Characterization of Expression Quantitative Trait Loci in Pedigrees from Colombia and Costa Rica Ascertained for Bipolar Disorder

Abstract

ABSTRACT: The observation that variants regulating gene expression (expression quantitative trait loci, eQTL) are at a high frequency among SNPs associated with complex traits has made the genome-wide characterization of gene expression an important tool in genetic mapping studies of such traits. As part of a study to identify genetic loci contributing to bipolar disorder and other quantitative traits in members of 26 pedigrees from Costa Rica and Colombia, we measured gene expression in lymphoblastoid cell lines derived from 786 pedigree members. The study design enabled us to comprehensively reconstruct the genetic regulatory network in these families, provide estimates of heritability, identify eQTL, evaluate missing heritability for the eQTL, and quantify the number of different alleles contributing to any given locus. In the eQTL analysis, we utilize a recently proposed hierarchical multiple testing strategy which controls error rates regarding the discovery of functional variants. Our results elucidate the heritability and regulation of gene expression in this unique Latin American study population and identify a set of regulatory SNPs which may be relevant in future investigations of complex disease in this population. Since our subjects belong to extended families, we are able to compare traditional kinship-based estimates with those from more recent methods that depend only on genotype information. Author Summary: We assess the heritability and genetic regulation of gene expression in a population of 786 individuals from Costa Rica and Colombia. The subjects, originally recruited in a study of bipolar disorder, are related within 26 extended families. This design allows us to compare estimates of the heritability of gene expression obtained using both traditional and genotype-based methods. We address questions regarding the architecture of genetic regulation including the extent to which gene expression is influenced by variants located nearby vs. far away on the genome and how many variants affect the expression of a given gene. In addition, we identify genetic variants which regulate gene expression; these serve as candidates for future studies to establish the genetic basis of complex traits, including those related to bipolar disorder, and also provide insight into the architecture of genetic regulation in this unique Latin American study population.