Format

Send to

Choose Destination
PLoS Genet. 2018 Aug 24;14(8):e1007607. doi: 10.1371/journal.pgen.1007607. eCollection 2018 Aug.

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

Author information

1
Systems Genomics Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
2
The Royal Melbourne Hospital, Melbourne Health, Parkville, Victoria, Australia.
3
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, Victoria, Australia.
4
Cambridge Baker Systems Genomics Initiative, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
5
Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
6
Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
7
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
8
The Alan Turing Institute, British Library, London, United Kingdom.
9
Department of Molecular Neuroscience, University College London Institute of Neurology, Russell Square House, Russell Square, London, United Kingdom.
10
Department of Medicine, Division of Brain Sciences, Imperial College London, Burlington Danes, London, United Kingdom.

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.

PMID:
30142156
PMCID:
PMC6126875
DOI:
10.1371/journal.pgen.1007607
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center