Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

Elaine G.Y. Chew; Zhehao Liu; Zheng Li; Sun Ju Chung; Michelle M. Lian; Moses Tandiono; Yue Jing Heng; Ebonne Y. Ng; Louis C.S. Tan; Wee Ling Chng; Tiak Ju Tan; Esther K.L. Peh; Ying Swan Ho; Xiao Yin Chen; Erin Y.T. Lim; Chu Hua Chang; Jonavan J. Leong; Ting Xuan Peh; Ling Ling Chan; Yinxia Chao; Wing Lok Au; Kumar M. Prakash; Jia Lun Lim; Yi Wen Tay; Vincent Mok; Anne Y.Y. Chan; Juei Jueng Lin; Beom S. Jeon; Kyuyoung Song; Clement C. Tham; Chi Pui Pang; Jeeyun Ahn; Kyu Hyung Park; Janey L. Wiggs; Tin Aung; Ai Huey Tan; Azlina Ahmad Annuar; Mary B. Makarious; Cornelis Blauwendraat; Mike A. Nalls; Laurie A. Robak; Roy N. Alcalay; Ziv Gan-Or; Richard Reynolds; Shen Yang Lim; Yun Xia; Chiea Chuen Khor; Eng King Tan; Zhenxun Wang; Jia Nee Foo

doi:10.1038/s43587-024-00760-7

Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

Elaine G.Y. Chew, Zhehao Liu, Zheng Li, Sun Ju Chung, Michelle M. Lian, Moses Tandiono, Yue Jing Heng, Ebonne Y. Ng, Louis C.S. Tan, Wee Ling Chng, Tiak Ju Tan, Esther K.L. Peh, Ying Swan Ho, Xiao Yin Chen, Erin Y.T. Lim, Chu Hua Chang, Jonavan J. Leong, Ting Xuan Peh, Ling Ling Chan, Yinxia ChaoWing Lok Au, Kumar M. Prakash, Jia Lun Lim, Yi Wen Tay, Vincent Mok, Anne Y.Y. Chan, Juei Jueng Lin, Beom S. Jeon, Kyuyoung Song, Clement C. Tham, Chi Pui Pang, Jeeyun Ahn, Kyu Hyung Park, Janey L. Wiggs, Tin Aung, Ai Huey Tan, Azlina Ahmad Annuar, Mary B. Makarious, Cornelis Blauwendraat, Mike A. Nalls, Laurie A. Robak, Roy N. Alcalay, Ziv Gan-Or, Richard Reynolds, Shen Yang Lim, Yun Xia, Chiea Chuen Khor^*, Eng King Tan^*, Zhenxun Wang^*, Jia Nee Foo^*

^*Corresponding author for this work

Research output: Contribution to journal › Letter › peer-review

2 Scopus citations

Abstract

Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10⁻¹⁵) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10⁻⁸). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease.

Original language	English
Article number	e2302720120
Pages (from-to)	205-218
Number of pages	14
Journal	Nature Aging
Volume	5
Issue number	2
DOIs	https://doi.org/10.1038/s43587-024-00760-7
State	Published - Feb 2025
Externally published	Yes

Funding

Funders	Funder number
National Institutes of Health

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10.1038/s43587-024-00760-7

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Chew, E. G. Y., Liu, Z., Li, Z., Chung, S. J., Lian, M. M., Tandiono, M., Heng, Y. J., Ng, E. Y., Tan, L. C. S., Chng, W. L., Tan, T. J., Peh, E. K. L., Ho, Y. S., Chen, X. Y., Lim, E. Y. T., Chang, C. H., Leong, J. J., Peh, T. X., Chan, L. L., ... Foo, J. N. (2025). Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk. Nature Aging, 5(2), 205-218. Article e2302720120. https://doi.org/10.1038/s43587-024-00760-7

