purpose model and a computer program for combined segregation and path analysis (SEGPATH): automatically creating computer programs from symbolic language model specifications. Genet Epidemiol. 1995; 12:203–19; Province MA, Rice TK, Borecki IB, Gu C, Kraja A, Rao DC. Multivariate and multilocus variance components method, based on structural relationships to assess quantitative trait linkage via SEGPATH. Genet Epidemiol. 2003;24:128–38]; and 2) MapMaker Sibs (Kruglyak L, Lander E. Complete multipoint sib pair analysis of qualitative and quantitative traits. Am J Hum Genet. 1995;57:439–54).

D1S4681p36.321249 sib pairsBMILod = 2.75(669)
  1249 sib pairsBMIMLS = 2.09(669)
  994 subjectsBMILod = 2.5(670)
D1S5081p36.23-22994 subjectsBMILod = 2.5(670)
  994 subjectsBMILod = 2.5(670)
PGD1p36.22>168 pairsSkinfolds, suprailiacp = 0.03(671)
D1S5521p36.13 BMI (in whites)p = 0.002(182)
D1S37211p34.1157 subjects; 7 familiesBMI (in whites)p = 0.0099(184)
D1S1931p34.1202 to 251 pairsBMI (Quebec Family Study)p = 0.03(672)
D1S1971p33202 to 251 pairsInsulin level, fasting (Quebec Family Study)p = 0.05(672)
D1S2001p32.2202 to 251 pairsFat mass (Quebec Family Study)p = 0.009(672)
D1S4761p32.2202 to 251 pairsInsulin level, integrated, following oral glucose tolerance test (Quebec Family Study)p = 0.02(672)
LEPR1p31.3302 subjects; 57 familiesBlood glucose, fasting (in Mexican Americans)p = 0.018(673)
  302 subjects; 57 familiesBlood pressure, diastolic (in Mexican Americans)p = 0.003(673)
LEPR-IVS16CTTT1p31.3268 to 324 pairsFat-free massp = 0.007(581)
  268 to 324 pairsFat massp = 0.05(581)
LEPR-IVS3CA1p31.3268 to 324 pairsBMIp = 0.05(581)
  268 to 324 pairsFat-free massp = 0.05(581)
  268 to 324 pairsFat massp = 0.05(581)
  268 to 324 pairsSkinfolds, sum of 6p = 0.05(581)
LEPR-Q223R1p31.3268 to 324 pairsFat massp = 0.005(581)
  268 to 324 pairsBMIp = 0.02(581)
  268 to 324 pairsSkinfolds, sum of 6p = 0.02(581)
  268 to 324 pairsFat-free massp = 0.02(581)
D1S16651p31.1198 subjectsLeptinLod = 3.4(674)
D1S5501p31.1236 pairsRespiratory quotient, 24-hour (in Pima Indians)Lod = 2.8(675)
D1S5341p11.2769 subjects; 182 familiesBMI (in Africans)Lod = 2.24(181)
  521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2.3(676)
D1S16791q21-223027 subjects; 401 familiesBMI (National Heart, Lung and Blood Institute Family Heart Study)Lod = 1.8(677)
ATP1A21q23.1171 families; 289 pairsRespiratory quotient (Quebec Family Study)p = 0.02(518)
  295 subjects; 164 familiesAdipocyte sizeLod = 1.7(678)
D1S4761p32.2202 to 251 pairsInsulin level, integrated, following oral glucose tolerance test (Quebec Family Study)p = 0.02(672)
ATP1B11q23.394 pairsRespiratory quotientp = 0.04(517)
ACP12p25300 pairsBMIp = 0.004(679)
  >168 pairsSkinfolds, tricepsp = 0.02(671)
D2S23372p24.1 Leptin (in French Caucasians)Lod = 2(680)
D2S1652p23.31100 subjects; 170 familiesAdiponectin (in Northern Europeans)Lod = 2.7(681)
  264 pairsLeptinLod = 2.4(190)
D2S3672p23.11100 subjects; 170 familiesAdiponectin (in Northern Europeans)Lod = 2.7(681)
  264 pairsLeptinLod = 2.7(190)
D2S17882p22.3 LeptinLod = 4.9(189)
   Fat massLod = 2.8(189)
  337 subjectsLeptinLod = 7.5(615)
  349 subjectsBMI (in whites)Lod = 3.08(183)
  720 subjects; 230 familiesLeptinp = 0.008(682)
  720 subjects; 230 familiesBMIp = 0.008(682)
D2S4412p13.3668 subjects; 99 familiesAbdominal subcutaneous fatLod = 1.9(683)
IGKC2p11.2>168 pairsSkinfolds, tricepsp = 0.03(671)
D2S1602q131249 sib pairsBMILod = 2.56(669)
D2S3472q14.31249 sib pairsBMILod = 4.04(669)
  1249 sib pairsBody fat, percentageLod = 1.91(669)
  1249 sib pairsFat massLod = 2.03(669)
  1249 sib pairsBMIMLS = 4.44(669)
D2S13342q21.3668 subjects; 99 familiesAbdominal visceral fatLod = 2.3(683)
D2S13992q23.3668 subjects; 99 familiesAbdominal visceral fatLod = 2.3(683)
D2S4342q35668 subjects; 99 familiesAbdominal visceral fatLod = 2.5(683)
D3S23873p26.3668 subjects; 99 familiesAbdominal subcutaneous fatLod = 2.2(683)
D3S12593p25.21055 pairsBMILod = 2(684)
D3S30383p24.3 BMI, paternal effect (in whites)p = 0.0065(182)
D3S24323p22.3377 pairsBody fat, percentage (in Pima Indians)Lod = 2(685)
D3S17683p22.2580 familiesBMILod = 3.4 
D3S17643q22.31055 pairsBMILod = 3.4(684)
D3S24273q26.332209 subjects; 507 familiesBMILod = 3.3(191)
  2209 subjects; 507 familiesWaist circumferenceLod = 2.4(191)
  545 subjects; 128 familiesBMI (in African Americans)Lod = 2.4(185)
  545 subjects; 128 familiesBMI (in African Americans)Lod = 4.3(185)
  1055 pairsBMILod = 3.4(684)
  618 subjects; 202 familiesBMILod = 1.8(686)
D3S36763q26.33545 subjects; 128 familiesBMI (in African Americans)Lod = 4.3(185)
D3S13113q29668 subjects; 99 familiesAbdominal subcutaneous fatLod = 2.5(683)
D4S23974p15.2521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2.4(676)
D4S33504p15.1994 subjectsBMILod = 9.2(670)
  994 subjectsBMIp = 11.3(670)
  994 subjectsBMIMLS = 9.2(670)
D4S26324p15.1994 subjectsBMIp = 5.3(670)
  994 subjectsBMIMLS = 6.1 HLOD(670)
D4S15924q121249 sib pairsBMILod = 2.29(669)
D4S24174q31.1 BMI, paternal effect (in whites)p = 0.005(182)
  521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 1.8(676)
GYPA4q31.1160 pairsSkinfolds, trunk to extremity ratiop = 0.02(687)
