Objective: This study investigated the link between rare variants in sphingolipid-related genes and Parkinson’s disease (PD) in a Chinese mainland population.

Background: Recently, growing evidence has highlighted the critical role of sphingolipid dysregulation in PD across genetic, biochemical, and cellular pathway levels^[1]. While sphingolipid metabolism dysfunction is implicated in PD etiology, the impact of rare genetic variants in these genes, especially in non-European groups like Chinese mainland patients, remains underexplored.

Method: We analyzed the association between rare variants in 62 sphingolipid-related genes and PD using data from 6,697 PD patients and 4,426 controls from the Parkinson’s Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC)^[2]. Next-generation sequencing identified rare variants (MAF <0.01 and <0.001), assessed via the SKAT-O test^[3].

Results: We identified 3,147 rare variants (MAF <0.01). A significant burden of these variants in sphingolipid-related genes was observed in PD patients (p < 0.05, Table 1). In addition to GBA, several genes—including SMPD1, CERK, CERS1, DGAT1, ELOVL2, ELOVL3, ENPP7, and FADS3—showed suggestive associations with PD (MAF <0.01, Figure 1 and Figure 2). With MAF <0.001, SMPD1, CERK, CERS1, CERS5, DGAT2, ELOVL3, ELOVL5, FADS3, and SMPD4 were also suggestively linked to PD (Figure 1 and Figure 3).

Conclusion: Our findings confirm the association of sphingolipid-related gene variants with PD, identifying novel candidate genes in Chinese mainland patients.

Table 1

Figure 1.

Figure 2.

Figure 3.

References: 1. Lin G, Wang L, Marcogliese PC, Bellen HJ. Sphingolipids in the Pathogenesis of Parkinson’s Disease and Parkinsonism. Trends Endocrinol Metab. 2019;30(2):106-117.
2. Zhao Y, Qin L, Pan H, Liu Z, Jiang L, He Y, Zeng Q, Zhou X, Zhou X, Zhou Y, Fang Z, Wang Z, Xiang Y, Yang H, Wang Y, Zhang K, Zhang R, He R, Zhou X, Zhou Z, Yang N, Liang D, Chen J, Zhang X, Zhou Y, Liu H, Deng P, Xu K, Xu K, Zhou C, Zhong J, Xu Q, Sun Q, Li B, Zhao G, Wang T, Chen L, Shang H, Liu W, Chan P, Xue Z, Wang Q, Guo L, Wang X, Xu C, Zhang Z, Chen T, Lei L, Zhang H, Wang C, Tan J, Yan X, Shen L, Jiang H, Zhang Z, Hu Z, Xia K, Yue Z, Li J, Guo J, Tang B. The role of genetics in Parkinson’s disease: a large cohort study in Chinese mainland population. Brain. 2020;143(7):2220-2234.
3. Lee S, Wu MC, Lin X. Optimal tests for rare variant effects in sequencing association studies. Biostatistics. 2012;13(4):762-775.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rare-variant-analysis-of-sphingolipid-related-genes-in-large-chinese-parkinson-s-disease-cohorts/