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Mapping genotype-expression associations in Heterogeneous Stock rat brains to advance behavioral genetics research [Lateral habenula]

ABSTRACT: Research into the genetic influences of impulsivity and reward motivated behavior relies heavily on outbred animal populations, including Heterogeneous Stock (HS) rats, for the genetic diversity necessary to identify genotype-trait associations. Many such associations have been detected, but it is not always clear which gene or other feature near the identified genomic location is functionally responsible for the association. Since these traits are in part mediated by gene expression, mapping the associations between genotype and gene expression in these animals will enable the discovery and deeper understanding of these trait associations. We therefore obtained genotypes and RNA-Seq gene expression for five brain regions from 88 HS rats and mapped expression quantitative trait loci (eQTLs) for each region. We identified cis-eQTLs in over 3,000 genes per brain region and validated their effect sizes using allele specific expression. This resource will enable new discoveries of the genetic influences of complex behavioral traits.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE173138 | GEO | 2021/04/23

REPOSITORIES: GEO

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Project description:Most loci identified in genome wide association studies (GWAS) of complex traits reside in non-coding DNA and may contribute to phenotype via changes in gene regulation. The discovery of expression quantitative trait loci (?eQTLs?) can thus be used to more precisely identify modest but real disease associations and provide insights into their underlying molecular mechanisms. This is particularly true for analyses of expression in non-transformed cells from tissues relevant to the complex traits of interest. We have conducted two independent studies to identify genetic, including both SNPs and copy-number variants, and environmental determinants of human liver gene expression variation. We analyzed two sets of primary livers (primary dataset: n=220; replication dataset: n=60) using Agilent and Illumina expression arrays and Illumina SNP genotyping (550K). At least 30% of genetic and non-genetic factors that meet genome-wide significance (p <1 x10-9) in one study fail to replicate in the second study, suggesting that artifacts, like unknown SNPs that affect RNA-probe hybridization or hidden confounding variables, often result in statistically significant but biologically irrelevant correlations. These data confirm the value of independent replications to enrich for truly predictive eQTLs, and given our study design we are able to identify hundreds of reproducible correlations. We show that such information can be used to provide insights into disease-relevant phenotypes, with specific examples including eQTLs related to lipid levels (e.g. LDL cholesterol), immune system function (e.g. HLA), and drug response (e.g. warfarin). Furthermore, in the interest of both fine-mapping and mechanistic annotation, we hypothesized that promoters and 3?UTRs are enriched for causal eQTL variants. Therefore, we re-sequenced the promoter and 3?UTR regions of 25 genes with eQTLs, cloned each discovered haplotype, and quantified their impact on transcription using a luciferase-based assay. These data reveal multiple examples of robust, haplotype-specific in vitro functional differences that correlate directly with in vivo expression levels. This suggests that many eQTLs can be rapidly fine-mapped to one or a few single-nucleotide variants and mechanistically characterized using such assays. Integration of functional assays with eQTL discovery, and eQTLs with complex trait associations, is a powerful means to exploit GWAS data and improve their biological interpretability. RNA expression levels were quantified on Illumina gene expression microarrays for 60 normal human livers. Expression quantitative trait loci were identified by genome wide association mapping.

Project description:Most loci identified in genome wide association studies (GWAS) of complex traits reside in non-coding DNA and may contribute to phenotype via changes in gene regulation. The discovery of expression quantitative trait loci (‘eQTLs’) can thus be used to more precisely identify modest but real disease associations and provide insights into their underlying molecular mechanisms. This is particularly true for analyses of expression in non-transformed cells from tissues relevant to the complex traits of interest. We have conducted two independent studies to identify genetic, including both SNPs and copy-number variants, and environmental determinants of human liver gene expression variation. We analyzed two sets of primary livers (primary dataset: n=220; replication dataset: n=60) using Agilent and Illumina expression arrays and Illumina SNP genotyping (550K). At least 30% of genetic and non-genetic factors that meet genome-wide significance (p <1 x10-9) in one study fail to replicate in the second study, suggesting that artifacts, like unknown SNPs that affect RNA-probe hybridization or hidden confounding variables, often result in statistically significant but biologically irrelevant correlations. These data confirm the value of independent replications to enrich for truly predictive eQTLs, and given our study design we are able to identify hundreds of reproducible correlations. We show that such information can be used to provide insights into disease-relevant phenotypes, with specific examples including eQTLs related to lipid levels (e.g. LDL cholesterol), immune system function (e.g. HLA), and drug response (e.g. warfarin). Furthermore, in the interest of both fine-mapping and mechanistic annotation, we hypothesized that promoters and 3’UTRs are enriched for causal eQTL variants. Therefore, we re-sequenced the promoter and 3’UTR regions of 25 genes with eQTLs, cloned each discovered haplotype, and quantified their impact on transcription using a luciferase-based assay. These data reveal multiple examples of robust, haplotype-specific in vitro functional differences that correlate directly with in vivo expression levels. This suggests that many eQTLs can be rapidly fine-mapped to one or a few single-nucleotide variants and mechanistically characterized using such assays. Integration of functional assays with eQTL discovery, and eQTLs with complex trait associations, is a powerful means to exploit GWAS data and improve their biological interpretability. RNA expression levels were quantified on Agilent gene expression microarrays for 206 normal human livers (464 unique arrays corresponding to those samples). Genotypes were also derived from 224 of these samples using Illumina SNP chips. Expression quantitative trait loci were identified by genome wide association mapping. This submission represents the primary transcriptome component of study.

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Mapping genotype-expression associations in Heterogeneous Stock rat brains to advance behavioral genetics research [Lateral habenula]

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