D4S16294q32.1 BMI, maternal effect (in whites)p = 0.005(182)
D4S24314q34.1668 subjects; 99 familiesAbdominal subcutaneous fatLod = 2.3(683)
D5S8175p15.21100 subjects; 170 familiesAdiponectin (in Northern Europeans)Lod = 4.1(681)
  618 subjects; 202 familiesBMILod = 1.9(686)
D5S4265p13.3264 pairsLeptinLod = 2.9(190)
D5S24895p13.21526 pairsBMI (in Pima Indians)Lod = 1.7(688)
ISL15q11.2226 pairsObesityp = 0.03(689)
  226 pairsLeptinp = 0.0004(689)
  226 pairsBMIp = 0.0004(689)
D5S4075q11.21249 sib pairsFat-free massLod = 1.59(669)
D5S25005q12.11526 pairsBMI (in Pima Indians)Lod = 1.7(688)
D5S6585q31.3668 subjects; 99 familiesAbdominal subcutaneous fatLod = 2.1(683)
NR3C15q3188 pairsBMIp = 0.009(689)
D5S14805q32668 subjects; 99 familiesAbdominal total fatLod = 2.1(683)
D5S14715q35.1 BMI (in whites)p = 0.0006(182)
D5S2115q35.23027 subjects; 401 familiesBMI (National Heart, Lung and Blood Institute Family Heart Study)Lod = 1.8(677)
D5S4085q35.3157 subjects; 7 familiesBMI (in whites)p = 0.0039(184)
D6S19596p22.3-2618 subjects; 202 familiesBody fat, percentageLod = 2.7(686)
D6S2766p22.1624 subjects; 28 familiesEating behavior, restraint (in Old Order Amish)Lod = 2.3(690)
TNF6p21.3>255 pairsBody fat, percentage (in Pima Indians)p = 0.002(643)
BF6p21.31>168 pairsSkinfolds, subscapularp = 0.01(671)
  >168 pairsSkinfolds, tricepsp = 0.01(671)
  >168 pairsSkinfolds, suprailiacp = 0.01(671)
GLO16p21.2>168 pairsBody weightp = 0.004(671)
  >168 pairsSkinfolds, suprailiacp = 0.004(671)
D6S2716p21.11199 pairsLeptinLod = 2.1(691)
D6S4036q23.3261 subjects(BMI, leptin, FSI) (in Mexican Americans)Lod = 4.2(692)
D6S10036q24.1261 subjects(BMI, leptin, FSI) (in Mexican Americans)Lod = 4.2(692)
D6S2646q27261 subjects(Systolic and diastolic blood pressure) (in Mexican Americans)Lod = 4.9(692)
D6S2816q271249 sib pairsBMILod = 1.77(669)
  1249 sib pairsFat massLod = 2.02(669)
D7S24777p22.3349 subjectsBMI (in whites)Lod = 2.53(183)
D7S18197p22.2349 subjectsBMI (in whites)Lod = 2.53(183)
D7S30517p21.11055 pairsBMILod = 2.7(684)
NPY7p15.3302 subjects; 57 familiesObesity (in Mexican Americans)p = 0.042(673)
  302 subjects; 57 familiesBody weight (in Mexican Americans)p = 0.02(673)
  302 subjects; 57 familiesAbdominal circumference (in Mexican Americans)p = 0.031(673)
  302 subjects; 57 familiesHip circumference (in Mexican Americans)p = 0.012(673)
  302 subjects; 57 familiesBlood pressure, diastolic (in Mexican Americans)p = 0.005(673)
  302 subjects; 57 families(Body mass, body size) (in Mexican Americans)p = 0.048(673)
D7S18087p15.1 Fat-free mass (Quebec Family Study)Lod = 2.72(693)
D7S8177p14.3769 subjects; 182 familiesBMI (in Africans)Lod = 3.83(181)
D7S4797q22.1261 subjects(HDL, ln-TG) (in Mexican Americans)Lod = 3.2(692)
D7S6927q22.31020 subjects; 200 familiesBMI (in whites)p = 0.0002(186)
D7S5237q31.11020 subjects; 200 familiesBMI (in whites)p = 0.0009(186)
D7S4717q31.1261 subjects(HDL, ln-TG) (in Mexican Americans)Lod = 3.2(692)
D7S28477q31.311055 pairsBMILod = 2.4(684)
D7S6807q32.260 pairsBMIp = 0.002(694)
D7S5147q32.260 pairsBMIp = 0.002(694)
  545 pairsBMI (in Mexican Americans)p = 0.0001(695)
  545 pairsSkinfolds, extremity (in Mexican Americans)p = 0.0001(695)
  545 pairsWaist circumference (in Mexican Americans)p = 0.0001(695)
  545 pairsFat mass (in Mexican Americans)p = 0.0001(695)
D7S5047q32.246 pairsBMI (in African Americans)p = 0.001(696)
  59 pairsBMIp = 0.04(697)
D7S18757q32.2302 subjects; 57 familiesWaist-to-hip ratio (in Mexican Americans)p = 0.009(673)
  521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2(676)
  88 pairsBMIp = 0.04(698)
LEP7q32.2302 subjects; 57 familiesWaist-to-hip ratio (in Mexican Americans)p = 0.01(673)
  302 subjects; 57 familiesCholesterol, total (in Mexican Americans)p = 0.03(673)
  302 subjects; 57 familiesCholesterol, HDL (in Mexican Americans)p = 0.026(673)
  47 pairsBody fatp = 0.008(699)
D7S5307q32.360 pairsBMIp = 0.002(694)
D7S18047q32.33027 subjects; 401 familiesBMI (National Heart, Lung and Blood Institute Family Heart Study)MLS = 4.7 p < 0.00001(677)
  3027 subjects; 401 familiesBMI (National Heart, Lung and Blood Institute Family Heart Study)MLS = 3.2 p < 0.00007(677)
D7S6407q33672 subjectsLeptin (in Old Order Amish)p = 1.9(700)
D7S4957q34545 pairsBMI (in Mexican Americans)p = 0.0001(695)
  545 pairsSkinfolds, extremity (in Mexican Americans)p = 0.0001(695)
  545 pairsFat mass (in Mexican Americans)p = 0.0001(695)
  545 pairsWaist circumference (in Mexican Americans)p = 0.0001(695)
D7S18247q34157 subjects; 7 familiesBMI (in whites)p = 0.0008(184)
KEL7q35160 pairsBMIp = 0.0001(687)
  160 pairsSkinfolds, sum of 6p = 0.0001(687)
D7S21957q35157 subjects; 7 familiesBMI (in whites)p = 0.001(184)
D7S30687q35157 subjects; 7 familiesBMI (in whites)p = 0.004(184)
D7S6367q36.1672 subjectsLeptin (in Old Order Amish)p = 1.9(700)
D7S30707q36.2668 subjects; 99 familiesAbdominal total fatLod = 2.5(683)
D8S2778p23.1 BMI, paternal effect (in whites)p = 0.003(182)
GATA151F028p22769 subjects; 182 familiesBMI (in Africans)Lod = 2.34(181)
D8S5498p221249 sib pairsFat massLod = 1.95(669)
D8S2828p21.3994 subjectsBMILod = 2(670)
D8S11218p11.23470 subjectsBMI (in Mexican Americans)Lod = 3.2(701)
