. 2023 Sep;38(9):1625-1635.

doi: 10.1002/mds.29508. Epub 2023 Jul 20.

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease

Thiago P Leal¹, Shilpa C Rao², Jennifer N French-Kwawu³, Mateus H Gouveia⁴, Victor Borda³, Sara Bandres-Ciga⁵, Miguel Inca-Martinez¹, Emily A Mason⁶, Andrea R V R Horimoto⁷, Douglas P Loesch³, Elif I Sarihan¹, Mario R Cornejo-Olivas^{8

9}, Luis E Torres¹⁰, Pilar E Mazzetti-Soler^{9

11}, Carlos Cosentino¹⁰, Elison H Sarapura-Castro⁹, Andrea Rivera-Valdivia⁹, Angel C Medina¹², Elena M Dieguez¹³, Víctor E Raggio¹⁴, Andrés Lescano¹³, Vitor Tumas¹⁵, Vanderci Borges¹⁶, Henrique B Ferraz¹⁶, Carlos R Rieder¹⁷, Artur Schumacher Schuh^{18

19}, Bruno L Santos-Lobato²⁰, Carlos Velez-Pardo²¹, Marlene Jimenez-Del-Rio²¹, Francisco Lopera²¹, Sonia Moreno²¹, Pedro Chana-Cuevas²², William Fernandez²³, Gonzalo Arboleda²³, Humberto Arboleda²³, Carlos E Arboleda Bustos²³, Dora Yearout^{24

25}, Maira T Barbosa^{26

27}, Francisco E C Cardoso²⁸, Paulo Caramelli²⁶, Mauro C Q Cunningham^{26

28}, Débora P Maia²⁸, Maria F Lima-Costa²⁹, Eduardo Tarazona-Santos³⁰, Cyrus P Zabetian^{24

25}; International Parkinson Disease Genomics Consortium (IPDGC); Timothy A Thornton³¹, Timothy D O'Connor^{3

32

33

34}, Ignacio F Mata¹; Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD)

Affiliations

¹ Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
² The Parkinson's Foundation, Miami, Florida, USA.
³ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁴ Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, Maryland, USA.
⁶ University of South Carolina School of Medicine, Columbia, South Carolina, USA.
⁷ Division of Aging, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁸ Neurogenetics Working Group, Universidad Científica del Sur, Lima, Peru.
⁹ Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
¹⁰ Movement Disorders Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
¹¹ Departamento de Medicina Humana, Universidad Nacional Mayor de San Marcos, Lima, Peru.
¹² Universidad Nacional del Altiplano, Puno, Peru.
¹³ Neurology Institute, Universidad de la República, Montevideo, Uruguay.
¹⁴ Department of Genetics, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
¹⁵ Ribeirão Preto Medical School, Universidade de São Paulo, Ribeirão Preto, Brazil.
¹⁶ Movement Disorders Unit, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil.
¹⁷ Departamento de Neurologia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.
¹⁸ Serviço de Neurologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
¹⁹ Departamento de Farmacologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
²⁰ Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém, Brazil.
²¹ Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, Universidad de Antioquia, Medellín, Colombia.
²² CETRAM, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago, Chile.
²³ Neuroscience and Cell Death Research Groups, Medical School and Genetic Institute, Universidad Nacional de Colombia, Bogotá, Colombia.
²⁴ Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
²⁵ Department of Neurology, University of Washington, Seattle, Washington, USA.
²⁶ Behavioral and Cognitive Neurology Unit, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
²⁷ Geriatric Medicine, Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Brazil.
²⁸ Movement Disorders Unit, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
²⁹ Instituto René Rachou da Fundação Oswaldo Cruz, Belo Horizonte, Brazil.
³⁰ Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
³¹ Department of Biostatistics, University of Washington, Seattle, Washington, USA.
³² Program in Health Equity and Population Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
³³ Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
³⁴ Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

PMID: 37469269
PMCID: PMC10524402
DOI: 10.1002/mds.29508

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease

Thiago P Leal et al. Mov Disord. 2023 Sep.

. 2023 Sep;38(9):1625-1635.

doi: 10.1002/mds.29508. Epub 2023 Jul 20.

