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Keywords:

  • hormones;
  • psychoses;
  • sex-specificity;
  • sex chromosomes;
  • genetic transmission

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EARLY STUDIES IDENTIFYING SEX DIFFERENCES IN TRANSMISSION
  5. ROLE OF THE SEX CHROMOSOMES
  6. OTHER EVIDENCE FOR SEX-DEPENDENT OR SEX-SPECIFIC GENETIC RISK?
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Although there is a long history to examinations of sex differences in the familial (and specifically, genetic) transmission of schizophrenia, there have been few investigators who have systematically and rigorously studied this issue. This is true even in light of population and clinical studies identifying significant sex differences in incidence, expression, neuroanatomic and functional brain abnormalities, and course of schizophrenia. This review highlights the history of work in this arena from studies of family transmission patterns, linkage and twin studies to the current molecular genetic strategies of large genome-wide association studies. Taken as a whole, the evidence supports the presence of genetic risks of which some are sex-specific (i.e., presence in one sex and not the other) or sex-dependent (i.e., quantitative differences in risk between the sexes). Thus, a concerted effort to systematically investigate these questions is warranted and, as we argue here, necessary in order to fully understand the etiology of schizophrenia. © 2013 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EARLY STUDIES IDENTIFYING SEX DIFFERENCES IN TRANSMISSION
  5. ROLE OF THE SEX CHROMOSOMES
  6. OTHER EVIDENCE FOR SEX-DEPENDENT OR SEX-SPECIFIC GENETIC RISK?
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Schizophrenia, a devastating psychiatric disorder, has a lifetime prevalence of approximately 1% worldwide. The familial nature of the disease is well established. Relatives of persons with schizophrenia have a higher risk for schizophrenia than that in the general population, the greatest risk being among first-degree relatives [Gottesman, 1994]. Early evidence from family, twin, and adoption studies all suggested a strong genetic component with heritability up to ∼70–80% [Kendler, 1988; Lyons et al., 2000, 2002; Tsuang et al., 2001; Kremen et al., 2006]. Recent molecular genetic strategies have identified several plausible polymorphisms and rare mutations [Owen et al., 2010; Mowry and Gratten, 2013]. It has been suggested that the genetic architecture for schizophrenia is multifactorial in nature, caused by an amalgamation of rare and common polymorphisms and copy number variants, and environmental factors interacting with genes via epigenetic mechanisms [Tsuang et al., 2001; Malhotra and Sebat, 2012; Maric and Svrakic, 2012].

Further, the prevailing ideology has been that the familial (and specifically, genetic) risk of schizophrenia does not vary by the proband's gender [Gottesman and Shields, 1982; Wyatt et al., 1988], even though there has been a wealth of information demonstrating significant differences in the disease between men and women. Men with schizophrenia have an earlier age at onset, poorer premorbid history, more pre- and peri-natal complications, more deficit symptoms, poorer course, and poorer response to typical antipsychotic medications [Goldstein and Walder, 2006; Abel et al., 2010]. We and others have identified sex differences in structural and functional brain abnormalities, whose origins we know occur during brain development [Goldstein et al., 2002, 2007; Gur et al., 2004; Goldstein and Walder, 2006; Elsabagh et al., 2009; Abbs et al., 2011]. In fact, population studies demonstrated that the incidence of schizophrenia is significantly higher in men, with a 1.4 male to female ratio [Castle et al., 1993; Aleman et al., 2003; McGrath et al., 2008]. Thus, some of us in the field have argued that it is important to investigate whether there is a sex-specific genetic risk for schizophrenia [Bellodi et al., 1986; Shimizu et al., 1987; DeLisi and Crow, 1989; Goldstein et al., 1990, 1995, 2011; Pulver et al., 1990; Goldstein, 1995], given the high genetic heritability and the sex-dependent incidence of the illness. Here, we review the evidence for the sex-specific and sex-dependent genetic risk for schizophrenia. Sex-specific evidence suggests that the genetic polymorphisms(s) or mutation(s) are only associated with risk in one sex and not the other, while sex-dependent genetic risk indicates that there are sex differences in risk that are quantitatively different.

EARLY STUDIES IDENTIFYING SEX DIFFERENCES IN TRANSMISSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EARLY STUDIES IDENTIFYING SEX DIFFERENCES IN TRANSMISSION
  5. ROLE OF THE SEX CHROMOSOMES
  6. OTHER EVIDENCE FOR SEX-DEPENDENT OR SEX-SPECIFIC GENETIC RISK?
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

In an early critical review of the literature from 1920 to 1995, Goldstein [1995] noted that of the 100 studies investigating the familial transmission of schizophrenia, only 26 conducted sex-specific analyses or reported data in such a way to make it possible to do so. The earliest report comparing inheritance of psychotic disorders in families of male versus female probands was by Pollack et al. [1939]. Among 2,515 first- and second-degree relatives of 175 dementia praecox patients (53% male) there was a slightly higher risk for psychosis (assessed using the family history method) in relatives of male probands, although no formal tests were conducted. Reed et al. [1973] examined the morbidity risk to first-degree relatives of 89 state hospital patients in 1917 (64% female) and found that mothers with psychosis produced approximately twice as many offspring with psychosis than did fathers with psychosis. This raised the issue of potential confounding by differential fertility effects in male and female probands [Vogel, 1979].