D8S11108q11.22 LeptinLod = 2.2(189)
D8S11138q12.1 BMI (in whites)p = 0.0013(182)
D8S5568q23.1522 subjects; 99 familiesBMI (HERITAGE, in whites)Lod = 2(702)
D8S11328q23.1157 subjects; 7 familiesBMI (in whites)p = 0.005(184)
D9S11229q21.32521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2.4(676)
D9S2579q22.1521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2.4(676)
ORM19q33.1>168 pairsSkinfolds, suprailiacp = 0.03(671)
AK19q34.13>168 pairsSkinfolds, suprailiacp = 0.01(671)
D9S1589q34.3522 subjects; 99 familiesBMI (HERITAGE, in whites)Lod = 2.3(702)
D10S143510p15.3522 subjects; 99 familiesBMI (HERITAGE, in whites)Lod = 2.7(702)
  522 subjects; 99 familiesFat mass (HERITAGE, in whites)Lod = 2.7(702)
  1526 pairsBMI (in Pima Indians)Lod = 1.7(688)
D10S18910p15.1522 subjects; 99 familiesBMI (HERITAGE, in whites)MLS = 2.7 SEGPATH(702)
  522 subjects; 99 familiesBMI (HERITAGE, in whites)MLS = 2.3 Mapmaker/Sibs(702)
  522 subjects; 99 familiesFat mass (HERITAGE, in whites)MLS = 1 Mapmaker/Sibs(702)
  1526 pairsBMI (in Pima Indians)Lod = 1.7(688)
D10S178110p13-q11386 subjects; 93 familiesObesityLod = 2.5(703)
D10S142310p12.33 BMI, paternal effect (in whites)p = 0.005(182)
D10S58210p12.31667 subjects; 244 familiesObesity (in whites and African Americans)NPL = 2.68(187)
  862 subjects; 170 familiesObesityp = 0.0005(704)
D10S19710p12.2264 pairsObesityLod = 4.9(190)
  369 subjects; 89 familiesObesity (in white children and adolescents)Lod = 2.24(188)
D10S20410p12.1386 subjects; 93 familiesObesityLod = 2.5(703)
D10S19310p12.1386 subjects; 93 familiesObesityLod = 2.5(703)
D10S20810p11.23667 subjects; 244 familiesObesity (in whites and African Americans)NPL = 2.68(187)
  862 subjects; 170 familiesObesityp = 0.0005(704)
SHGC-3148010p11.23386 subjects; 93 familiesObesityLod = 2.5(703)
D10S22010q21.1672 subjectsLeptin (in Old Order Amish)Lod = 2.7(700)
D10S10710q21.1862 subjects; 170 familiesObesityp = 0.0005(704)
D10S164610q22.1667 subjects; 244 familiesWaist circumference (in whites and African Americans)Lod = 2.5(187)
  667 subjects; 244 familiesBMI (in whites and African Americans)NPL = 2.24(187)
D10S53510q22.3667 subjects; 244 familiesWaist circumference (in whites and African Americans)Lod = 2.5(187)
  667 subjects; 244 familiesBMI (in whites and African Americans)NPL = 2.24(187)
D10S167910q26.13667 subjects; 244 familiesWaist-to-hip ratio (in whites and African Americans)NPL = 2.22(187)
  667 subjects; 244 familiesObesity (in whites and African Americans)NPL = 2.25(187)
D10S165610q26.2667 subjects; 244 familiesWaist-to-hip ratio (in whites and African Americans)NPL = 2.22(187)
  667 subjects; 244 familiesObesity (in whites and African Americans)NPL = 2.25(187)
D10S21210q26.3198 subjectsBMILod = 3.3(674)
CCKBR11p15.4226 pairsLeptinp = 0.01(689)
C11P15_311p15.2668 subjects; 99 familiesAbdominal subcutaneous fatLod = 1.9(683)
D11S41911p15.267 pairsBMI (in French Caucasians)p = 0.003(453)
ATA34E0811p14.1668 subjects; 99 familiesAbdominal subcutaneous fatLod = 1.8(683)
D11S131311q12.1369 subjects; 89 familiesObesity (in white children and adolescents)Lod = 1.65(188)
D11S91611q13.3640 subjectsResting metabolic rate (Quebec Family Study)p = 0.006(705)
D11S132111q13.3640 subjectsResting metabolic rate (Quebec Family Study)p = 0.02(705)
  640 subjectsBody fat, percentage (Quebec Family Study)p = 0.04(705)
  640 subjectsFat mass (Quebec Family Study)p = 0.02(705)
D11S91111q13.4640 subjectsResting metabolic rate (Quebec Family Study)p = 0.000002(705)
D11S200011q22.3769 subjects; 182 familiesBMI (in Africans)Lod = 3.35(181)
  377 pairsBody fat, percentage (in Pima Indians)Lod = 2.8(685)
  157 subjects; 7 familiesBMI (in whites)p = 0.0079(184)
D11S236611q23.1377 pairsBody fat, percentage (in Pima Indians)p = 2.1(685)
  377 pairsBody fat, percentage (in Pima Indians)p = 2.8(685)
D11S199811q23.31526 pairsBMI (in Pima Indians)Lod = 2.7(688)
D11S97611q23.3236 pairsEnergy expenditure, 24-hour (in Pima Indians)Lod = 2(675)
D11S446411q24.11526 pairsBMI (in Pima Indians)Lod = 2.7(688)
  994 subjectsBMILod = 2.8(670)
D11S93411q24.2994 subjectsBMILod = 2.8(670)
D11S91211q24.31766 pairsBMILod = 3.6(706)
  994 subjectsBMILod = 2.8(670)
D3S239512p13.31 BMI, paternal effect (in whites)p = 0.006(182)
D12S104212p12.1522 subjects; 99 familiesBMI (HERITAGE, in whites)MLS = 2.1 Mapmaker/Sibs(702)
  522 subjects; 99 familiesFat mass (HERITAGE, in whites)MLS = 1.2 SEGPATH(702)
D12S104512p11.23-q13.12521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2.9(676)
D12S8312q13.31249 sib pairsFat-free massLod = 1.79(669)
D12S105212q21.1349 subjectsBMI (in whites)Lod = 3.41(183)
D12S106412q21.33349 subjectsBMI (in whites)Lod = 3.41(183)
IGF112q23.3521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 1.9(676)
  352 pairsAbdominal visceral fatp = 0.02(556)
D12S207812q24.32521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2.9(676)
D13S17513q12.11580 familiesBMILod = 3.3 
D13S22113q12.13580 familiesBMILod = 3.3 
ESD13q14.11160 pairsBody fat, percentagep = 0.04(687)
  160 pairsSkinfolds, sum of 6p = 0.04(687)
D13S25713q14.23027 subjects; 401 familiesBMI (National Heart, Lung and Blood Institute Family Heart Study)MLS = 3.2 p < 0.00006(677)
