Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals

Abstract

Aims/hypothesis We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA. Method Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico. Result The top signals (unadjusted p value <1×10−5) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (PER3, PARD3B, EPHA4, TOMM7, PTPRD, HNT [also known as RREB1], LOC729993 and IL34) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene PER3, a system recently implicated in diabetes. We also report a second signal (minimum p value 1.52× 10−6) within PTPRD, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions HNF1A and KCNQ1. Annotation of top association signals in both studies revealed a marked excess of trans-acting eQTL in both adipose and muscle tissues. Conclusions/Interpretation In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues.

Cross-Tissue and Tissue-Specific eQTLs: Partitioning the Heritability of a Complex Trait

“…43 In contrast, a strong correlation between PC 1 and T2D has been previously reported in the MCM data set. However, the control individuals in the MCM study had greater European ancestry that was strongly confounded by socioeconomic status (SES).…”

“…43,44 We therefore hypothesized that eQTLs mapped in metabolically important tissues might also account for much of the heritability of T2D. In order to evaluate this hypothesis, we partitioned the set of GWAS-interrogated SNPs into subsets composed of eQTLs and performed joint analyses of variance components ( Figures 1A-1C).…”

“…The first data set was previously used in a GWAS 43 of T2D in a Mexican American population from Starr County, TX (SCT data set), and consisted of 837 case and 781 control subjects (Table S1, available online). As previously described, 43 individuals were genotyped on the Affymetrix Genome-Wide SNP Array 6.0, and the set of typed SNPs was imputed to a HapMap2 reference panel, resulting in a set of~1.8 million SNPs after quality-control measures. A total set of 1,733,064 SNPs remained after we removed SNPs with HWE-departure p values < 5% and SNPs with MAF < 1%.…”

“…39 Importantly, eQTLs mapped in human adipose and skeletal-muscle tissue are enriched among sets of T2D-associated SNPs, whereas eQTLs mapped in human lymphoblastoid cell lines (LCLs) exhibit no such enrichment. 39,43,44 It is thus reasonable to hypothesize that at least some of the overall heritability of T2D might be attributable to variants that regulate gene expression in insulin-responsive peripheral tissues (IRPTs).…”

A Genome‐Wide Search for Type 2 Diabetes Susceptibility Genes in an Extended Arab Family

“…There are more than 30 T2D GWAS listed in the Catalogue of Published GWAS Web site (http://www.genome.gov/gwastudies, accessed on 1st April, 2013) and more than 64 genetic variants are identified as associated with T2DM at a genome-wide significance level of P < 5.0 × 10 −8 (Saxena et al, 2007;Scott et al, 2007;WTCCC, 2007;Zeggini et al, 2007Zeggini et al, , 2008Voight et al, 2010;. Recent extension of this technology has begun to focus on identification of genetic risk factors for T2D and related traits in other ethnic groups, including African Americans (Murea et al, 2011;Cooke et al, 2012;Hester et al, 2012;Ng et al, 2012;Palmer et al, 2012), Amish (Rampersaud et al, 2007), Asian (Yasuda et al, 2008;Takeuchi et al, 2009;Kooner et al, 2011;Cho, Chen et al, 2012;Dastani et al, 2012), Indian (Chandak et al, 2007;Kooner et al, 2011), Mexicans (Hayes et al, 2007;Below et al, 2011;Parra et al, 2011) and Pima Indians (Hanson et al, 2007). Variants in some genes have been observed to be common and to show consistent directions of effect across multiple populations (Helgason et al, 2007;Haiman et al, 2012;Li et al, 2012).…”