Cross-tissue and tissue-specific eQTLs: partitioning the heritability of a complex trait.

Torres JM, Gamazon ER, Parra EJ, Below JE, Valladares-Salgado A, Wacher N, Cruz M, Hanis CL, Cox NJ
Am J Hum Genet. 2014 95 (5): 521-34

PMID: 25439722 · PMCID: PMC4225593 · DOI:10.1016/j.ajhg.2014.10.001

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.

Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

MeSH Terms (15)

Adipose Tissue Analysis of Variance Body Mass Index Diabetes Mellitus, Type 2 Genome-Wide Association Study Humans Linear Models Mexican Americans Mexico Muscle, Skeletal Phenotype Polymorphism, Single Nucleotide Principal Component Analysis Quantitative Trait Loci Texas

Connections (2)

This publication is referenced by other Labnodes entities:

Links