Parlar Sitki Cem, Senkevich Konstantin, Yu Eric, Ruskey Jennifer A, Ahmad Jamil, Asayesh Farnaz, Spiegelman Dan, Waters Cheryl, Monchi Oury, Dauvilliers Yves, Dupré Nicolas, Greenbaum Lior, Hassin-Baer Sharon, Miliukhina Irina, Timofeeva Alla, Emelyanov Anton, Pchelina Sofya, Alcalay Roy N, Fon Edward A, Trempe Jean-François, Gan-Or Ziv
Department of Human Genetics, McGill University, Montréal, QC, Canada.
The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.
NPJ Parkinsons Dis. 2025 Apr 29;11(1):102. doi: 10.1038/s41531-025-00934-z.
LRRK2 variants are key genetic risk factors for Parkinson's Disease (PD). We conducted a per-domain rare coding variant burden analysis, including 8,888 PD cases and 69,412 controls. In meta-analysis, the Kinase domain was strongly associated with PD (Exonic: P = 1.61 × 10, Non-synonymous: P = 1.54 × 10, CADD > 20: P = 3.09 × 10). Excluding the p.G2019S variant nullified this effect. Nominal associations were found in the ANK and Roc-COR domains, with potentially protective variants, p.R793M and p.Q1353K.
亮氨酸重复激酶2（LRRK2）变异是帕金森病（PD）的关键遗传风险因素。我们进行了一项按结构域的罕见编码变异负担分析，纳入了8888例PD病例和69412例对照。在荟萃分析中，激酶结构域与PD密切相关（外显子：P = 1.61×10，非同义：P = 1.54×10，综合注释依赖性损耗（CADD）>20：P = 3.09×10）。排除p.G2019S变异消除了这种效应。在ANK和Roc-COR结构域中发现了名义上的关联，存在潜在的保护性变异p.R793M和p.Q1353K。
