Expanding the Autosomal Recessive Gene Spectrum of Parkinson's Disease: A Study within the CPD10KGP

Yuwen Zhao; Hongxu Pan; Yige Wang; Juan Chen; Haoyu Guan; Zuowen Ren; Xiaoxia Zhou; Yaqin Xiang; Heng Wu; Jieqiong Tan; Qiying Sun; Qian Xu; Junling Wang; Lu Shen; Hong Jiang; Xinxiang Yan; Jinchen Li; Jifeng Guo; Zhenhua Liu; Beisha Tang

doi:10.1002/mds.70039

Expanding the Autosomal Recessive Gene Spectrum of Parkinson's Disease: A Study within the CPD10KGP

Mov Disord. 2025 Sep 17. doi: 10.1002/mds.70039. Online ahead of print.

Authors

Yuwen Zhao¹, Hongxu Pan¹, Yige Wang¹, Juan Chen¹, Haoyu Guan¹, Zuowen Ren¹, Xiaoxia Zhou¹, Yaqin Xiang¹, Heng Wu², Jieqiong Tan³, Qiying Sun⁴, Qian Xu¹, Junling Wang¹, Lu Shen^{1

5

6}, Hong Jiang^{1

5

6}, Xinxiang Yan¹, Jinchen Li^{4

5

7}, Jifeng Guo^{1

5

6}, Zhenhua Liu¹, Beisha Tang^{1

2

5

6}

Affiliations

¹ Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
² Department of Neurology, The First Affiliated Hospital and Clinical Research Center for Immune-Related Encephalopathy of Hunan Province, Hengyang Medical School, University of South China, Hengyang, China.
³ Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
⁴ Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China.
⁵ Bioinformatics Center, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁶ Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China.
⁷ Bioinformatics Center, Xiangya Hospital and Furong Laboratory, Central South University, Changsha, China.

PMID: 40959972
DOI: 10.1002/mds.70039

Abstract

Objectives: Parkinson's disease (PD) has a complex genetic etiology, with autosomal recessive (AR) genes significantly contributing. This study uses next-generation sequencing (NGS) and long-read sequencing data (LRS) in Chinese AR-PD families to uncover novel genes, enhancing our genetic comprehension of PD.

Methods: We investigated 162 AR-PD families and 1570 sporadic early-onset PD patients, combining homozygous mapping and whole-exome sequencing (WES) to identify candidates. Using the GenoPriori-WeightSchem approach, we conducted population-based prioritization of candidate genes. We prioritized biallelic loss-of-function variants in the candidate gene pool. LRS dataset were analyzed to investigate genes with structural genomic variants. The identified candidates were further validated in 3947 PD cases from our in-house whole-genome sequencing (WGS) dataset, along with 3100 PD cases derived from the UK Biobank WES dataset.

Results: Analysis of WES data from 25 core AR-PD families revealed five candidate genes: ROBO1, LMBR1L, RIOX2, INTS2, and H6PD. The GenoPriori-WeightSchem approach highlighted an additional five candidate genes: SORL1, PSD2, BRD9, EPG5, and SH3PXD2A. Focusing on homozygous loss-of-function variants, indicative of severe genetic impact, we identified six genes in AR-PD families: LRPPRC, PPP1R1B, C1RL, LNPK, HSD11B1L, and PPP1R3E. LRS data from 38 families revealed a homozygous structure variant, a 6.3 kb deletion, in the COL24A1 gene. Finally, eight of the identified candidate genes were consistently associated with PD in two independent replication stages.

Conclusions: Our study identified eight promising candidate genes using a large sample of AR-PD families, combining NGS and LRS data, which may expand the spectrum of candidate autosomal recessive genes responsible for PD. © 2025 International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; autosomal recessive genes; core families; whole‐exome sequencing data; long‐read sequencing data.

Abstract

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