Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
Hum Mol Genet. 2019 Dec 15;28(24):4161-4172. doi: 10.1093/hmg/ddz263.
Integration of genome-wide association study (GWAS) signals with expression quantitative trait loci (eQTL) studies enables identification of candidate genes. However, evaluating whether nearby signals may share causal variants, termed colocalization, is affected by the presence of allelic heterogeneity, different variants at the same locus impacting the same phenotype. We previously identified eQTL in subcutaneous adipose tissue from 770 participants in the Metabolic Syndrome in Men (METSIM) study and detected 15 eQTL signals that colocalized with GWAS signals for waist-hip ratio adjusted for body mass index (WHRadjBMI) from the Genetic Investigation of Anthropometric Traits consortium. Here, we reevaluated evidence of colocalization using two approaches, conditional analysis and the Bayesian test COLOC, and show that providing COLOC with approximate conditional summary statistics at multi-signal GWAS loci can reconcile disagreements in colocalization classification between the two tests. Next, we performed conditional analysis on the METSIM subcutaneous adipose tissue data to identify conditionally distinct or secondary eQTL signals. We used the two approaches to test for colocalization with WHRadjBMI GWAS signals and evaluated the differences in colocalization classification between the two tests. Through these analyses, we identified four GWAS signals colocalized with secondary eQTL signals for FAM13A, SSR3, GRB14 and FMO1. Thus, at loci with multiple eQTL and/or GWAS signals, analyzing each signal independently enabled additional candidate genes to be identified.
全基因组关联研究 (GWAS) 信号与表达数量性状基因座 (eQTL) 研究的整合使候选基因的鉴定成为可能。然而,评估附近信号是否可能共享因果变异,称为共定位,受到等位基因异质性的影响,即同一基因座的不同变体影响同一表型。我们之前在代谢综合征男性 (METSIM) 研究的 770 名参与者的皮下脂肪组织中鉴定了 eQTL,并检测到 15 个与身体质量指数 (BMI) 调整后的腰围臀围比 (WHRadjBMI) 的 GWAS 信号共定位的 eQTL 信号,这些信号来自遗传因素对人体测量特征的研究协会。在这里,我们使用两种方法,条件分析和贝叶斯测试 COLOC,重新评估了共定位的证据,并表明在多信号 GWAS 基因座上为 COLOC 提供近似条件汇总统计数据可以调和这两种测试之间的共定位分类分歧。接下来,我们对 METSIM 皮下脂肪组织数据进行条件分析,以识别条件上有区别或次要的 eQTL 信号。我们使用这两种方法来检测与 WHRadjBMI GWAS 信号的共定位,并评估这两种测试之间共定位分类的差异。通过这些分析,我们确定了四个与 FAM13A、SSR3、GRB14 和 FMO1 的次要 eQTL 信号共定位的 GWAS 信号。因此,在存在多个 eQTL 和/或 GWAS 信号的基因座上,独立分析每个信号可以鉴定出更多的候选基因。
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