Until the mid-1980s, there were few studies of the effect of sex on the transmission of schizophrenia, given little interest and strong critiques of the early literature that purported to show an effect [Gottesman and Shields, 1972, 1982]. In Italy and Japan, respectively, Bellodi et al. [1986] and Shimizu et al. [1987] independently reported a higher morbidity risk to relatives of female patients with schizophrenia versus relatives of males, using more conservative diagnostic criteria (DSM-III criteria) than the earlier studies that used DSM-II criteria. In the US, studies by Nimgaonkar et al. [1988] and Nasrallah and Wilcox [1989] also reported higher rates of affected relatives of female probands, even in the face of using family history methods for assessing illness and their lack of control for age-of-onset differences by sex (as was true of the earlier studies by Bellodi and Shimizu and coworkers).

In the 1990s, Goldstein and Tsuang and Pulver and coworkers [Goldstein et al., 1990; Pulver et al., 1990; Pulver and Liang, 1991; Wolyniec et al., 1992] published a series of studies on sex-dependent familial transmission patterns, a mix of family interview and family history methods for assessing illness, using strict diagnostic criteria and adjustment for sex differences in age-at-onset and potential fertility effects. Female probands were significantly more likely to have come from multiply affected families compared with families of male probands. Risk to relatives was significantly correlated among relatives of female probands but not among those of male probands. Increased risk to relatives of female probands was consistent for all relative types and for relatives of both sexes. Additionally, Goldstein et al. [1993] reported a significantly higher rate of schizophrenia, schizophreniform, and schizoaffective disorders in relatives of female schizoaffective probands compared with relatives of male schizoaffective probands.

However, when the definition of illness in relatives was expanded to include the full spectrum (schizophrenia, schizoaffective disorder, schizophreniform, paranoid, atypical psychosis, and schizotypal personality disorder [SPD]), sex differences in familial risk were attenuated due to SPD, for which relatives of male probands had a significantly higher risk than relatives of females [Goldstein et al., 1990]. Taken together, studies of family transmission patterns suggested relatives of female probands were at higher risk for psychotic forms of the illness spectrum (schizophrenia and schizophreniform and schizoaffective disorders), whereas relatives of male probands were at higher risk for the non-psychotic form (SPD).

Twin studies have also contributed to investigations of sex-dependent genetic transmission, although not recently. Early twin studies found that concordance rates among female monozygotic (MZ) and dizygotic (DZ) twins were higher than among male MZ or DZ twins [Luxenberger, 1928, 1934; Rosanoff et al., 1934; Slater, 1958; Rosenthal, 1962]. This was consistent with a series of early sibling studies [Mott, 1910; Myerson, 1925; Schultz, 1932; Penrose, 1945; Tsuang, 1967]. Later twin studies were inconsistent with this [Gottesman and Shields, 1972; Lewine, 1979; Samuels, 1979], which some argued was due to differences in sampling methods in pre- and post-World War II studies. Most pre-World War II study samples consisted of chronic resident populations from institutions in which women were oversampled. In contrast, samples in post-World War II twin studies were obtained by matching psychiatric case registries and ascertaining consecutive admissions. It was argued that excessive female pair concordance among pre-World War II studies was an artifact of oversampling females from chronic institutionalized populations [Gottesman and Shields, 1982]. Further, early studies (based on DSM-I or DSM-II) used broad criteria that included patients now considered affective disorders, known to be more prevalent among women [Lewine et al., 1984; Goldstein and Link, 1988]. Thus, the arguments against sex-concordance, particularly for females, were sampling bias and diagnostic misclassification [Gottesman and Shields, 1982]. Post-World War II studies investigated twin concordance using a range of definitions for “affected.” In fact, higher concordance rates were found for female MZ pairs for narrower but not for broader definitions of schizophrenia [Kringlen, 1968; Fischer, 1973; Stromgren, 1987]. Given lack of investigation of sex-dependent effects in more current twin studies, with the exception of a relatively recent Finnish-based study that used population-based modeling which did not find evidence for sex-specific genetic effects [Cannon et al., 1998], these strategies have not yielded a definitive answer to the question of specificity of genetic risk by sex.

ROLE OF THE SEX CHROMOSOMES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EARLY STUDIES IDENTIFYING SEX DIFFERENCES IN TRANSMISSION
  5. ROLE OF THE SEX CHROMOSOMES
  6. OTHER EVIDENCE FOR SEX-DEPENDENT OR SEX-SPECIFIC GENETIC RISK?
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

The largest sex difference in genetics is found with the X and Y chromosomes. Has this difference been implicated in understanding the genetics of schizophrenia? Early evidence for sex chromosome involvement was first suggested by studies showing increased rates of psychoses among people with sex aneuploidies XXX and XXY [DeLisi et al., 1994, 2005; van Rijn et al., 2006; Boks et al., 2007; Roser and Kawohl, 2008]. Expanding on this idea was Crow and coworkers who proposed a genetic susceptibility locus for schizophrenia in the pseudoautosomal region of the sex chromosomes [Crow, 1988; Crow et al., 1989; DeLisi and Crow, 1989; Collinge et al., 1991]. Based on this theory, there was an expectation of concordance by sex among siblings when the gene was paternally inherited. This concordance was found in early investigations of affected siblings [Mott, 1910; Myerson, 1925; Schultz, 1932; Penrose, 1945; Tsuang, 1967] and in later studies of Crow and coworkers [Crow et al., 1989; Crow et al., 1990]. Four reports [Collinge et al., 1991; Asherson et al., 1992; D'Amato et al., 1992; Gorwood et al., 1992] attempted to replicate these findings resulting in two replications [Collinge et al., 1991; Gorwood et al., 1992], and lack of replication in the other two. In the two inconsistent studies, same-sex concordance among siblings was reported, but no significant effect of paternal versus maternal inheritance was observed, arguing against the pseudoautosomal gene location.

