Dataset Information

Identification of expression quantitative trait loci associated with schizophrenia and affective disorders in normal brain tissue.

ABSTRACT: Schizophrenia and the affective disorders, here comprising bipolar disorder and major depressive disorder, are psychiatric illnesses that lead to significant morbidity and mortality worldwide. Whilst understanding of their pathobiology remains limited, large case-control studies have recently identified single nucleotide polymorphisms (SNPs) associated with these disorders. However, discerning the functional effects of these SNPs has been difficult as the associated causal genes are unknown. Here we evaluated whether schizophrenia and affective disorder associated-SNPs are correlated with gene expression within human brain tissue. Specifically, to identify expression quantitative trait loci (eQTLs), we leveraged disorder-associated SNPs identified from 11 genome-wide association studies with gene expression levels in post-mortem, neurologically-normal tissue from two independent human brain tissue expression datasets (UK Brain Expression Consortium (UKBEC) and Genotype-Tissue Expression (GTEx)). Utilizing stringent multi-region meta-analyses, we identified 2,224 cis-eQTLs associated with expression of 40 genes, including 11 non-coding RNAs. One cis-eQTL, rs16969968, results in a functionally disruptive missense mutation in CHRNA5, a schizophrenia-implicated gene. Importantly, comparing across tissues, we find that blood eQTLs capture < 10% of brain cis-eQTLs. Contrastingly, > 30% of brain-associated eQTLs are significant in tibial nerve. This study identifies putatively causal genes whose expression in region-specific tissue may contribute to the risk of schizophrenia and affective disorders.

SUBMITTER: Bhalala OG

PROVIDER: S-EPMC6126875 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of expression quantitative trait loci associated with schizophrenia and affective disorders in normal brain tissue.

Bhalala Oneil G OG Nath Artika P AP Inouye Michael M Sibley Christopher R CR

PLoS genetics 20180824 8

Schizophrenia and the affective disorders, here comprising bipolar disorder and major depressive disorder, are psychiatric illnesses that lead to significant morbidity and mortality worldwide. Whilst understanding of their pathobiology remains limited, large case-control studies have recently identified single nucleotide polymorphisms (SNPs) associated with these disorders. However, discerning the functional effects of these SNPs has been difficult as the associated causal genes are unknown. Her ...[more]

PMID: 30142156

Similar Datasets

Project description:The discovery of expression quantitative trait loci ("eQTLs") can help to unravel genetic contributions to complex traits. We identified genetic determinants of human liver gene expression variation using two independent collections of primary tissue profiled with Agilent (n?=?206) and Illumina (n?=?60) expression arrays and Illumina SNP genotyping (550K), and we also incorporated data from a published study (n?=?266). We found that ?30% of SNP-expression correlations in one study failed to replicate in either of the others, even at thresholds yielding high reproducibility in simulations, and we quantified numerous factors affecting reproducibility. Our data suggest that drug exposure, clinical descriptors, and unknown factors associated with tissue ascertainment and analysis have substantial effects on gene expression and that controlling for hidden confounding variables significantly increases replication rate. Furthermore, we found that reproducible eQTL SNPs were heavily enriched near gene starts and ends, and subsequently resequenced the promoters and 3'UTRs for 14 genes and tested the identified haplotypes using luciferase assays. For three genes, significant haplotype-specific in vitro functional differences correlated directly with expression levels, suggesting that many bona fide eQTLs result from functional variants that can be mechanistically isolated in a high-throughput fashion. Finally, given our study design, we were able to discover and validate hundreds of liver eQTLs. Many of these relate directly to complex traits for which liver-specific analyses are likely to be relevant, and we identified dozens of potential connections with disease-associated loci. These included previously characterized eQTL contributors to diabetes, drug response, and lipid levels, and they suggest novel candidates such as a role for NOD2 expression in leprosy risk and C2orf43 in prostate cancer. In general, the work presented here will be valuable for future efforts to precisely identify and functionally characterize genetic contributions to a variety of complex traits.

Dataset Information

Identification of expression quantitative trait loci associated with schizophrenia and affective disorders in normal brain tissue.

Publications

Identification of expression quantitative trait loci associated with schizophrenia and affective disorders in normal brain tissue.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets