Zhang Kailin, Pan Hongxu, Zhao Yuwen, Wang Yige, Zeng Qian, Zhou Xun, He Runcheng, Zhou Xiaoxia, Xiang Yaqin, Zhou Zhou, Li Yu, Xu Qian, Sun Qiying, Tan Jieqiong, Yan Xinxiang, Li Jinchen, Guo Jifeng, Tang Beisha, Liu Zhenhua
Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Mol Neurobiol. 2022 Sep;59(9):5443-5451. doi: 10.1007/s12035-022-02920-5. Epub 2022 Jun 17.
Molecular chaperones were reported to play an important role in PD pathogenesis. Recent studies revealed the association of several HSP40/DNAJ family genes with PD, but no genetic analysis of all the DNAJ family genes in PD has been conducted. To systematically analyze the genetic impact of all the DNAJ family genes in PD, we performed genetic analysis for these genes in a large case-control study. We analyzed the rare variants in 49 DNAJ family genes from 3879 PD patients and 2931 healthy controls by whole-exome sequencing and whole-genome sequencing. All rare missense variants and the subgroups of rare damaging missense (Dmis) and loss-of-function (LoF) variants were gathered to test the accumulated association of these variants in each gene with PD. In total, 1617 rare nonsynonymous variants of DNAJ family genes with minor allele frequency less than 1% were identified in our cohort. We identified 82 rare missense variants for DNAJC26 in sporadic early-onset PD (sEOPD) or familial PD (FPD), and 17 Dmis and one LoF variant were detected among them. Gene-based burden analysis showed that the rare Dmis variants alone or Dmis plus LoF variants together of DNAJC26 were significantly enriched in PD patients. We also found suggestive associations of DNAJB2 and DNAJC18 with PD in sEOPD or FPD and DNAJC2, DNAJC10, DNAJC22, DNAJC24, DNAJC27, DNAJC28, and DNAJC29 with PD in sporadic late-onset PD. In conclusion, rare missense variants of DNAJC26 were significantly enriched in FPD or sEOPD. Moreover, DNAJB2, DNAJC2, DNAJC10, DNAJC18, DNAJC22, DNAJC24, DNAJC27, DNAJC28, and DNAJC29 were suggestively associated with PD.
据报道，分子伴侣在帕金森病（PD）发病机制中起重要作用。最近的研究揭示了几个热休克蛋白40（HSP40）/DNAJ家族基因与PD的关联，但尚未对PD中所有DNAJ家族基因进行遗传学分析。为了系统分析所有DNAJ家族基因对PD的遗传影响，我们在一项大型病例对照研究中对这些基因进行了遗传学分析。我们通过全外显子组测序和全基因组测序分析了3879例PD患者和2931例健康对照中49个DNAJ家族基因的罕见变异。收集所有罕见错义变异以及罕见有害错义（Dmis）和功能丧失（LoF）变异亚组，以检验每个基因中这些变异与PD的累积关联。在我们的队列中，总共鉴定出1617个DNAJ家族基因的罕见非同义变异，其次要等位基因频率小于1%。我们在散发性早发性PD（sEOPD）或家族性PD（FPD）中鉴定出82个DNAJC26的罕见错义变异，其中检测到17个Dmis变异和1个LoF变异。基于基因的负荷分析表明，单独的罕见Dmis变异或DNAJC26的Dmis加LoF变异在PD患者中显著富集。我们还发现，在sEOPD或FPD中，DNAJB2和DNAJC18与PD存在提示性关联；在散发性晚发性PD中，DNAJC2、DNAJC第十、DNAJC22、DNAJC24、DNAJC27、DNAJC28和DNAJC29与PD存在提示性关联。总之，DNAJC26的罕见错义变异在FPD或sEOPD中显著富集。此外，DNAJB2、DNAJC2、DNAJC第十、DNAJC18、DNAJC22、DNAJC24、DNAJC27、DNAJC28和DNAJC29与PD存在提示性关联。
