Torres Jason M, Gamazon Eric R, Parra Esteban J, Below Jennifer E, Valladares-Salgado Adan, Wacher Niels, Cruz Miguel, Hanis Craig L, Cox Nancy J
Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, IL 60637, USA.
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Am J Hum Genet. 2014 Nov 6;95(5):521-34. doi: 10.1016/j.ajhg.2014.10.001. Epub 2014 Oct 30.
Top signals from genome-wide association studies (GWASs) of type 2 diabetes (T2D) are enriched with expression quantitative trait loci (eQTLs) identified in skeletal muscle and adipose tissue. We therefore hypothesized that such eQTLs might account for a disproportionate share of the heritability estimated from all SNPs interrogated through GWASs. To test this hypothesis, we applied linear mixed models to the Wellcome Trust Case Control Consortium (WTCCC) T2D data set and to data sets representing Mexican Americans from Starr County, TX, and Mexicans from Mexico City. We estimated the proportion of phenotypic variance attributable to the additive effect of all variants interrogated in these GWASs, as well as a much smaller set of variants identified as eQTLs in human adipose tissue, skeletal muscle, and lymphoblastoid cell lines. The narrow-sense heritability explained by all interrogated SNPs in each of these data sets was substantially greater than the heritability accounted for by genome-wide-significant SNPs (∼10%); GWAS SNPs explained over 50% of phenotypic variance in the WTCCC, Starr County, and Mexico City data sets. The estimate of heritability attributable to cross-tissue eQTLs was greater in the WTCCC data set and among lean Hispanics, whereas adipose eQTLs significantly explained heritability among Hispanics with a body mass index ≥ 30. These results support an important role for regulatory variants in the genetic component of T2D susceptibility, particularly for eQTLs that elicit effects across insulin-responsive peripheral tissues.
2型糖尿病（T2D）全基因组关联研究（GWASs）中的顶级信号富含在骨骼肌和脂肪组织中鉴定出的表达数量性状基因座（eQTLs）。因此，我们推测，此类eQTLs在通过GWASs检测的所有单核苷酸多态性（SNPs）估计的遗传力中可能占不成比例的份额。为了验证这一假设，我们将线性混合模型应用于威康信托病例对照协会（WTCCC）的T2D数据集以及代表德克萨斯州斯塔尔县的墨西哥裔美国人及墨西哥城的墨西哥人的数据集。我们估计了这些GWASs中检测的所有变异的加性效应以及在人类脂肪组织、骨骼肌和淋巴母细胞系中鉴定为eQTLs的一小部分变异所导致的表型变异比例。这些数据集中所有检测的SNPs所解释的狭义遗传力显著高于全基因组显著SNPs所解释的遗传力（约10%）；GWAS SNPs在WTCCC、斯塔尔县和墨西哥城数据集中解释了超过50%的表型变异。WTCCC数据集和瘦西班牙裔中跨组织eQTLs所致遗传力的估计值更高，而脂肪eQTLs在体重指数≥30的西班牙裔中显著解释了遗传力。这些结果支持调控变异在T2D易感性遗传成分中发挥重要作用，特别是对于在胰岛素反应性外周组织中产生效应eQTLs。