D13S28513q34521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 1.9(676)
D14S74214q11.2522 subjects; 99 familiesFat mass (HERITAGE, in whites)MLS = 1.7 Mapmaker/Sibs(702)
  522 subjects; 99 familiesBMI (HERITAGE, in whites)MLS = 2.2 SEGPATH(702)
   BMI (in whites)p = 0.002(182)
D14S28314q11.2522 subjects; 99 familiesFat mass (HERITAGE, in whites)p = 0.0006(702)
  522 subjects; 99 familiesLeptin (HERITAGE, in whites)p = 0.003(702)
  522 subjects; 99 familiesFat mass (HERITAGE, in whites)MLS = 2 Mapmaker/Sibs(702)
  522 subjects; 99 familiesBMI (HERITAGE, in whites)MLS = 1.8 SEGPATH(702)
D14S128014q11.2522 subjects; 99 familiesFat-free mass (HERITAGE, in whites)MLS = 1.1 SEGPATH(702)
  522 subjects; 99 familiesBMI (HERITAGE, in whites)MLS = 2.4 SEGPATH(702)
D14S60814q121100 subjects; 170 familiesAdiponectin (in Northern Europeans)Lod = 3.2(681)
D14S59914q13.11100 subjects; 170 familiesAdiponectin (in Northern Europeans)Lod = 3.2(681)
D14S27614q22.2672 subjectsWaist circumference (in Old Order Amish)Lod = 1.8(700)
D14S58814q24.1668 subjects; 99 familiesAbdominal subcutaneous fatLod = 2.4(683)
D14S7414q24.3672 subjectsLeptin (in Old Order Amish)Lod = 2.5(700)
D14S28014q32.12672 subjectsLeptin (in Old Order Amish)Lod = 2.5(700)
D14S61714q32.121055 pairsBMILod = 2.2(684)
D15S123215q13.33027 subjects; 401 familiesBMI (National Heart, Lung and Blood Institute Family Heart Study)Lod = 1.7(677)
D15S65215q26.1 Fat-free mass (Quebec Family Study)Lod = 3.56(693)
D15S65715q26.2 Fat-free mass (Quebec Family Study)Lod = 2(693)
D16S51016p13.3672 subjectsLeptin (in Old Order Amish)Lod = 1.7(700)
  672 subjectsBMI (in Old Order Amish)Lod = 1.7(700)
D16S40416p13.2 BMI (in whites)p = 0.00025(182)
D16S76416p13.12 BMI (in whites)p = 0.0006(182)
D16S262016q211055 pairsBMILod = 2.6(684)
D16S26516q211199 pairsLeptinLod = 2(691)
D17S94717p121100 subjects; 170 familiesAdiponectin (in Northern Europeans)Lod = 1.7(681)
  2209 subjects; 507 familiesLeptinLod = 5(191)
  1055 pairsBMILod = 2.5(684)
D17S218017q21.32521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2.2(676)
D17S129017q23.2521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2.2(676)
D17S130117q25.2521 subjects; 156 familiesAbdominal subcutaneous fat (Quebec Family Study)Lod = 2.2(676)
MC5R18p11.21289 pairsBMI (Quebec Family Study)p = 0.001(603)
  289 pairsSkinfolds, sum of 6 (Quebec Family Study)p = 0.005(603)
  289 pairsFat mass (Quebec Family Study)p = 0.001(603)
  289 pairsBody fat, percentage (Quebec Family Study)p = 0.02(603)
  289 pairsFat-free mass (Quebec Family Study)p = 0.008(603)
  289 pairsResting metabolic rate (Quebec Family Study)p = 0.002(603)
D18S87718q12.1 Fat-free mass (Quebec Family Study)Lod = 3.6(693)
  236 pairsBody fat, percentage (in Pima Indians)Lod = 2.3(675)
D18S53518q12.3 Fat-free mass (Quebec Family Study)Lod = 3.58(693)
D18S115518q21.32193 pairsObesity (in Finns)Lod = 2.4(707)
MC4R18q21.32289 pairsRespiratory quotient (Quebec Family Study)p = 0.04(603)
LDLR19p13.2522 subjects; 99 familiesSkinfolds, sum of 8 (HERITAGE, in whites)p = 0.002(702)
  522 subjects; 99 familiesLeptin (HERITAGE, in whites)p = 0.0009(702)
  522 subjects; 99 familiesBody fat, percentage (HERITAGE, in whites)p = 0.009(702)
D19S41419q13.11369 subjects; 89 familiesObesity (in white children and adolescents)Lod = 1.97(188)
D20S48220p13 BMI (in whites)p = 0.00016(182)
D20S85120p12.3 BMI (in whites)p = 0.000046(182)
D20S60120q11.22-q11.23236 pairsRespiratory quotient, 24-hour (in Pima Indians)Lod = 3(675)
D20S47820q12994 subjectsBMILod = 2.2(670)
D20S43820q121711 subjectsBMI (in Utah pedigrees)Lod = 3.5(708)
  994 subjectsBMILod = 2.2(670)
D20S46520q12994 subjectsBMILod = 2.2(670)
D20S10720q12513 subjects; 92 families; 423 pairsBMILod = 3.2(709)
  513 subjects; 92 families; 423 pairsBody fat, percentageLod = 3.2(709)
ADA20q13.12160 pairsBMIp = 0.001(687)
  160 pairsSkinfolds, sum of 6p = 0.001(687)
D20S48120q13.12994 subjectsBMILod = 2.2(670)
D20S1720q13.12650 subjects; 139 to 226 pairsBody fat, percentagep = 0.0078(410)
D20S17820q13.13667 subjects; 244 familiesBody fat, percentage (in whites and African Americans)NPL = 2.57(187)
D20S21120q13.2513 subjects; 92 families; 423 pairsBMILod = 3.2(709)
  513 subjects; 92 families; 423 pairsBody fat, percentageLod = 3.2(709)
D20S12020q13.2650 subjects; 139 to 226 pairsBody fat, percentagep = 0.004(410)
D20S47620q13513 subjects; 92 families; 423 pairsBMILod = 3.06(709)
D20S14920q13.31-qter667 subjects; 244 familiesBody fat, percentage (in whites and African Americans)NPL = 2.57(187)
  513 subjects; 92 families; 423 pairsBMILod = 3.2(709)
  513 subjects; 92 families; 423 pairsBody fat, percentageLod = 3.2(709)
D3S360820q13.33624 subjects; 28 familiesEating behavior, restraint (in Old Order Amish)Lod = 2.5(690)
D22S26422q11.21668 subjects; 99 familiesAbdominal subcutaneous fatLod = 2(683)
A4GALT22q13.31>168 pairsBody weightp = 0.03(671)
DXS8099Xp22.13994 subjectsBMILod = 2.6(670)
DXS997Xp21.3208 subjects; 43 familiesWaist-to-hip ratioLod = 2.7(710)
DXS1003Xp11.3208 subjects; 43 familiesWaist-to-hip ratioLod = 2.7(710)
DXS1059Xq23994 subjectsBMILod = 2(670)
DXS6804Xq23193 pairsObesity (in Finns)Lod = 3.1(707)

