Abstract
We previously identified a low-frequency (1.1 %) coding variant (G45R; rs200573126) in the adiponectin gene (ADIPOQ) which was the basis for a multipoint microsatellite linkage signal (LOD = 8.2) for plasma adiponectin levels in Hispanic families. We have empirically evaluated the ability of data from targeted common variants, exome chip genotyping, and genome-wide association study data to detect linkage and association to adiponectin protein levels at this locus. Simple two-point linkage and association analyses were performed in 88 Hispanic families (1,150 individuals) using 10,958 SNPs on chromosome 3. Approaches were compared for their ability to map the functional variant, G45R, which was strongly linked (two-point LOD = 20.98) and powerfully associated (p value = 8.1 × 10−50). Over 450 SNPs within a broad 61 Mb interval around rs200573126 showed nominal evidence of linkage (LOD > 3) but only four other SNPs in this region were associated with p values < 1.0 × 10−4. When G45R was accounted for, the maximum LOD score across the interval dropped to 4.39 and the best p value was 1.1 × 10−5. Linked and/or associated variants ranged in frequency (0.0018–0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r 2 < 0.20). In addition, the two-point linkage approach empirically outperformed multipoint microsatellite and multipoint SNP analysis. In the absence of data for rs200573126, family-based linkage analysis using a moderately dense SNP dataset, including both common and low-frequency variants, resulted in stronger evidence for an adiponectin locus than association data alone. Thus, linkage analysis can be a useful tool to facilitate identification of high-impact genetic variants.
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Acknowledgments
This work was supported by the grant R01 HG007112 from the National Human Genome Research Institute (D.W.B. and C.D.L.). The GUARDIAN study which contributed the IRASFS GWAS genotypes to this project is supported by grant R01 DK085175 from the NIDDK (L.E.W.). The provision of GWAS genotyping data was supported in part by UL1TR000124 (CTSI), and DK063491 (DRC). A subset of the IRASFS exome chips were contributed with funds from the Department of Internal Medicine at the University of Michigan (E.K.S.). Computational support was provided by the Center for Public Health Genomics at Wake Forest School of Medicine.
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Hellwege, J.N., Palmer, N.D., Brown, M.W. et al. Empirical characteristics of family-based linkage to a complex trait: the ADIPOQ region and adiponectin levels. Hum Genet 134, 203–213 (2015). https://doi.org/10.1007/s00439-014-1511-8
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DOI: https://doi.org/10.1007/s00439-014-1511-8