Department of Medicine, University of Chicago, Chicago, 60607-7173, USA.
Mol Psychiatry. 2013 Mar;18(3):340-6. doi: 10.1038/mp.2011.174. Epub 2012 Jan 3.
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.
我们对双相情感障碍的全基因组关联（GWA）研究中的顶级易感变异进行了系统研究，以深入了解影响疾病风险的遗传变异的功能后果。我们在此报告了探索这些易感变异对人类小脑样本中 DNA 甲基化和 mRNA 表达影响的实验结果。在顶级易感变异中，我们鉴定了对 mRNA 表达（eQTLs）有顺式调控作用的 cis 调控基因座的富集，以及对 DNA CpG 甲基化有显著过量的数量性状基因座（mQTLs）。顺式调节同一基因的小脑表达和甲基化的双相情感障碍易感性变异体在双相情感障碍易感性变异体中所占比例非常小。这一发现表明，mQTLs 和 eQTLs 为在大脑病理生理学研究背景下对基因变异进行功能注释提供了正交的方法。未发现淋巴细胞 mQTL 富集，这表明 mQTL 富集是小脑特有的，与 eQTLs 相反。另外，我们发现使用 mQTL 信息来限制研究的单核苷酸多态性的数量可以增强我们检测显著关联的能力。利用这种基于观察到的功能富集的先验限制，我们从另外两项双相情感障碍的 GWA 研究（TGen+GAIN；2191 例病例和 1434 例对照）中鉴定出一个显著关联（rs12618769，P(bonferroni)<0.05），我们在一项独立的 GWA 研究（WTCCC）中进行了复制。总之，我们的研究结果强调了整合基因表达和 DNA 甲基化的遗传变异的功能注释对推进双相情感障碍的生物学理解的重要性。
