The causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinson’s disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we found evidence that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus, and that the variants responsible modulate alpha-synuclein expression. Results put forth testable hypotheses on the role of gut microbiome in the pathogenesis of PD, the incomplete penetrance of PD susceptibility genes, and potential triggers of pathology in the gut.

尽管数十年的环境风险流行病学研究和全基因组研究已经发现了每种疾病的数十或数百个易感位点，但复杂疾病的原因仍然是一个谜。我们假设微生物组是缺失的环节。遗传研究表明，α-突触核蛋白是帕金森病 (PD) 的一种关键病理蛋白，其过度表达可导致家族性 PD，而 α-突触核蛋白基因座的变异会增加特发性 PD 的风险。最近，确定了 PD 中肠道微生物群的生态失调：发现了三个微生物群的丰度改变，其中一个由机会性病原体组成。使用两个大型数据集，我们发现证据表明 PD 肠道中机会性病原体的过多受到 α-突触核蛋白基因座的宿主基因型的影响，并且负责调节α-突触核蛋白表达的变体。结果对肠道微生物组在 PD 发病机制中的作用、PD 易感基因的不完全外显以及肠道病理学的潜在触发因素提出了可检验的假设。