Lack of consistency in studies using the affected sibling pair method may have been due to differences in sample sizes (resulting in differences in statistical power), definition of the phenotype, and in the genetic assumptions regarding penetrance parameters and gene frequencies. For example, studies using the sibling pair method that reported positive results had larger samples than ones reporting negative results. Even a difference as small as six sibling pairs can affect the level of significance, as demonstrated by D'Amato et al. [1992] who reported non-significant same sex concordance in a subgroup (33 pairs) of the sample in which Gorwood et al. [1992] reported significant same-sex concordance among paternally derived pairs (39 pairs). In addition, studies differed as to whether they included other psychoses, such as affective psychoses, in the definition of the phenotype. As critiqued previously, how “affected” is operationalized is critical in evaluating the impact of sex, that is, defined as schizophrenia alone, schizophrenia and the traditional psychotic spectrum (i.e., schizophreniform and schizoaffective disorder), schizophrenia and the full spectrum (i.e., including SPD), or schizophrenia and other types of psychoses. Further, findings were generally not presented under different genetic assumptions [Risch, 1991; Asherson et al., 1992]. The pseudoautosomal hypothesis was later revised by the same investigators who proposed it [Crow et al., 1994; DeLisi et al., 1994]. They suggested that the inconsistent results from linkage studies implicated a schizophrenia gene in a nearby sex-specific region of the X and Y chromosomes. Their results showed some support for a dominant X–Y model of transmission in which homologous genes on X and Y contributed to the genetic susceptibility to schizophrenia.

Recently, our group presented further evidence for X-linked transmission of psychosis, including schizophrenia [Goldstein et al., 2011]. Elevated rates of psychosis among offspring of affected parents were generally comparable for males and females, when parent gender was not considered. However, a sex-dependent pattern of transmission emerged when both parent gender and offspring gender were considered. The rate of psychosis among sons of mothers with psychosis was substantially higher (18.8%) than among the daughters of these women (9.5%). In contrast, the rate of psychosis in daughters was higher when the father was affected (15.2%) compared with that among the sons of these fathers (3.1%). These findings demonstrated a significant difference in the male:female ratio of ill offspring among ill mothers versus ill fathers. Similar patterns were observed when analyses included affective psychoses, suggesting non-specificity of the sex-dependent risk for type of psychosis. In addition, inclusion of non-psychotic spectrum disorders attenuated the sex-specific transmission pattern, again suggesting (as did our early studies [Goldstein et al., 1990]), specificity of the sex-dependent effect for risk of psychosis but not for risk of non-psychotic spectrum disorders. Much earlier, a 1945 study of a large sample of familial pairs [Penrose, 1945] suggested increased frequency of psychosis in mother–son pairs compared with father–son pairs, although mother–son transmission was only higher for affective psychoses and not for schizophrenia. However, the early definitions of “schizophrenia” and “affective” categories were very heterogeneous compared with those based on current criteria, thus likely contributing to differences between our findings and those of Penrose when applied to schizophrenia per se. In fact, when examined by psychosis in general, the findings were consistent across both studies.

These results also suggested that reduced penetrance, multifactorial effects, and/or X inactivation of the risk chromosome may have decreased susceptibility in females, as was previously suggested for both psychosis [Crow, 2007] and bipolar disorder [Rosa et al., 2008]. Lower penetrance in females compared with males was indicated in the Goldstein study [Goldstein et al., 2011] by the lower proportion of psychosis among daughters compared with sons of affected mothers. Since both sexes had an equal chance of receiving the putative mutant X chromosome from an affected mother, the disparity in psychosis risk suggested sex-dependent disease penetrance.

However, when studies have specifically investigated X chromosome involvement in schizophrenia at the molecular level, there was initially only weak evidence (e.g., at Xp11, Xq21, and Xq26 [Paterson, 1999]). In fact, a consensus report reviewing X chromosome involvement [Paterson, 1999] and a large sibling pair cohort study [DeLisi et al., 2000] reported overall negative evidence for X linkage with schizophrenia. Reasons for the discrepancies across studies likely included false-positive results, small sample sizes with insufficient statistical power to identify a locus, genetic and clinical heterogeneity of samples, and statistical methods unable to take into account the complexity of gene–gene or of gene–environment transmission [Szatmari et al., 1998; Porteous et al., 2003; Bearden et al., 2004; Alaerts and Del-Favero, 2009].

