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

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.

Fig 1. Expression heritability and proportion of genetic variance due to local effects.

Distribution of estimated heritability of probe expression obtained using Mendel for all 34,030 probes (left), and distribution of the proportion of total genetic variance attributed to local genetic variation (right) for the 9,458 significantly heritable probes (FDR<0.05) where partitioning using the multiple GRM approach in GCTA was possible.

Fig 2. Characteristics of local and distal eSNPs.

Position of local eSNPs relative to transcription start site (TSS) of the gene queried by the associated probe (left). Number of genes controlled by distal eSNPs (center), excluding SNP kgp22834062, which was associated to 129 genes. Effect sizes (absolute values of the regression coefficients) of the most significant SNP for each probe with any local or distal associations (right).

Fig 3. Distribution of proportion of genetic variance due to eSNPs.

Proportion of genetic variance due to eSNPs (estimated as 1—the ratio of the genetic variance component when eSNPs are included as fixed effects to the genetic variance component when eSNPs are not included) for the 7,280 heritable probes with local or distal associations, assuming values less than 0 (12%) are exactly 0.

Fig 4. Distribution of percentage of variance explained.

Percentage of variance explained (model r²) by the most strongly associated eSNP and by the best set of eSNPs selected using multivariate model selection for the 7,280 heritable probes with local or distal eAssociations.