A genome scan of BMI allowing for potential effects of imprinting was performed on a sample of 1909 individuals from 255 three-generation pedigrees who took part in the Rochester Family Heart Study (182). Linkage between BMI and 372 autosomal markers was tested in the whole sample (893 sibpairs) and in two age groups: children 5 to 11 years old (101 sibpairs) and young adults 17 to 30 years old (173 sibpairs). Analyses of all sibpairs revealed significant evidence of linkage on 1p36 with marker D1S552 [logarithm of odds (Lod) = 2.03; p = 0.002)]. In children 5 to 11 years, evidence of linkage to BMI was found on chromosomes 5q34-q35 (Lod = 2.48 with marker D5S1471), 16p13 (Lod = 3.12 with D16S404), 16p11.2-p13.1 (Lod = 2.45 with D16S764), 20p12-p13 (Lod = 3.55 with D20S482), and 20p11.2-pter (Lod = 4.08 with D20S851). None of these regions showed evidence of parent-specific linkage (imprinting). However, evidence of linkage of BMI to paternally derived alleles was found on chromosomes 3p23-p24 (Lod = 1.77 with D3S3038), 10p14-q11.2 (Lod = 1.89 with D10S1423), and 12p12-pter (Lod = 1.83 with GATA49D12), whereas linkage to maternally derived alleles was found on chromosome 4q31.1-q33 (Lod = 1.89 with D4S1629). In the 17- to 30-years of age group, evidence of linkage was found on 8p11-q13 (Lod = 2.05 with D8S1113) and 14q11.2-q21.3 (Lod = 1.95 with D14S742), whereas linkage to paternally derived alleles was found on chromosomes 4q31-qter (Lod = 1.84 with D4S2417) and 8p (Lod = 1.98 with D8S277).