Given these reports (even though they were over a decade ago), investigators had been less likely to pursue this hypothesis. However, more recently, there has been more molecular genetic evidence that the X chromosome is involved, though most studies used small samples so replication is still necessary [Wei and Hemmings, 2006; Philibert et al., 2007; Crow, 2008; Carrera et al., 2009; Feng et al., 2009; Roser and Kawohl, 2010; Piton et al., 2011]. For example, male-specific association with schizophrenia has been reported for haplotypes of the MAOB gene on Xp11.23 [Carrera et al., 2009] and for an association between an MAOB polymorphism and psychotic disorders [Bergen et al., 2009]. Furthermore, the SYP/CACNA1F locus in the Xp11 region [Wei and Hemmings, 2006], the GPR50 gene at Xq28 [Thomson et al., 2005], and the HOPA gene at Xq13 [Philibert et al., 2001, 2007; Sandhu et al., 2003] have been associated with schizophrenia or with psychosis in general. In addition, the protocadherin 11 X and Y(PCDH11XY) gene pair was proposed in the etiology of psychosis [Crow, 2008, 2012]. Further, the distal long arm (q) of the X chromosome has been linked to schizophrenia spectrum diagnoses in females with Fragile X syndrome [Reiss et al., 1988], juvenile-onset mood disorders [Wigg et al., 2009], bipolar and related affective disorders (such as schizoaffective bipolar disorder) [Mendlewicz et al., 1980; Del Zompo et al., 1984; Baron et al., 1987; Zandi et al., 2003], suggesting that polymorphisms in this region of the X chromosome may be associated with psychosis in general rather than specifically with schizophrenia. Interestingly, rare variants in microRNA genes, which negatively regulate gene expression, located on the X chromosome were implicated in schizophrenia risk [Feng et al., 2009]. Of possible further relevance to the presence of X chromosome involvement was the finding that a missense mutation in the Xq28 gene methyl-CpG binding-protein 2 (MECP2), which epigenetically regulates transcription via binding methylated DNA, is responsible for PPM-X syndrome, a male-specific X-linked mental retardation syndrome of psychosis, pyramidal signs, and macro-orchidism [Klauck et al., 2002].

Taken together, studies have re-raised the question of sex chromosome involvement in schizophrenia. Genome-wide association studies (GWAS) have not in general demonstrated sex chromosome SNPs surpassing conventional genome-wide significance thresholds. However, one of the first GWAS of schizophrenia reported strong association with rs4129148 near CSF2RA in the pseudoautosomal region [Lencz et al., 2007], although the sample was small (321 subjects) compared with current studies, thus raising potential concern for Type I error (a false positive result). In a much larger study, Stefansson et al. [2009] reported rs1882411 and rs6639583 at the NLGN4X gene at Xp22.33 among their best results, while Shi et al. [2009] reported a SNP approximately 2.5 Mb away near MXRA5 (rs1635239) as the 6th top SNP in their European-ancestry sample. Many genome wide association studies have tested the X chromosome (although not thoroughly), and the mega-analyses of the Psychiatric Genetics Consortium (that consolidated the individual GWAS results) have not yet tested the X chromosome. Thus, evaluation of this chromosome is clearly warranted.

Converging evidence from clinical, behavioral, and neuroanatomic studies support the presence of X chromosome involvement in schizophrenia. Partial or full X chromosome monosomies in Turner's syndrome [Murphy et al., 1997; Ross et al., 2000; Haberecht et al., 2001] have been associated with cognitive deficits in memory, spatial working memory, language ability, and attention, functional deficits for which sex differences in schizophrenia have been reported [Goldstein et al., 1998]. Further, structural brain abnormalities and brain activity deficits in hippocampus, amygdala, orbitofrontal cortex, have also been reported in Turner's syndrome (e.g., [Murphy et al., 1997; Haberecht et al., 2001; Molko et al., 2004]), that is, brain regions that develop in sex-dependent ways [Ross et al., 2000; Goldstein et al., 2001], and for which we and others have previously demonstrated sex differences in brain volumes in schizophrenia [Goldstein et al., 2002; Gur et al., 2004; Elsabagh et al., 2009; Abbs et al., 2011]. In addition, sex chromosome dosage related to cerebral asymmetry in both Turner's and Kleinfelter's syndromes suggests relevance to the genetic basis of psychosis [Rezaie et al., 2009]. Furthermore, Weickert et al. [2009] reported specific genes on the sex chromosomes that influenced the development of prefrontal cortex in a sex-specific manner, a key brain region contributing to schizophrenia pathology. These findings thus provide some evidence that sex-specific transmission of psychosis related to the sex chromosomes has functional relevance for understanding sex differences in the neurobiology of schizophrenia and potentially of other psychoses.

OTHER EVIDENCE FOR SEX-DEPENDENT OR SEX-SPECIFIC GENETIC RISK?

