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

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.

• Authors: Ming Li, Xiong-jian Luo, Mikael Landén, Sarah E Bergen, Christina M Hultman, Xiao Li, Wen Zhang, Yong-Gang Yao, Chen Zhang, Jiewei Liu, Manuel Mattheisen, Sven Cichon, Thomas W Mühleisen, Franziska A Degenhardt, Markus M Nöthen, Thomas G Schulze, Maria Grigoroiu-Serbanescu, Hao Li, Chris K Fuller, Chunhui Chen, Qi Dong, Chuansheng Chen, Stéphane Jamain, Marion Leboyer, Frank Bellivier, Bruno Etain, Jean-Pierre Kahn, Chantal Henry, Martin Preisig, Zoltán Kutalik, Enrique Castelao, Adam Wright, Philip B Mitchell, Janice M Fullerton, Peter R Schofield, Grant W Montgomery, Sarah E Medland, Scott D Gordon, Nicholas G Martin, MooDS Consortium, Swedish Bipolar Study Group, Marcella Rietschel, Chunyu Liu, Joel E Kleinman, Thomas M Hyde, Daniel R Weinberger, Bing Su
• Journal: The British journal of psychiatry : the journal of mental science (Br J Psychiatry) Vol. 208 Issue 2 Pg. 128-37 (Feb 2016) ISSN: 1472-1465 [Electronic] England
• PMID: 26338991 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Royal College of Psychiatrists 2016.

Topics

• Aged
• Bayes Theorem
• Bipolar Disorder (genetics)
• Case-Control Studies
• Chromosomes, Human, Pair 22
• Cognition
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Hippocampus (pathology)
• Humans
• Logistic Models
• Polymorphism, Single Nucleotide