Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants

被引：118

作者：

Gamazon, E. R. ^{[1
]}

Badner, J. A. ^{[2
]}

Cheng, L. ^{[3
]}

Zhang, C. ^{[3
]}

Zhang, D. ^{[4
]}

Cox, N. J. ^{[1
]}

Gershon, E. S. ^{[2
]}

Kelsoe, J. R. ^{[5
]}

Greenwood, T. A. ^{[5
]}

Nievergelt, C. M. ^{[5
]}

Chen, C. ^{[3
]}

McKinney, R. ^{[5
]}

Shilling, P. D. ^{[5
]}

Schork, N. J. ^{[6
]}

Smith, E. N. ^{[6
]}

Bloss, C. S. ^{[6
]}

Nurnberger, J. I. ^{[7
]}

Edenberg, H. J. ^{[8
]}

Foroud, T. ^{[8
]}

Koller, D. L. ^{[7
]}

Scheftner, W. A. ^{[9
]}

Coryell, W. ^{[10
]}

Rice, J. ^{[11
]}

Lawson, W. B. ^{[12
]}

Nwulia, E. A. ^{[12
]}

Hipolito, M. ^{[12
]}

Byerley, W. ^{[13
]}

McMahon, F. J. ^{[14
]}

Schulze, T. G. ^{[14
,15
]}

Berrettini, W. H. ^{[16
]}

Potash, J. B. ^{[17
]}

Zandi, P. P. ^{[17
]}

Mahon, P. B. ^{[17
]}

McInnis, M. G. ^{[18
]}

Zoellner, S. ^{[18
]}

Zhang, P. ^{[18
]}

Craig, D. W. ^{[19
]}

Szelinger, S. ^{[19
]}

Barrett, T. B. ^{[20
]}

Liu, C. ^{[3
]}

机构：

[1] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[2] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA

[3] Univ Illinois, Dept Psychiat, Chicago, IL 60607 USA

[4] Zhejiang Univ, Sch Med, Hangzhou, Zhejiang, Peoples R China

[5] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[6] Scripps Genom Med & Scripps Translat Sci Inst, La Jolla, CA USA

[7] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA

[8] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA

[9] Rush Univ, Dept Psychiat, Chicago, IL 60612 USA

[10] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA

[11] Washington Univ, Div Biostat, St Louis, MO USA

[12] Howard Univ, Dept Psychiat, Washington, DC 20059 USA

[13] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA

[14] NIMH, Genet Basis Mood & Anxiety Disorders Unit, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA

[15] Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany

[16] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA

[17] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA

[18] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA

[19] Translat Genom Res Inst, Neurogen Div, Phoenix, AZ USA

[20] Portland VA Med Ctr, Dept Psychiat, Portland, OR USA

来源：

MOLECULAR PSYCHIATRY | 2013年 / 18卷 / 03期

关键词：

bipolar disorder; eQTL; GWAS; mQTL; WHOLE-GENOME ASSOCIATION; WIDE ASSOCIATION; EPIGENETICS;

D O I：

10.1038/mp.2011.174

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P-bonferroni < 0.05) from two other GWA studies (TGen + GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder. Molecular Psychiatry (2013) 18, 340-346; doi:10.1038/mp.2011.174; published online 3 January 2012

引用

页码：340 / 346

页数：7

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