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EARLY STUDIES IDENTIFYING SEX DIFFERENCES IN TRANSMISSION
  5. ROLE OF THE SEX CHROMOSOMES
  6. OTHER EVIDENCE FOR SEX-DEPENDENT OR SEX-SPECIFIC GENETIC RISK?
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

With the increased sophistication of molecular studies and statistical power provided by the formation of large international collaborative efforts [Tsuang et al., 1999], evidence for candidate genes were identified at several chromosomes in linkage studies (although replication was not consistent), including 6p24-22 [Antonarakis et al., 1995; Schwab et al., 1995; Straub et al., 1995; Wang et al., 1995; Moises et al., 1995a; Wildenauer et al., 1996; Arolt et al., 1996; Maziade et al., 1997], 8p21-22 [Pulver et al., 1995; Wildenauer et al., 1996], 10p11-22 [Faraone et al., 1998; Schwab et al., 1998; Straub et al., 1998], 13q32 [Blouin et al., 1998], 15q13-14 [Freedman et al., 1997; Kaufmann et al., 1998], and 22q12-13 [Coon et al., 1994; Polymeropoulos et al., 1994; Pulver et al., 1994; Lasseter et al., 1995; Vallada et al., 1995; Moises et al., 1995b; Gill et al., 1996; Ng et al., 2008].

More recent molecular studies using a candidate gene approach have suggested sex-dependent and/or sex-specific effects on schizophrenia risk. However, for the most part, samples were relatively small, analyses exploratory, and thus Type I errors were a concern. Regarding sex-dependency, schizophrenia risk was associated with the SPEC2, PDZ-GEF2 and ACSL6 genes on chromosome 5q22-33 (though not consistently across five study samples) [Chen et al., 2006]. For a high density Irish family study, abnormalities in females predominated, while nuclear family studies showed both female and male abnormalities, depending on the study (see Table I). Mixed results by sex were present for other regions on chromosome 5 (5q31.2) (SNPs rs3891636, rs7728773, rs2189663, rs3864283, and rs2526303; the HINT1 gene) that, for example, were significant among the female subjects alone, whereas SNP rs7735116 was significant among males alone [Chen et al., 2008]. Further, using postmortem brain tissue comparing cases of schizophrenia with controls, Weickert et al. [2008] found that variants of the estrogen receptor alpha (ESR1) gene located on chromosome 6q25.1 contributed to risk for schizophrenia. Although sex differences were not tested, we know the density of these receptors differ in the male and female brain and thus this warrants further investigation by sex.

Table I. Molecular Genetics and Sex-Differences Literature Review
ChromosomeGeneMarkerSex dependentSex specificCandidate geneGWASStudy designDXGene functionRefs.
  1. Candidate genes and GWAS.

