4.8 Article

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

期刊

MOLECULAR PSYCHIATRY
卷 18, 期 3, 页码 340-346

出版社

NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2011.174

关键词

bipolar disorder; eQTL; GWAS; mQTL

资金

  1. PAAR (Pharmacogenetics of Anti-cancer Agents Research) [U01 GM61393]
  2. ENDGAMe (ENhancing Development of Genome-wide Association Methods) initiative [U01 HL084715]
  3. Genotype-Tissue Expression project (GTeX) [R01 MH090937]
  4. [5R01MH080425]
  5. MRC [G1001799] Funding Source: UKRI
  6. Medical Research Council [G1001799] Funding Source: researchfish

向作者/读者索取更多资源

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

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