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

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.