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

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 ChenQi 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, Marcella Rietschel, Chunyu Liu, Joel E. Kleinman, Thomas M. Hyde, Daniel R. Weinberger, Bing Su

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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 = 5.8561075). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.5461078). 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.

Original languageEnglish (US)
Pages (from-to)128-137
Number of pages10
JournalBritish Journal of Psychiatry
Issue number2
StatePublished - Feb 2016

ASJC Scopus subject areas

  • Psychiatry and Mental health


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