Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Hum Mol Genet. 2014 Feb 1;23(3):831-41. doi: 10.1093/hmg/ddt465. Epub 2013 Sep 20.
Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain.
帕金森病（PD）有许多已知的遗传风险因素。临床和流行病学研究表明，存在中间因素可能与 PD 的额外风险相关。我们使用与这些特定表型相关的已知全基因组关联研究（GWAS）位点构建与这些特定表型相关的其他流行病学和临床因素的遗传风险概况，以在系统评价中估计遗传共病。我们根据与精神分裂症和克罗恩病风险相关的 GWAS 变体确定遗传风险概况。调整与 PD 和精神分裂症或 PD 和克罗恩病相关的 SNPs 后进行条件分析表明，与精神分裂症和 PD 相关的空间重叠位点解释了大部分共同发病，而 PD 和克罗恩病共享的已知近端位点以外的变异解释了它们的共同遗传共病。我们检查了与精神分裂症和克罗恩病位点附近的大脑甲基化和表达特征，以推断与导致遗传共病的变体相关的大脑功能变化。我们将我们的结果与流行病学文献的系统评价进行了比较，虽然结果在一定程度上存在差异；边缘遗传关联证实了遗传和流行病学数据中关联的方向性。我们表明 PD 与克罗恩病以及 PD 与精神分裂症之间存在很强的遗传定义的共病水平，与相关变体相关的大脑功能后果可能发生。