@article{954da63fb487450fab3269c94bff9741,

title = "Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson{\textquoteright}s disease risk",

abstract = "Parkinson{\textquoteright}s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10−15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10−8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease.",

author = "Chew, {Elaine G.Y.} and Zhehao Liu and Zheng Li and Chung, {Sun Ju} and Lian, {Michelle M.} and Moses Tandiono and Heng, {Yue Jing} and Ng, {Ebonne Y.} and Tan, {Louis C.S.} and Chng, {Wee Ling} and Tan, {Tiak Ju} and Peh, {Esther K.L.} and Ho, {Ying Swan} and Chen, {Xiao Yin} and Lim, {Erin Y.T.} and Chang, {Chu Hua} and Leong, {Jonavan J.} and Peh, {Ting Xuan} and Chan, {Ling Ling} and Yinxia Chao and Au, {Wing Lok} and Prakash, {Kumar M.} and Lim, {Jia Lun} and Tay, {Yi Wen} and Vincent Mok and Chan, {Anne Y.Y.} and Lin, {Juei Jueng} and Jeon, {Beom S.} and Kyuyoung Song and Tham, {Clement C.} and Pang, {Chi Pui} and Jeeyun Ahn and Park, {Kyu Hyung} and Wiggs, {Janey L.} and Tin Aung and Tan, {Ai Huey} and {Ahmad Annuar}, Azlina and Makarious, {Mary B.} and Cornelis Blauwendraat and Nalls, {Mike A.} and Robak, {Laurie A.} and Alcalay, {Roy N.} and Ziv Gan-Or and Richard Reynolds and Lim, {Shen Yang} and Yun Xia and Khor, {Chiea Chuen} and Tan, {Eng King} and Zhenxun Wang and Foo, {Jia Nee}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2025",

month = feb,

doi = "10.1038/s43587-024-00760-7",

language = "אנגלית",

volume = "5",

pages = "205--218",

journal = "Nature Aging",

issn = "2662-8465",

publisher = "Springer",

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Chew, EGY, Liu, Z, Li, Z, Chung, SJ, Lian, MM, Tandiono, M, Heng, YJ, Ng, EY, Tan, LCS, Chng, WL, Tan, TJ, Peh, EKL, Ho, YS, Chen, XY, Lim, EYT, Chang, CH, Leong, JJ, Peh, TX, Chan, LL, Chao, Y, Au, WL, Prakash, KM, Lim, JL, Tay, YW, Mok, V, Chan, AYY, Lin, JJ, Jeon, BS, Song, K, Tham, CC, Pang, CP, Ahn, J, Park, KH, Wiggs, JL, Aung, T, Tan, AH, Ahmad Annuar, A, Makarious, MB, Blauwendraat, C, Nalls, MA, Robak, LA, Alcalay, RN, Gan-Or, Z, Reynolds, R, Lim, SY, Xia, Y, Khor, CC, Tan, EK, Wang, Z & Foo, JN 2025, 'Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk', Nature Aging, vol. 5, no. 2, e2302720120, pp. 205-218. https://doi.org/10.1038/s43587-024-00760-7

TY - JOUR

T1 - Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

AU - Chew, Elaine G.Y.

AU - Liu, Zhehao

AU - Li, Zheng

AU - Chung, Sun Ju

AU - Lian, Michelle M.

AU - Tandiono, Moses

AU - Heng, Yue Jing

AU - Ng, Ebonne Y.

AU - Tan, Louis C.S.

AU - Chng, Wee Ling

AU - Tan, Tiak Ju

AU - Peh, Esther K.L.

AU - Ho, Ying Swan

AU - Chen, Xiao Yin

AU - Lim, Erin Y.T.

AU - Chang, Chu Hua

AU - Leong, Jonavan J.

AU - Peh, Ting Xuan

AU - Chan, Ling Ling

AU - Chao, Yinxia

AU - Au, Wing Lok

AU - Prakash, Kumar M.

AU - Lim, Jia Lun

AU - Tay, Yi Wen

AU - Mok, Vincent

AU - Chan, Anne Y.Y.

AU - Lin, Juei Jueng

AU - Jeon, Beom S.

AU - Song, Kyuyoung

AU - Tham, Clement C.

AU - Pang, Chi Pui

AU - Ahn, Jeeyun

AU - Park, Kyu Hyung

AU - Wiggs, Janey L.

AU - Aung, Tin

AU - Tan, Ai Huey

AU - Ahmad Annuar, Azlina

AU - Makarious, Mary B.

AU - Blauwendraat, Cornelis

AU - Nalls, Mike A.

AU - Robak, Laurie A.

AU - Alcalay, Roy N.

AU - Gan-Or, Ziv

AU - Reynolds, Richard

AU - Lim, Shen Yang

AU - Xia, Yun

AU - Khor, Chiea Chuen

AU - Tan, Eng King

AU - Wang, Zhenxun

AU - Foo, Jia Nee

PY - 2025/2

Y1 - 2025/2

N2 - Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10−15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10−8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease.

AB - Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10−15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10−8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease.

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JO - Nature Aging

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ER -

Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

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