1q42DISC1rs751229, rs3738401 (HEP3) Significant under-transmission among females only (P = 0.00024), non-significant in malesYes 458 Finnish families ascertained for SCZDSM-IV (includes SCZ, schizoaffective, schizophrenia spectrum, bp and MDD)DISC1 is functionally involved neuronal proliferation, differentiation, migration, cAMP signaling, cytoskeletal modulation, and translational regulation via various signaling pathways in the regulation of neural development and brain maturation. Possible role in neuroplasticity via interactions with molecules of the cytoskeleton and centrosome, such as NUDEL and LIS1. Enables the activity of dynein, a microtubule protein, the transport of which is involved in neuronal migration, neurite outgrowth, and axon formation. Levels of the protein in cycling neural progenitor cells affects whether they differentiate into neurons or remain as progenitorsHennah et al. [2003]
1q43RYR2rs16834822, rs16834824 Female; strong association in Eur-Amer sample (P = 2 × 10(−6)); nominal association in MGS sample (P < 0.005) YesGWAS of age at onset (AAO); European-American (1,162 [814 M, 348 F] case, 1,178 cntrl); molecular genetics of schizophrenia (MGS non-GAIN) (1,090 case)DSM-IV (SCZ and schizoaffective)The RYR2 protein is a component of a calcium channel that supplies ions to the cardiac muscle. The calcium channel is composed of both RYR2 tetramers and FK506-binding proteinsWang et al. [2011]
2p13-14NogoCAA and TATC polymorphisms Female (P = 0.036 and 0.016)Yes Ethnic Chinese patients/volunteers, SCZ case (270 M, 93 F), cntrl (124 M, 129 F)DSM-IV SCZReticulon-4, also known as Neurite outgrowth inhibitor or Nogo, is a protein identified as an inhibitor of neurite outgrowth specific to the central nervous system. The gene belongs to the family of reticulon-encoding genes which are associated with the endoplasmic reticulum, and involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. It is a potent neurite outgrowth inhibitor that may also help block the regeneration of the central nervous systemTan et al. [2005]
2q32.1ZNF804Ars7597593 Female (P = 0.0002 across 4 samples)Yes Association study in 4 GWAS cohorts (all Caucasian. Germany [526 case, 520 cntrl], Scotland [597 case, 540 cntrl], United States [936 case, 1,190 cntrl], from Genetic Association Information Network [{GAIN}], CBDB [284 case, 430 cntrl]); Postmortem brain mRNA expression analyses (63 M, 26 F)NAZNF804A is expressed in the brain expressed, but with unknown function. Repeated GWAS association with SCZZhang et al. [2011]
3q13.3DRD3Ser9Gly polymorphism Female Gly allele carriers—poorer social functioning and earlier AAO (P = 0.008 and 0.04)Yes Association study with premorbid social functioning and AAO; SCZ cases (72 M, 69 F)DSM_IVThe D3 subtype receptor is mediated by G proteins which inhibit adenylyl cyclase and is localized to the limbic areas of the brain, which are associated with cognitive, emotional, and endocrine functionsGodlewska et al. [2010]
5q22-33SPEC2, PDZ-GEF2/ACSL624 markersResults vary by study design (ISHDSF: female only; ICCSS: female only; ITRIO: both males and females; German: mostly male; Pittsburgh: female only) Yes Irish Study of High Density Schziophrenia Families (ISHDSF, 101 M, 42 F); Irish Case–Cntrl (ICCSS, Case 436 M, 221 F; Cntrl 233 M, 178 F); Parent-Proband Trio (ITRIO) (cases only: 158 M, 58 F); German nuclear family (cases only: 184 M, 152 F); Pittsburgh nuclear family sample (cases only: 166 M, 82 F)ISHDSF (DSM-III SCZ, “poor outcome” schizoaffective, simple schizophrenia); ICCSS (DSM-III-R SCZ or “poor outcome” schizoaffective); ITRIO (DSM-III-R SCZ or “poor outcome” schizoaffective); German (DSM-IIIR SCZ or RDC Schizoaffective disorder, schizophrenic subtype); Pittsburgh (DSM-IV SCZ and schizoaffective)Non-kinase effector protein (SPEC2) of the CDC42 protein which is involved with cell skeleton assembly via regulation of filamentous actin; the PDZ-domain containing guanine exchange factor 1 (PDZ-GEF2) induces activation of Rap1 and increases integrin-mediated cell adhesion; acyl CoA synthetase long chain member 6 (ACSL6I) gene codes for an enzyme that activates the polyunsaturated long chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation. Plays an important role in fatty acid metabolism in brain and the acyl-CoAs produced may be utilized exclusively for the synthesis of the brain lipidChen et al. [2006]
5q31.2HINT1rs3891636, rs7728773, rs2189663, rs3864283, rs2526303, rs7735116Results vary by study design (rs3891636, rs7728773, rs2189663, rs3864283, rs2526303 [ISHDSF, FEMALE]; rs7735116 [ISHDSF, MALE]; rs3864283 [ICCSS, MALE]; interaction DX × rs3864283 × sex [Postmortem]) Yes Irish Study of High Density Schziophrenia Families (ISHDSF, 1,350 subjects, 273 pedigrees); Irish Case–Cntrl (ICCSS, 655 [436 M, 219 F] case, 626 [354 M, 269 F] cntrl; postmortem cDNA (35 SCZ, 34 BP, 35 cntrl)ISHDSF (DSM-III SCZ, “poor outcome” schizoaffective, simple schizophrenia); ICCSS (DSM-III-R schiophrenia, schizoaffective); Postmortem (DSM-IV SCZ and BP)The protein encoded by this gene hydrolyzes substrates such as AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester, and AMP-NH2, and has been found to be a tumor suppressing geneChen et al. [2008]
7q22Reelin (RELN)rs7341475 Female; significant in AJ (P = 2.9 × 10(−5)) and UK (P = 1.8 × 10(−3)) sample, same direction in other samples but not significant (P > 0.05) YesAshkenazi Jewish (AJ) Case–Cntrl (745 case, 759 cntrl); UK (SCZ cases only [320 M, 155 F]); Irish Case–Cntrl (ICCSS, 980 [669 M, 311 F] case, 582 [337 M, 245 F] cntrl); USA (Family-Based (Clinical Brain Disorders Branch/National Institute of Mental Health Sibling Study) 400 [295 M, 105 F] case, 434 [202 M, 232 F] cntrl); Han Chinese (SCZ patients, their families, cntrls. 415 [222 M, 193 F] case, 458 [229 M, 229 F] cntrl)DSM-IV (AJ), DSM-IV (UK), DSM-III-R (Irish Case-Cntrl, SCZ and schizoaffective), DSM-IV (USA), DSM-III/DSM-IV/chart (Han Chinese, SCZ)Reelin is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. It promotes the differentiation of progenitor cells into radial glia and affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts. Reelin also takes part in the developmental change of NMDA receptor configuration, increasing mobility of NR2B-containing receptors and thus decreasing the time they spend at the synapse. Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low levelShifman et al. [2008]
7q22.3Near PBEF1rs179863, rs179862, rs2704955, rs2704952 Female; strong association in Eur-Amer sample (4.57 × 10(−6)); non-significant in MGS sample YesGWAS of age at onset (AAO); European-American (1,162 [814 M, 348 F] case, 1,178 cntrl); Molecular Genetics of Schizophrenia (MGS non-GAIN) (1,090 case)DSM-IV (SCZ and schizoaffective)Nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt) also known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin is an enzyme that promotes B cell maturation and inhibits neutrophil apoptosis. It is an adipokine that is localized to the bloodstream and has various functions, including the promotion of vascular smooth muscle cell maturation and inhibition of neutrophil apoptosis. It also activates insulin receptor and has insulin-mimetic effects, lowering blood glucose and improving insulin sensitivity. The protein is highly expressed in visceral fat and serum levels of the protein correlate with obesityWang et al. [2011]
8p22Lipoprotein lipase (LPL)rs253 Significant association in males (P < 1 × 10(−6))Yes Han Chinese Case–Cntrl. 319 SCZ, 575 cntrlDSM-IV-RCode a water soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule. It is also involved in promoting the cellular uptake of chylomicron remnants, cholesterol-rich lipoproteins, and free fatty acids. LPL requires ApoC-II as a cofactorXie et al. [2011]
17p11.2-q25.1Protein kinase C, alpha (PRKCA)rs62621678, rs62621679, rs6261677, rs62621676 (haplotype C-HAP) Male; significant in pedigree and UK Case–Cntrl sample; non-significant in 4 other samplesYes Linkage study (353 sib pairs w SCZ); Pedigree fine-mapping; Association mapping studies, 5 samples (UK Case-Cntrl [669 SCZ, 1,736 BPI, 62 schizoaffective, 2,824 cntrl]), Irish Case–Cntrl [312 SCZ, 89 schizoaffective, 1,804 cntrl], Bulgarian Case–Cntrl [93 schizoaffective, 658 cntrl], Bulgarian Parent-Proband Trios [431 SCZ probands, 156 BP1 probands, 49 schizoaffective probands], and German Case–Cntrl [758 SCZ, 1,897 cntrl])DSM-IV (SCZ with BP comorbidity in GWAS pedigree; UK sample (30% of cases SCZ); Irish, Bulgarian, and German samples predominantly SCZ dx among cases)Protein kinase C-alpha (PKC-α) is a specific member of the protein kinase family. These enzymes are characterized by their ability to add a phosphate group to other proteins, thus changing their function. The primary mode of PKC-α's regulation, however, involves its interaction with the cell membrane, not direct interaction with specific molecules. The cell membrane consists of phospholipids. At warmer temperatures, phospholipids exist in a more fluid state as a result of increased intramolecular motion. The more fluid the cell membrane, the greater PKC-α's activityWilliams et al. [2003], Carroll et al. [2010]
22q11COMTrs165599 Significant in females (P < 0.00001)Yes Ashkenazi Jewish Case–Cntrl. 724 SCZ, 4,014 cntrlDSM-IV (any of the schizophrenia subtypes)Catechol-O-methyltransferase (COMT) is involved in metabolism of catecholamines catalyzing the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. COMT is localized to postsynaptic neurons where it degrades neurotransmitters following their releaseShifman et al. [2002]
Xq28GPR50rs2072621 Strong association in females (P = 0.0014)Yes Scotland Case–Cntrl. cases (BP [264], MDD [226], SCZ [263]), and Cntrl [562]. Each case group examined separatelyDSM-IVGPR50 is a member of the G protein-coupled receptor family of integral membrane proteins and is most closely related to the melatonin receptor by its ability to heterodimerize with both the MT1 and MT2 melatonin receptor subtypesThomson et al. [2005]