Authors

Affiliations

¹ Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
² The Parkinson's Foundation, Miami, Florida, USA.
³ Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁴ Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, Maryland, USA.
⁶ University of South Carolina School of Medicine, Columbia, South Carolina, USA.
⁷ Division of Aging, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁸ Neurogenetics Working Group, Universidad Científica del Sur, Lima, Peru.
⁹ Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
¹⁰ Movement Disorders Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.
¹¹ Departamento de Medicina Humana, Universidad Nacional Mayor de San Marcos, Lima, Peru.
¹² Universidad Nacional del Altiplano, Puno, Peru.
¹³ Neurology Institute, Universidad de la República, Montevideo, Uruguay.
¹⁴ Department of Genetics, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
¹⁵ Ribeirão Preto Medical School, Universidade de São Paulo, Ribeirão Preto, Brazil.
¹⁶ Movement Disorders Unit, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil.
¹⁷ Departamento de Neurologia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.
¹⁸ Serviço de Neurologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
¹⁹ Departamento de Farmacologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
²⁰ Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém, Brazil.
²¹ Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, Universidad de Antioquia, Medellín, Colombia.
²² CETRAM, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago, Chile.
²³ Neuroscience and Cell Death Research Groups, Medical School and Genetic Institute, Universidad Nacional de Colombia, Bogotá, Colombia.
²⁴ Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
²⁵ Department of Neurology, University of Washington, Seattle, Washington, USA.
²⁶ Behavioral and Cognitive Neurology Unit, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
²⁷ Geriatric Medicine, Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Brazil.
²⁸ Movement Disorders Unit, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
²⁹ Instituto René Rachou da Fundação Oswaldo Cruz, Belo Horizonte, Brazil.
³⁰ Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
³¹ Department of Biostatistics, University of Washington, Seattle, Washington, USA.
³² Program in Health Equity and Population Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.
³³ Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
³⁴ Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

PMID: 37469269
PMCID: PMC10524402
DOI: 10.1002/mds.29508

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. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; admixed populations; hipanic/latino; underrepresented populations; x-chromosome wide association study.

PubMed Disclaimer

Conflict of interest statement

Relevant conflicts of interest/financial disclosures: All authors declare that they have no conflicts of interest.

Figures

**FIG. 1.**
Results from X-chromosome–wide association study in LARGE-PD dataset for the discovery phase using LARGE-ALL (left) and LARGE-Meta (right). Each panel shows the Manhattan and Q-Q plot for Males (A, B), Females (C, D), Both (E, F), and Male+Female (G, H). The significance threshold was calculated based on the number of independent tests. Because we were not able to calculate the cutoff value for the LARGE-Meta, we opted to use the same cutoff value for the Both dataset.

See this image and copyright information in PMC

Update of

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson Disease.
Leal TP, French-Kwawu JN, Gouveia MH, Borda V, Inca-Martinez M, Mason EA, Horimoto AR, Loesch DP, Sarihan EI, Cornejo-Olivas MR, Torres LE, Mazzetti-Soler PE, Cosentino C, Sarapura-Castro EH, Rivera-Valdivia A, Medina AC, Dieguez EM, Raggio VE, Lescano A, Tumas V, Borges V, Ferraz HB, Rieder CR, Schumacher-Schuh A, Santos-Lobato BL, Velez-Pardo C, Jimenez-Del-Rio M, Lopera F, Moreno S, Chana-Cuevas P, Fernandez W, Arboleda G, Arboleda H, Arboleda Bustos CE, Yearout D, Lima-Costa MF, Tarazona E, Zabetian C, Thornton TA, O'Connor TD, Mata IF. Leal TP, et al. medRxiv [Preprint]. 2023 Feb 2:2023.01.31.23285199. doi: 10.1101/2023.01.31.23285199. medRxiv. 2023. Update in: Mov Disord. 2023 Sep;38(9):1625-1635. doi: 10.1002/mds.29508. PMID: 36778409 Free PMC article. Updated. Preprint.

Comment in

X-chromosome variants and PD in Latin America.
Wood H. Wood H. Nat Rev Neurol. 2023 Sep;19(9):508. doi: 10.1038/s41582-023-00861-8. Nat Rev Neurol. 2023. PMID: 37553389 No abstract available.

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X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease

Affiliations

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

Comment in

References

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Medical