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

Leal T.P.; Rao S.C.; French-Kwawu J.N.; Gouveia M.H.; Borda V.; Bandres-Ciga S.; Inca-Martinez M.; Mason E.A.; Horimoto A.R.V.R.; Loesch D.P.; Sarihan E.I.; Cornejo-Olivas M.R.; Torres L.E.; Mazzetti-Soler P.E.; Cosentino C.; Sarapura-Castro E.H.; Rivera-Valdivia A.; Medina A.C.; Dieguez E.M.; Raggio V.E.; Lescano A.; Tumas V.; Borges V.; Ferraz H.B.; Rieder C.R.; Schumacher Schuh A.; Santos-Lobato B.L.; Velez-Pardo C.; Jimenez-Del-Rio M.; Lopera F.; Moreno S.; Chana-Cuevas P.; Fernandez W.; Arboleda G.; Arboleda H.; Arboleda Bustos C.E.; Yearout D.; Barbosa M.T.; Cardoso F.E.C.; Caramelli P.; Cunningham M.C.Q.; Maia D.P.; Lima-Costa M.F.; Tarazona-Santos E.; Zabetian C.P.; Thornton T.A.; O'Connor T.D.; Mata I.F. · Movement Disorders (2023) · DOI: 10.1002/mds.29508

Resumen

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.

Instituciones: Universidad Nacional Mayor de San Marcos; Universidad Científica del Sur; Universidad Nacional del Altiplano