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Br J Psychiatry. 2016 Feb;208(2):128-37. doi: 10.1192/bjp.bp.114.156976. Epub 2015 Sep 3.

Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance.

Author information

1
Ming Li, PhD, State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China, and Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland, USA; Xiong-jian Luo, PhD, Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Mikael Landén, MD, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, and Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden; Sarah E. Bergen, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA; Christina M. Hultman, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Xiao Li, MSc, Wen Zhang, PhD, Yong-Gang Yao, PhD, Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Chen Zhang, PhD, Schizophrenia Program, Shanghai Mental Health Center, and Shanghai Jiao Tong University School of Medicine, Shanghai, China; Jiewei Liu, MSc, State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, and Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China; Manuel Mattheisen, MD, Department of Biomedicine, Aarhus University, Aarhus C, Denmark; Sven Cichon, PhD, Division of Medical Genetics, University of Basel, Basel, Switzerland, Institute of Human Genetics and Department of Genomics, Life and Brain Center, University of Bonn, Bonn, and Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organi

Abstract

BACKGROUND:

Bipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain.

AIMS:

We sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL.

METHOD:

To detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 5775) and cognitive performance (n = 342) among healthy individuals.

RESULTS:

Integrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P = 5.85 × 10(-5)). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.54 × 10(-8)). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals.

CONCLUSIONS:

Our findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.

PMID:
26338991
PMCID:
PMC4829352
DOI:
10.1192/bjp.bp.114.156976
[Indexed for MEDLINE]
Free PMC Article

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