Another genome scan based on data from 89 German families with two or more obese children and adolescents was published in 2003 (188). Obese sibships included one sibling with a BMI ≥95th percentile and other siblings with BMI ≥90th percentile. Linkage with obesity was tested with 452 genetic markers with an average intermarker distance of 8.4 centimorgans (cM). Only three regions provided evidence of linkage with Lod scores ≥1.5; these regions were on chromosomes 10p11.23 (Lod = 2.24 with D10S197), 11q11-q13.1 (Lod = 1.65 with D11S1313), and 19q12 (Lod = 1.97 with D19S414).

Three other genome-wide linkage analyses of obesity based on BMI have been reported. One was undertaken in 769 subjects from 182 Nigerian families with an average BMI of 21.3 kg/m2 (181). Subjects were genotyped for 402 autosomal markers, an average map density of 9 cM. The highest Lod scores were observed on chromosomes 7p14 with marker D7S817 (Lod = 3.83) and 11q22 with marker D11S2000 (Lod = 3.35). Significant evidence of linkage was also observed on chromosomes 1q21 (Lod = 2.24 with marker D1S534) and 8p22 (Lod = 2.34 with marker GATA151F02). In another genome scan, linkage between BMI and 384 markers was tested in 157 subjects from seven large nuclear families from the Old Order Amish population, selected on evidence for the segregation of a single locus with major effects on BMI (184). Sibpair linkage analyses identified QTLs for BMI on chromosomes 1p32 (p < 0.009), 5q35 (p < 0.004), 7q35 (p < 0.004 for 3 markers), 8q23 (p < 0.005), and 11q22 (p < 0.008). Typing of additional markers on 7q35 confirmed the linkage with BMI in a 10- to 15-cM region downstream from the leptin gene (184). Finally, another genome scan of obesity was undertaken in a cohort of families ascertained for probands with obstructive sleep apnea (183). Given that obesity is a major risk for patients suffering from obstructive sleep apnea, the authors tested linkage between BMI and 373 autosomal markers, with a mean spacing of 9.1 cM, genotyped in 349 subjects from 66 white pedigrees. Results revealed that BMI was linked to markers located on chromosomes 2p22 (Lod = 3.08), 7p22 (Lod = 2.53), and 12q21 (Lod = 3.41).

