Combined linkage and association analyses identify a novel locus for obesity near PROX1 in Asians

Authors

  • Hyun-Jin Kim,

    1. Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea
    2. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
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  • Yun Joo Yoo,

    1. Department of Mathematics Education, Seoul National University, Seoul, Republic of Korea
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  • Young Seok Ju,

    1. Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea
    2. Macrogen Inc., Seoul, Republic of Korea
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  • Seungbok Lee,

    1. Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea
    2. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
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  • Sung-il Cho,

    1. Seoul National University School of Public Health, Seoul, Republic of Korea
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  • Joohon Sung,

    1. Seoul National University School of Public Health, Seoul, Republic of Korea
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  • Jong-Il Kim,

    Corresponding author
    1. Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea
    2. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
    3. Psoma Therapeutics Inc., Seoul, Republic of Korea
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  • Jeong-Sun Seo

    Corresponding author
    1. Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Republic of Korea
    2. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
    3. Macrogen Inc., Seoul, Republic of Korea
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  • Disclosure: The authors declared no conflict of interest.

  • Funding agencies: This work was supported by National Research Foundation grant funded by the Korean Government (MEST, No. 2003-2001558; No. 2003-2001561; No. 2003-2001565), the National Research Foundation of Korea (2010-0025814), and the Center for Disease Control of Korea (budget no. 2009-E00500-00). This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIP) (No. 2011-0030738).

Abstract

Objective

Although genome-wide association studies (GWAS) have substantially contributed to understanding the genetic architecture, unidentified variants for complex traits remain an issue. One of the efficient approaches is the improvement of the power of GWAS scan by weighting P values with prior linkage signals. Our objective was to identify the novel candidates for obesity in Asian populations by using genemapping strategies that combine linkage and association analyses.

Design and Methods

To obtain linkage information for body mass index (BMI) and waist circumference (WC), we performed a multipoint genome-wide linkage study in an isolated Mongolian sample of 1,049 individuals from 74 families. Next, a family-based GWAS, which integrates within- and between-family components, was performed using the genotype data of 756 individuals of the Mongolian sample, and P values for association were weighted using linkage information obtained previously.

Results

For both BMI (LOD = 3.3) and WC (LOD = 2.6), the highest linkage peak was discovered at chromosome 10q11.22. In family-based GWAS combined with linkage information, six single-nucleotide polymorphisms (SNPs) for BMI and five SNPs for WC reached a significant level of association (linkage weighted P < 1 × 10-5). Of these, only one of the SNPs associated with WC (rs1704198) was replicated in 327 Korean families comprising 1,301 individuals. This SNP was located in the proximity of the prosperorelated homeobox 1 (PROX1) gene, the function of which was validated previously in a mouse model.

Conclusion

Our powerful strategic analysis enabled the discovery of a novel candidate gene, PROX1, associated with WC in an Asian population.

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