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

Gamazon ER, Badner JA, Cheng L, Zhang C, Zhang D, Cox NJ, Gershon ES, Kelsoe JR, Greenwood TA, Nievergelt CM, Chen C, McKinney R, Shilling PD, Schork NJ, Smith EN, Bloss CS, Nurnberger JI, Edenberg HJ, Foroud T, Koller DL, Scheftner WA, Coryell W, Rice J, Lawson WB, Nwulia EA, Hipolito M, Byerley W, McMahon FJ, Schulze TG, Berrettini WH, Potash JB, Zandi PP, Mahon PB, McInnis MG, Zöllner S, Zhang P, Craig DW, Szelinger S, Barrett TB, Liu C
Mol Psychiatry. 2013 18 (3): 340-6

PMID: 22212596 · PMCID: PMC3601550 · DOI:10.1038/mp.2011.174

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.

MeSH Terms (10)

Bipolar Disorder Cerebellum DNA Methylation Gene Expression Regulation Genetic Predisposition to Disease Genome-Wide Association Study Humans Methylation Polymorphism, Single Nucleotide Quantitative Trait Loci

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