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

Thiago P. Leal, Shilpa C. Rao, Jennifer N. French-Kwawu, Mateus H. Gouveia, Victor Borda, Sara Bandres-Ciga, Miguel Inca-Martinez, Emily A. Mason, Andrea R.V.R. Horimoto, Douglas P. Loesch, Elif I. Sarihan, Mario R. Cornejo-Olivas, Luis E. Torres, Pilar E. Mazzetti-Soler, Carlos Cosentino, Elison H. Sarapura-Castro, Andrea Rivera-Valdivia, Angel C. Medina, Elena M. Dieguez, Víctor E. RaggioAndrés Lescano, Vitor Tumas, Vanderci Borges, Henrique B. Ferraz, Carlos R. Rieder, Artur Schumacher Schuh, Bruno L. Santos-Lobato, Carlos Velez-Pardo, Marlene Jimenez-Del-Rio, Francisco Lopera, Sonia Moreno, Pedro Chana-Cuevas, William Fernandez, Gonzalo Arboleda, Humberto Arboleda, Carlos E. Arboleda Bustos, Dora Yearout, Maira T. Barbosa, Francisco E.C. Cardoso, Paulo Caramelli, Mauro C.Q. Cunningham, Débora P. Maia, Maria F. Lima-Costa, Eduardo Tarazona-Santos, Cyrus P. Zabetian, Timothy A. Thornton, Timothy D. O'Connor, Ignacio F. Mata

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish
Pages (from-to)1625-1635
Number of pages11
JournalMovement Disorders
Volume38
Issue number9
DOIs
StatePublished - Sep 2023

Keywords

  • Parkinson's disease
  • admixed populations
  • hipanic/latino
  • underrepresented populations
  • x-chromosome wide association study

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