Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance.
Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance.
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DOI：
10.1093/hmg/ddw348
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发表时间：
2016-12-15
影响因子：
3.5
通讯作者：
for International Parkinson’s Disease Genomics Consortium
中科院分区：
文献类型：
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作者：
Lubbe SJ;Escott-Price V;Gibbs JR;Nalls MA;Bras J;Price TR;Nicolas A;Jansen IE;Mok KY;Pittman AM;Tomkins JE;Lewis PA;Noyce AJ;Lesage S;Sharma M;Schiff ER;Levine AP;Brice A;Gasser T;Hardy J;Heutink P;Wood NW;Singleton AB;Williams NM;Morris HR;for International Parkinson’s Disease Genomics Consortium
少源遗传暗示了几种遗传因素在疾病病因学中的作用。我们研究了帕金森病（PD）的寡基因遗传，通过评估已知孟德尔基因和/或GBA中额外罕见变异的潜在负担，在两个大型独立队列中，共有7900例PD病例和6166例对照。与没有已知突变的PD病例（17%）和未受影响的对照组（16%）相比，具有已知主要遗传原因的病例中有超过（≥30%）的孟德尔PD基因有≥1个额外的罕见变异，这支持了我们的假设。额外孟德尔基因变异的携带者发病年龄更小（AAO）。在LRRK2 G2019S突变携带者中，额外的孟德尔变异（其中ATP13A2变异尤为常见）的影响可能解释了外显率的一些变化。与已知致病突变PD病例（8%）和对照组（5%）相比，约10%的无已知突变PD病例携带罕见的GBA变异，携带者有较早的aao。综上所述，这些数据表明，罕见孟德尔变异的少原遗传可能对原发性致病原因的患者很重要，而GBA增加了所有形式PD的风险。这项研究强调了孟德尔帕金森病潜在的遗传复杂性。潜在修饰变异体的鉴定通过潜在地分离相关变异体和良性变异体以及特定途径中基因之间的相互作用，为疾病机制提供了新的见解。在未来，这可能与PD患者及其家属的基因检测和咨询有关。
Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson’s (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognised primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.