AUTHOR=Zhao Yu-wen , Pan Hong-xu , Liu Zhenhua , Wang Yige , Zeng Qian , Fang Zheng-huan , Luo Teng-fei , Xu Kun , Wang Zheng , Zhou Xun , He Runcheng , Li Bin , Zhao Guihu , Xu Qian , Sun Qi-ying , Yan Xin-xiang , Tan Jie-qiong , Li Jin-chen , Guo Ji-feng , Tang Bei-sha 

TITLE=The Association Between Lysosomal Storage Disorder Genes and Parkinson’s Disease: A Large Cohort Study in Chinese Mainland Population

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=13

YEAR=2021

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.749109

DOI=10.3389/fnagi.2021.749109

ISSN=1663-4365

ABSTRACT=<p><bold>Background:</bold> Recent years have witnessed an increasing number of studies indicating an essential role of the lysosomal dysfunction in Parkinson’s disease (PD) at the genetic, biochemical, and cellular pathway levels. In this study, we investigated the association between rare variants in lysosomal storage disorder (LSD) genes and Chinese mainland PD.</p><p><bold>Methods:</bold> We explored the association between rare variants of 69 LSD genes and PD in 3,879 patients and 2,931 controls from Parkinson’s Disease &amp; Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) using next-generation sequencing, which were analyzed by using the optimized sequence kernel association test.</p><p><bold>Results:</bold> We identified the significant burden of rare putative LSD gene variants in Chinese mainland patients with PD. This association was robust in familial or sporadic early-onset patients after excluding the <italic>GBA</italic> variants but not in sporadic late-onset patients. The burden analysis of variant sets in genes of LSD subgroups revealed a suggestive significant association between variant sets in genes of sphingolipidosis deficiency disorders and familial or sporadic early-onset patients. In contrast, variant sets in genes of sphingolipidoses, mucopolysaccharidoses, and post-translational modification defect disorders were suggestively associated with sporadic late-onset patients. Then, <italic>SMPD1</italic> and other four novel genes (i.e., <italic>GUSB, CLN6, PPT1</italic>, and <italic>SCARB2</italic>) were suggestively associated with sporadic early-onset or familial patients, whereas <italic>GALNS</italic> and <italic>NAGA</italic> were suggestively associated with late-onset patients.</p><p><bold>Conclusion:</bold> Our findings supported the association between LSD genes and PD and revealed several novel risk genes in Chinese mainland patients with PD, which confirmed the importance of lysosomal mechanisms in PD pathogenesis. Moreover, we identified the genetic heterogeneity in early-onset and late-onset of patients with PD, which may provide valuable suggestions for the treatment.</p>