With regard to sex-specific findings in candidate gene studies comparing cases of schizophrenia to healthy controls, female-specific findings were found for a number of the studies. (1) Hennah and coworkers identified female-specific decreases in the transmission of the HEP3 haplotype of the DISC-1 gene on chromosome 1q42 in a Finnish sample [Hennah et al., 2003]; (2) the G/G genotype of the catechol-O-methyltransferase (COMT) gene on chromosome 22q11 (SNP rs165599) was associated with schizophrenia in women only [Shifman et al., 2002]; (3) the CAA and TATC polymorphisms of the Nogo gene (which codes for a myelin-associated protein involved in neutrite outgrowth and regeneration) was found among women alone [Tan et al., 2005]; (4) the GPR50 gene (rs2072621) on chromosome Xq28 showed female-specific association [Thomson et al., 2005]; and (5) Among schizophrenia patients alone, the functional polymorphism Ser9Gly of the dopamine D3 receptor (DRD3) gene was associated with lower social functioning and earlier age of onset only among females carrying one or two Gly alleles [Godlewska et al., 2010].

Male-specific findings were reported in a few recent molecular genetic studies (see Table I). (1) Male-specific abnormalities were found in the frequencies of the rs253 C allele and CC genotype of the lipoprotein lipase (LPL) gene on chromosome 8p22 [Xie et al., 2011]; (2) in a genome-wide linkage study of 353 sib pairs, Williams and coworkers identified a single pedigree of six affected male siblings (family C702) with genome-wide significant linkage to chromosome 17p11.2–q25.1 [Williams et al., 2003]. Subsequent fine-mapping in family C702 identified a haplotype in protein kinase C, alpha (PRKCA) that was over-transmitted to the affected males; and (3) a male-specific association was reported with SNP rs62621676 in a UK case–control cohort, although results were not replicated in four additional cohorts [Carroll et al., 2010].

Currently, there are fewer candidate gene studies and GWAS now dominate the genetics literature on schizophrenia. GWAS have implicated nearly 20 susceptibility loci surpassing stringent genome-wide significance thresholds, although with very small effects (<1.2-fold) on risk [Bergen and Petryshen, 2012]. The strongest and most consistent association is with the major histocompatibility complex (MHC) region [International Schizophrenia Consortium et al., 2009; Shi et al., 2009; Stefansson et al., 2009] containing hundreds of genes functioning not only in immunity, but also neurodevelopment, synaptic plasticity, and other processes. Other GWAS loci include zinc finger nuclease 804A (ZNF804A) [O'Donovan et al., 2008; Steinberg et al., 2011], and microRNA 137 (MIR137) whose putative regulated targets include other GWAS genes, namely transcription factor 4 (TCF4), the CACNA1C voltage-gated calcium channel subunit, CSMD1, and C10orf26 [Schizophrenia Psychiatric Genome-Wide Association Study (2011)].