Finally, four other studies were undertaken to test for linkages between BMI and markers located at specific chromosomal regions in an effort to replicate previous findings. In a study based on a sample of 1422 twin pairs from the Swedish Twin Registry (103), no evidence of linkage to five markers located in the area of the QTL reported earlier on 2p21 (189) or to 8 markers located in the area of the QTL reported on 10p12-p11 (190) was observed. In an attempt to replicate a linkage for BMI on 3q27 (191), a sample of 545 individuals from 128 African-American families were genotyped for 15 markers evenly spaced in a 112-cM region around the peak linkage previously identified. Evidence of linkage was found between marker D3S2427 at 188.3 cM and BMI (Lod = 2.4) (185). When analyses were repeated in a larger sample comprising 1163 individuals from 330 families, the peak linkage (Lod = 4.3) was found at 187.6 cM between markers D3S3676 and D3S2427. The authors concluded that 3q27 should be considered as a strong candidate region in the search for obesity-related genes (185).

To identify genes potentially involved in obesity on chromosome 7q, Li et al. (186) examined linkage between BMI and 21 markers located in a 40-cM region flanking the leptin gene on 7q22.1-q35. Significant evidence of linkage was obtained with D7S692 (Lod = 2.75) and D7S523 (Lod = 2.11) on 7q31.1. These markers define a 20-cM region upstream of the leptin gene which could harbor an obesity-related gene (186). The last linkage study at a candidate region was undertaken on 200 white families with 542 siblings and 44 African-American families with 125 siblings, with the aim of testing epistatic interactions among five loci located on chromosomes 10 and 20 (187). Linkage analyses performed in the combined sample of 244 families revealed evidence of linkage on 10p11.2-cent with obesity (BMI ≥27 kg/m2), on 10q22 with waist circumference and BMI, on 10q25 with obesity and WHR, and on 20q13.1-q13.2 with percentage of body fat (187).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

