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. 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

Ming Li  1 , Xiong-jian Luo  1 , Mikael Landén  1 , Sarah E Bergen  1 , Christina M Hultman  1 , Xiao Li  1 , Wen Zhang  1 , Yong-Gang Yao  1 , Chen Zhang  1 , Jiewei Liu  1 , Manuel Mattheisen  1 , Sven Cichon  1 , Thomas W Mühleisen  1 , Franziska A Degenhardt  1 , Markus M Nöthen  1 , Thomas G Schulze  1 , Maria Grigoroiu-Serbanescu  1 , Hao Li  1 , Chris K Fuller  1 , Chunhui Chen  1 , Qi Dong  1 , Chuansheng Chen  1 , Stéphane Jamain  1 , Marion Leboyer  1 , Frank Bellivier  1 , Bruno Etain  1 , Jean-Pierre Kahn  1 , Chantal Henry  1 , Martin Preisig  1 , Zoltán Kutalik  1 , Enrique Castelao  1 , Adam Wright  1 , Philip B Mitchell  1 , Janice M Fullerton  1 , Peter R Schofield  1 , Grant W Montgomery  1 , Sarah E Medland  1 , Scott D Gordon  1 , Nicholas G Martin  1 ; MooDS Consortium; Swedish Bipolar Study Group; Marcella Rietschel  1 , Chunyu Liu  1 , Joel E Kleinman  1 , Thomas M Hyde  1 , Daniel R Weinberger  1 , Bing Su  1
Affiliations

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

Ming Li et al. Br J Psychiatry. 2016 Feb.

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.

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Figures

Figure 1
Figure 1. Flow chart of the present study
Based on the hypothesis that BPD risk variants are enriched among eQTL, we systematically integrated BPD GWAS and genome-wide brain eQTL data by using Sherlock. The top genes identified by Sherlock were then replicated in independent BPD samples and eQTL datasets. Finally, the successfully replicated SNP (rs6088662) was further tested for the association with BPD biological phenotypes including hippocampal volume and cognitive performance.
Figure 2
Figure 2. Rs6088662 is significantly associated with TRPC4AP mRNA expression
(A) Results in 193 neuropathologically normal human brain (cortical) samples of European subjects. (B) Results in 176 Alzheimer’s disease human brain (cortical) samples of European subjects.
Figure 3
Figure 3. Rs6088662 is significantly associated with GGT7 mRNA expression
(A) Results in 193 neuropathologically normal human brain (cortical) samples of European subjects. (B) Results in 320 healthy human brain DLPFC samples of Caucasian and African American individuals. (C) Results in 176 Alzheimer’s disease human brain (cortical) samples of European subjects.
Figure 4
Figure 4. Forest plot of odds ratios with 95% confidence interval for total replication-I bipolar disorder samples included in meta-analysis of rs6088662
The G allele of rs6088662 is overrepresented in BPD cases in all of the tested cohorts (except for the Iceland sample).
Figure 5
Figure 5
Plot of chromosome region showing a genomic area of high linkage disequilibrium with rs6088662 in European populations.
See this image and copyright information in PMC

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