X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease
- Thiago P. Leale(Author),
- Shilpa C. Raog(Author),
- Jennifer N. French-Kwawuc(Author),
- Mateus H. Gouveial(Author),
- Victor Bordac(Author),
- Sara Bandres-Cigab(Author)
- ,
- bNIH,
- cUniversity of Maryland School of Medicine,
- dUniversidad de Santiago de Chile,
- eCleveland Clinic Foundation,
- fUniversidade Federal do Pará
Research Output: Contribution to journal Article Peer-review
Publication Information
Output type
Research Output: Contribution to journal Article Peer-review
Original language
EnglishPages from-to (Number of pages)
Pages 1625-1635 (11 pages)Journal (Volume, Issue Number)
Movement Disorders (Volume 38, Issue 9)Publication milestones
- Accepted/In press - 2023
- Published - 09/2023
Publication status
Published - 09/2023
ISSN
0885-3185External Publication IDs
- Scopus: 85165612886
- PubMed: 37469269
Abstract
Background: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. Objective: The objective of this study was to perform the first X-chromosome–wide association study for PD risk in a Latin American cohort. Methods: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. Results: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478–0.77], P = 3.13 × 10−5 replication odds ratio: 0.60 [0.37–0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome–wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. Conclusions: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies.
Funding Details
This work was supported by the National Institutes of Health (NIH) grants (R01 1R01NS112499-01A1 to T.P.L and I.F.M.; T32 AG000262 to J.N.F.-K; Intramural Research Program (IRP), National Human Genome Research Institute (NHGRI) of the NIH to M.H.G.; IRP of the NIH, National Institute on Aging (NIA), ZO1 AG000535, and ZIA AG000949 to S.B.-C; T32HL007698 to D.P.L.; D43TW009345 to M.R.C.-O; R35HG010692 to T.D.O.), “The Committee for Development and Research” (Comité para el desarrollo y la investigación-CODI)-Universidad de Antioquia (Grant 2020-31455 to C.V.-P. and M.J.-D.-R), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (grant RED 00314-16 to E.T.-S.), Brazilian Ministry of Health (Programa Nacional de Genômica e Saúde de Precisão – Genomas Brasil to E.T.-S.), Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq (E.T.-S.), Parkinson's Foundation (International Research Grants Program award to C.P.Z. and I.F.M.), Stanley Fahn Junior Faculty Award (I.F.M.), American Parkinson's Disease Association (I.F.M.), Michael J. Fox Foundation (I.F.M.), ASAP-GP2 (I.F.M.), and with resources and the use of facilities at the Veterans Affairs Puget Sound Health Care System (C.P.Z. and I.F.M.). We are grateful to the DNA-Neurogenetics Bank of the Instituto Nacional de Ciencias Neurológicas (INCN - Peru) for supporting the collection of DNA samples and associated data used in this publication. We thank all of the individuals who participated in LARGE-PD. We also thank all the support staff at the different Latin American sites for their efforts and support building this incredible resource. We thank Cassandra Talerico, PhD, a salaried employee of the Cleveland Clinic, for assistance with manuscript review and editing. We thank Dr. Maira Tonidandel and Dr. Paulo Caramelli for their help with PD cases in the Bambuí cohort. We also thank members of the International Parkinson Disease Genomics Consortium (IPDGC) for their contributions of both data and expertise to this project. [Correction added on 28 July 2023, after first online publication: Acknowledgments are updated in this version.].
This work was supported by National Institutes of Health (NIH) grants (R01 1R01NS112499‐01A1 to T.P.L. and I.F.M.; T32 AG000262 to J.N.F.‐K.), Intramural Research Program of the National Human Genome Research Institute of the NIH through the Center for Research on Genomics and Global Health (M.H.G.), Intramural Research Program of the NIH, National Institute on Aging grants (ZO1 AG000535 and ZIA AG000949 to S.B.‐C.; T32HL007698 to D.P.L.; R35HG010692 to T.D.O.), “The Committee for Development and Research” (Comité para el desarrollo y la investigación)‐Universidad de Antioquia (Grant 2020–31455 to C.V.‐P. and M.J.‐D.‐R.), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (grant RED 00314–16 to E.T.‐S.), Brazilian Ministry of Health (Programa Nacional de Genômica e Saúde de Precisão – Genomas Brasil to E.T.‐S.), Conselho Nacional de Desenvolvimento Científico e Tecnológico–CNPq (E.T.‐S.), Parkinson's Foundation (International Research Grants Program award to C.P.Z. and I.F.M.), Stanley Fahn Junior Faculty Award (to I.F.M.), American Parkinson's Disease Association (I.F.M.), The Michael J. Fox Foundation (I.F.M.), ASAP‐GP2 (I.F.M.), and with resources and the use of facilities at the Veterans Affairs Puget Sound Health Care System (C.P.Z. and I.F.M.). International Parkinson Disease Genomics Consortium (IPDGC). Funding Agencies:
This work was supported by National Institutes of Health (NIH) grants (R01 1R01NS112499‐01A1 to T.P.L. and I.F.M.; T32 AG000262 to J.N.F.‐K.), Intramural Research Program of the National Human Genome Research Institute of the NIH through the Center for Research on Genomics and Global Health (M.H.G.), Intramural Research Program of the NIH, National Institute on Aging grants (ZO1 AG000535 and ZIA AG000949 to S.B.‐C.; T32HL007698 to D.P.L.; R35HG010692 to T.D.O.), “The Committee for Development and Research” (Comité para el desarrollo y la investigación)‐Universidad de Antioquia (Grant 2020–31455 to C.V.‐P. and M.J.‐D.‐R.), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (grant RED 00314–16 to E.T.‐S.), Brazilian Ministry of Health (Programa Nacional de Genômica e Saúde de Precisão – Genomas Brasil to E.T.‐S.), Conselho Nacional de Desenvolvimento Científico e Tecnológico–CNPq (E.T.‐S.), Parkinson's Foundation (International Research Grants Program award to C.P.Z. and I.F.M.), Stanley Fahn Junior Faculty Award (to I.F.M.), American Parkinson's Disease Association (I.F.M.), The Michael J. Fox Foundation (I.F.M.), ASAP‐GP2 (I.F.M.), and with resources and the use of facilities at the Veterans Affairs Puget Sound Health Care System (C.P.Z. and I.F.M.). We thank all of the individuals who participated in LARGE‐PD. We also thank all the support staff at the different Latin American sites for their efforts and support building this incredible resource. We thank Cassandra Talerico, PhD, a salaried employee of the Cleveland Clinic, for assistance with manuscript review and editing. We thank Dr. Maira Tonidandel and Dr. Paulo Caramelli for their help with PD cases in the Bambuí cohort. We also thank members of the International Parkinson Disease Genomics Consortium (IPDGC) for their contributions of both data and expertise to this project.
FundersFunding numbers
ASAP-GP2
-Committee for Development and Research
-INCN
-Instituto Nacional de Ciencias Neurológicas
-International Parkinson Disease Genomics Consortium
-NIH
T32 AG000262, R01 1R01NS112499‐01A1
NIA
D43TW009345, T32HL007698, ZIA AG000949, R35HG010692, ZO1 AG000535
NHGRI
-MJFF
ASAP‐GP2
APDA
-CC
-PF
-CNPq
-FAPEMIG
RED 00314–16
UdeA
2020–31455
Ministério da Saúde
-Access to documents
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