Figure 1 depicts the human obesity gene map and incorporates >430 loci from single-gene mutation rodent models of obesity, human obesity cases due to single-gene (or digenic) mutations, and QTLs from crossbreeding experiments and genome-wide scans, all relevant Mendelian disorders that have been mapped, genes or markers that have been shown to be associated or linked with an obesity phenotype, and genes that have been evidenced in Tg or KO experiments. The map reveals that putative loci affecting obesity-related phenotypes are found on all but chromosome Y of the human chromosomes. In the case of chromosome 21, it is important to note that there are only two loci from animal models and none that has been confirmed in human studies. It is obvious that several genomic regions are characterized by a high density of concordant positive findings. As we now have a final draft of the human genome sequence and, with it, a more exhaustive annotation of the genome, we expect continuous advances in the understanding of the genetic basis of the predisposition to human obesity.

image

Figure 1. The 2003 human obesity gene map. The map includes all obesity-related genes and QTLs identified from the various lines of evidence reviewed in this article. This year's map consists of an updated 850-band-resolution cytogenetic map overlaid with build 34 of the human genome sequence available from NCBI (http:www.ncbi.nlm.nih.gov). This allows the human genes (as abbreviated in the Tables and Appendix and located to the right of each chromosome in this figure) to be placed at precise positions on both the sequence and the cytogenetic map. For all loci, we used the name preferred by UniSTS or LocusLink. Regions of the human genome homologous to the animal QTLs from Table 5 are represented on the human map (on left). The ruler to the left of each figure represents kilo basepairs. Chromosomes are drawn to scale only within a given page. These maps, along with information from this report, can be browsed and searched interactively at the Obesity Gene Map website (http:obesitygene.pbrc.edu).

Download figure to PowerPoint

The number of genes and other markers associated or linked with human obesity phenotypes continues to expand. The progress made over the last decade is exemplified in the numbers collated in Table 8. The human obesity gene map has become significantly more detailed and complex since the first version developed in 1994. Of interest is the fact that there are now 15 candidate genes that are supported by a minimum of five independent association studies. Of course, many of these loci on the map will turn out to be more important than others, and many will eventually be proven to be false positives. The main goals remain to identify the combination of genes and mutations that are contributing to the predisposition to human obesity and to determine the environmental circumstances under which these gene combinations and mutations occur.

Table 8. . Evolution in the status of the Human Obesity Gene Map
 1994199519961997199819992000200120022003
  • From Refs. (1, 2, 3, 4, 5, 6, 7, 8, 9) and this review.

  • *

    Number of genes, not number of mutations.

Single-gene mutations*   2666666/7
KO and Tg        3855
Mendelian disorders with map location8121316162024253341
Animal QTLs7924556798115165168183
Human QTLs from genome scans   3814213368139
Candidate genes with positive findings9101321294048587190

Most of the advances to date have come from an understanding of the single-gene mutations that have the potential to cause obesity in a small number of individuals. With the developments in human and model organisms genome sequences and the progress in laboratory technologies, analytical tools, and bioinformatics, one can anticipate that it will be possible to define the genes and mutations involved in the predisposition or the resistance to obesity. It is likely that the oligogenic cases in which a small number of genes (digenic, trigenic, etc.) with large effects will be resolved first. We hope that this publication will contribute to this enormous challenge.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map

Our research on the genetics of obesity is funded by the Canadian Institutes for Health Research (MOP-13960), the Pennington Biomedical Research Center, and an unrestricted grant from Bristol-Myers Squibb. C.B. is supported by the George A. Bray Chair in Nutrition. Our gratitude goes to Nina Laidlaw for her help with the final version of the paper. The list of genes and markers currently in the map, as well as the pictorial representation of the map, is also available online at http:obesitygene.pbrc.edu (Pennington Biomedical Research Center, Human Genomics Laboratory).

Footnotes
  • 1

    Nonstandard abbreviations: QTL, quantitative trait locus; Tg, transgenic; KO, knockout; NCBI, National Center for Biotechnology Information; OGMDB, Obesity Gene Map Database; AHO, Albright Hereditary Osteodystrophy; WAGR, Wilms’ tumor-aniridia-genital anomalies-mental retardation; md, Mahoganoid; LH, luteinizing hormone; AR, androgen; DH, double heterozygote; Lod, logarithm of odds; cM, centimorgan(s).

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Bioinformatics Issues
  5. Single-Gene and Digenic Obesity Cases
  6. Mendelian Disorders
  7. Single-Gene Mutations in Mice
  8. Knockout and Transgenic Models
  9. QTLs from Crossbreeding Experiments
  10. Discussion
  11. Acknowledgment
  12. References
  13. Appendix. Symbols, full names, and cytogenetic location of genes and loci of the 2003 human obesity gene map
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