Data_Sheet_1_Genetic Analysis of Six Transmembrane Protein Family Genes in Parkinson’s Disease in a Large Chinese Cohort.zip

ObjectivesParkinson’s disease (PD) is a neurodegenerative disorder with the manifestation of motor symptoms and non-motor symptoms. Previous studies have indicated the role of several transmembrane (TMEM) protein family genes in PD pathogenesis.
Materials and MethodsIn order to better investigate the genetic role of PD-related TMEM protein family genes in PD, including TMEM230, TMEM59, TMEM108, TMEM163, TMEM175, and TMEM229B, 1,917 sporadic early onset PD (sEOPD) or familial PD (FPD) patients and 1,652 healthy controls were analyzed by whole-exome sequencing (WES) while 1,962 sporadic late-onset PD (sLOPD) and 1,279 healthy controls were analyzed by whole-genome sequencing (WGS). Rare and common variants for each gene were included in the analysis.
ResultsOne hundred rare damaging or loss of function variants of six genes were found at the threshold of MAF < 0.1%. Three rare Dmis variants of TMEM230 were specifically identified in PD. Rare missense variants of TMEM59 were statistically significantly associated with PD in the WES cohort, indicating the role of TMEM59 in FPD and sEOPD. Rare missense variants of TMEM108 were suggestively associated with PD in the WGS cohort, indicating the potential role of TMEM108 in sLOPD. The rare variant of the other three genes and common variants of six genes were not significantly associated with PD.
ConclusionWe performed a large case-control study to systematically investigate the role of several PD-related TMEM protein family genes in PD. We identified three PD-specific variants in TMEM230, the significant association of TMEM59 with FPD, and sEOPD and the suggestive association of TMEM108 with sLOPD.

**研究目的**：帕金森病（Parkinson’s disease, PD）是一种以运动症状与非运动症状为主要临床表现的神经退行性疾病。既往研究表明，若干跨膜蛋白（transmembrane, TMEM）家族基因在PD的发病机制中发挥重要作用。

**材料与方法**：为深入探究PD相关跨膜蛋白家族基因（包括TMEM230、TMEM59、TMEM108、TMEM163、TMEM175及TMEM229B）在PD中的遗传调控作用，本研究纳入1917例散发性早发型PD（sporadic early onset PD, sEOPD）或家族性PD（familial PD, FPD）患者，以及1652名健康对照，采用全外显子测序（whole-exome sequencing, WES）进行基因分析；同时纳入1962例散发性迟发型PD（sporadic late-onset PD, sLOPD）患者与1279名健康对照，采用全基因组测序（whole-genome sequencing, WGS）开展分析。本研究将各基因的罕见变异与常见变异均纳入分析范围。

**结果**：在次要等位基因频率（minor allele frequency, MAF）<0.1%的筛选阈值下，本研究共检出6个目标基因的100个罕见有害变异或功能丧失变异。研究在PD患者中特异性鉴定出TMEM230的3个罕见有害错义变异。在全外显子测序队列中，TMEM59的罕见错义变异与PD存在统计学显著关联，提示TMEM59在家族性PD与散发性早发型PD的发病过程中发挥作用。在全基因组测序队列中，TMEM108的罕见错义变异与PD存在提示性关联，表明TMEM108可能在散发性迟发型PD中发挥潜在作用。其余3个目标基因的罕见变异，以及6个基因的常见变异均未与PD呈现显著相关性。

**结论**：本研究开展了一项大样本病例对照研究，系统探究了多个PD相关跨膜蛋白家族基因在PD中的作用。本研究明确了TMEM230中存在3个PD特异性变异，证实TMEM59与家族性PD及散发性早发型PD存在显著关联，并发现TMEM108与散发性迟发型PD存在提示性关联。