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

  • Ming Li (a1), Xiong-jian Luo (a2), Mikael Landén (a3), Sarah E. Bergen (a4), Christina M. Hultman (a5), Xiao Li (a2), Wen Zhang (a2), Yong-Gang Yao (a2), Chen Zhang (a6), Jiewei Liu (a7), Manuel Mattheisen (a8), Sven Cichon (a9), Thomas W. Mühleisen (a10), Franziska A. Degenhardt (a11), Markus M. Nöthen (a12), Thomas G. Schulze (a13), Maria Grigoroiu-Serbanescu (a14), Hao Li (a15), Chris K. Fuller (a15), Chunhui Chen (a16), Qi Dong (a16), Chuansheng Chen (a17), Stéphane Jamain (a18), Marion Leboyer (a19), Frank Bellivier (a20), Bruno Etain (a21), Jean-Pierre Kahn (a22), Chantal Henry (a21), Martin Preisig (a23), Zoltán Kutalik (a24), Enrique Castelao (a23), Adam Wright (a25), Philip B. Mitchell (a25), Janice M. Fullerton (a26), Peter R. Schofield (a26), Grant W. Montgomery (a27), Sarah E. Medland (a27), Scott D. Gordon (a27), Nicholas G. Martin (a27), MooDS Consortium (a27), The Swedish Bipolar Study Group (a27), Marcella Rietschel (a28), Chunyu Liu (a29), Joel E. Kleinman (a30), Thomas M. Hyde (a30), Daniel R. Weinberger (a30) and Bing Su (a31)...

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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Copyright

Corresponding author

Bing Su, Kunming Institute of Zoology, Chinese Academy of Sciences, 32 East Jiao-chang Road, Kunming 650223, Yunnan, China. Email: sub@mail.kiz.ac.cn; Ming Li, Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD, USA. Email: limingkiz@gmail.com

Footnotes

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These authors contributed equally to the work.

a

A list of the additional members is provided in the online Data Supplement to this paper.

This work was supported by grants from the National 973 project of China (2011CBA00401), the National Natural Science Foundation of China (U1202225, 31130051, 31071101 and 31221003), the German Federal Ministry of Education and Research, the National Genome Research Network, Germany, the Integrated Genome Research Network MooDS, Germany (grant 01GS08144 to S.C. and M.M.N., grant 01GS08147 to M.R. and T.G.S.), the 111 Project (B07008) of the Ministry of Education of China, the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020000), the National Authority for Scientific Research, Bucharest, Romania (UEFISCDI – PN-II-89/2012) and Personal Genetics SRL, Bucharest, Romania.

Declaration of interest

None.

Footnotes

References

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

  • Ming Li (a1), Xiong-jian Luo (a2), Mikael Landén (a3), Sarah E. Bergen (a4), Christina M. Hultman (a5), Xiao Li (a2), Wen Zhang (a2), Yong-Gang Yao (a2), Chen Zhang (a6), Jiewei Liu (a7), Manuel Mattheisen (a8), Sven Cichon (a9), Thomas W. Mühleisen (a10), Franziska A. Degenhardt (a11), Markus M. Nöthen (a12), Thomas G. Schulze (a13), Maria Grigoroiu-Serbanescu (a14), Hao Li (a15), Chris K. Fuller (a15), Chunhui Chen (a16), Qi Dong (a16), Chuansheng Chen (a17), Stéphane Jamain (a18), Marion Leboyer (a19), Frank Bellivier (a20), Bruno Etain (a21), Jean-Pierre Kahn (a22), Chantal Henry (a21), Martin Preisig (a23), Zoltán Kutalik (a24), Enrique Castelao (a23), Adam Wright (a25), Philip B. Mitchell (a25), Janice M. Fullerton (a26), Peter R. Schofield (a26), Grant W. Montgomery (a27), Sarah E. Medland (a27), Scott D. Gordon (a27), Nicholas G. Martin (a27), MooDS Consortium (a27), The Swedish Bipolar Study Group (a27), Marcella Rietschel (a28), Chunyu Liu (a29), Joel E. Kleinman (a30), Thomas M. Hyde (a30), Daniel R. Weinberger (a30) and Bing Su (a31)...

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

  • Ming Li (a1), Xiong-jian Luo (a2), Mikael Landén (a3), Sarah E. Bergen (a4), Christina M. Hultman (a5), Xiao Li (a2), Wen Zhang (a2), Yong-Gang Yao (a2), Chen Zhang (a6), Jiewei Liu (a7), Manuel Mattheisen (a8), Sven Cichon (a9), Thomas W. Mühleisen (a10), Franziska A. Degenhardt (a11), Markus M. Nöthen (a12), Thomas G. Schulze (a13), Maria Grigoroiu-Serbanescu (a14), Hao Li (a15), Chris K. Fuller (a15), Chunhui Chen (a16), Qi Dong (a16), Chuansheng Chen (a17), Stéphane Jamain (a18), Marion Leboyer (a19), Frank Bellivier (a20), Bruno Etain (a21), Jean-Pierre Kahn (a22), Chantal Henry (a21), Martin Preisig (a23), Zoltán Kutalik (a24), Enrique Castelao (a23), Adam Wright (a25), Philip B. Mitchell (a25), Janice M. Fullerton (a26), Peter R. Schofield (a26), Grant W. Montgomery (a27), Sarah E. Medland (a27), Scott D. Gordon (a27), Nicholas G. Martin (a27), MooDS Consortium (a27), The Swedish Bipolar Study Group (a27), Marcella Rietschel (a28), Chunyu Liu (a29), Joel E. Kleinman (a30), Thomas M. Hyde (a30), Daniel R. Weinberger (a30) and Bing Su (a31)...
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