The International Schizophrenia Consortium was the first to report evidence for a polygenic contribution to schizophrenia [International Schizophrenia Consortium et al., 2009], where thousands of common variants in aggregate explain an estimated one-third or more of the variation in schizophrenia risk [Schizophrenia Psychiatric Genome-Wide Association Study (2011)], comprising the largest risk factor ever identified for this disorder. Copy number variants—large chromosomal deletions or duplications—have also been implicated in schizophrenia, with many of the recurring CNVs being pleiotropic in other disorders [Malhotra and Sebat, 2012], although CNVs do not appear to have a major effect in bipolar disorder [Bergen et al., 2012].

Sex-specific genes implicated by GWAS include the following: (1) Female-specific association with rs7341475 in the Reelin gene (RELN), that was consistent across five different populations (although statistically significant in only two) [Shifman et al., 2008]; (2) female-specific association in a study of schizophrenia age at onset in two SNPs (rs16834822 and rs16834824) at 1q43 in the RYR2 gene in two different populations [Wang et al., 2011]; and (3) in the same study of age-at-onset, female-specific association with SNPs near the PBEF1 gene in females in one European-American population [Wang et al., 2011]. In addition, a follow-up study of ZNF804A (2q32.1) that had been implicated by previous GWAS identified female-specific association of SNP rs7597593 in four cohorts of European ancestry [Zhang et al., 2011].

Taken together with candidate gene studies, GWAS report sex-specific effects that were primarily among females with the illness. This is consistent with previous earlier studies of family transmission patterns in which the density of illness was greater in female proband families. On the other hand, genetic risk among males may include X chromosome abnormalities, CNVs (although sex-specificity for CNVs has not been systematically tested), or otherwise other untested genetic risk loci that may emerge if there was systematic investigation of this in schizophrenia genetic studies.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EARLY STUDIES IDENTIFYING SEX DIFFERENCES IN TRANSMISSION
  5. ROLE OF THE SEX CHROMOSOMES
  6. OTHER EVIDENCE FOR SEX-DEPENDENT OR SEX-SPECIFIC GENETIC RISK?
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

In summary, findings from the 1920s to the present concerning the hypothesis that there is sex-specific or sex-dependent genetic risk for schizophrenia are not conclusive but warrant further systematic investigation. We would argue that the reason for the inconsistency is that the genetic strategies for understanding schizophrenia have not, for the most part, been systematically applied to test the presence of the impact of sex. It is important that we investigate this question given the significant differences in incidence, presentation, neuroanatomy, behavior, and treatment responses between men and women with the illness. In order to do this, it is critical to incorporate a study design that addresses sex-specificity or sex-dependence in genetic risk, rather than use the common approach of analyzing data by sex post-study completion. Investigators argue they will not have the statistical power to test for genetic sex effects. However, a recent simulation study demonstrated that the incorporation of sex-specific tests can increase statistical power, when these effects are present, even in the face of smaller sample sizes [Magi et al., 2010].

Scientists in the field also contend that non-replicable findings are in part due to substantial variability of the illness presentation. We reason here, and in our previous studies over the last 25 years, that the examination of sex differences in schizophrenia can substantially reduce potential confounds due to subject variability. Further, while scientists have not fully evaluated the X chromosome and have yet to probe the Y chromosome using the GWAS approach, it is important to more fully investigate the role of the sex chromosomes given that it may contribute to understanding higher incidence rates among males. Given the large consortium studies in the field at this time, we have the statistical power to test for sex effects and initial evidence that it will be an important contribution to the field. As reviewed here, post hoc analyses of the most recent studies reported both sex-dependent and sex-specific genetic polymorphisms. Thus, we would argue it is timely for the field to address this critical question systematically, as doing so will have significant clinical implications through the potential development of novel sex-specific or sex-dependent therapeutics.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EARLY STUDIES IDENTIFYING SEX DIFFERENCES IN TRANSMISSION
  5. ROLE OF THE SEX CHROMOSOMES
  6. OTHER EVIDENCE FOR SEX-DEPENDENT OR SEX-SPECIFIC GENETIC RISK?
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Funding for this work was supported by National Institute of Mental Health (NIMH) Mental Health Centers for Intervention Development and Applied Research (CIDAR) Grant P50 MH08272-02 (JMG, P.I. – Sex Differences, Hormones and Memory Project). Funding for the ideas in this review were also supported by work on NIMH RO1 MH50647 (1999–2003, Tsuang, P.I.; 2003–2006, Goldstein, P.I.) and NIMH RO1 MH56956 (JMG, P.I.).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EARLY STUDIES IDENTIFYING SEX DIFFERENCES IN TRANSMISSION
  5. ROLE OF THE SEX CHROMOSOMES
  6. OTHER EVIDENCE FOR SEX-DEPENDENT OR SEX-SPECIFIC GENETIC RISK?
  7. CONCLUSIONS
  8. ACKNOWLEDGMENTS
  9. REFERENCES
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