title: Cross-tissue and tissue-specific eQTLs: partitioning the heritability of a complex trait.
abstract: 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.
authors.affiliation: Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Torres
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.affiliation: Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON L5L 1C6, Canada.
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Parra
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77225, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Below
authors.affiliation: Unidades de Investigacion Medica en Bioquimica y Unidad de Epidemiologia Clinica, Hospital de Especialidades, Centro Medico Nacional "Siglo XXI," Instituto Mexicano del Seguro Social, Mexico City, CP 06720, Mexico.
authors.forename: Adan
authors.initials: A
authors.lastname: Valladares-Salgado
authors.affiliation: Unidades de Investigacion Medica en Bioquimica y Unidad de Epidemiologia Clinica, Hospital de Especialidades, Centro Medico Nacional "Siglo XXI," Instituto Mexicano del Seguro Social, Mexico City, CP 06720, Mexico.
authors.forename: Niels
authors.initials: N
authors.lastname: Wacher
authors.affiliation: Unidades de Investigacion Medica en Bioquimica y Unidad de Epidemiologia Clinica, Hospital de Especialidades, Centro Medico Nacional "Siglo XXI," Instituto Mexicano del Seguro Social, Mexico City, CP 06720, Mexico.
authors.forename: Miguel
authors.initials: M
authors.lastname: Cruz
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77225, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Hanis
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: ncox@bsd.uchicago.edu.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
mesh_terms: D000273:Adipose Tissue / Q000737:chemistry; D000704:Analysis of Variance; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D006801:Humans; D016014:Linear Models; D017058:Mexican Americans / Q000235:genetics; D008800:Mexico; D018482:Muscle, Skeletal / Q000737:chemistry; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025341:Principal Component Analysis; D040641:Quantitative Trait Loci / Q000235:genetics*; D013781:Texas