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

Sex differences in Parkinson Disease (PD) risk are well-known. However, it is still unclear the role of sex chromosomes in the development and progression of PD. We performed the first X-chromosome Wide Association Study (XWAS) for PD risk in Latin American individuals. We used data from three admixed cohorts: (i) Latin American Research consortium on the GEnetics of Parkinson’s Disease (n=1,504) as discover cohort and (ii) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (iii) Bambui Aging cohort (n= 1,442) as replication cohorts. After developing a X-chromosome framework specifically designed for admixed populations, we identified eight linkage disequilibrium regions associated with PD. We fully replicated one of these regions (top variant rs525496; discovery OR [95%CI]: 0.60 [0.478 - 0.77], p = 3.13 × 10-5 ; replication OR: 0.60 [0.37-0.98], p = 0.04). rs525496 is an expression quantitative trait loci for several genes expressed in brain tissues, including RAB9B, H2BFM, TSMB15B and GLRA4 . We also replicated a previous XWAS finding (rs28602900), showing that this variant is associated with PD in non-European populations. Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement TPL was supported by the National Institutes of Health Grant R01 1R01NS112499 01A1. JNFK was supported by Research Training in the Epidemiology of Aging funded by the National Institute on Aging under Award Number T32 AG000262. MHG was supported by the Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health (NIH) through the Center for Research on Genomics and Global Health (CRGGH). CVP and MJDR were supported by The Committee for Development and Research (Comite para el desarrollo y la investigacion CODI) Universidad de Antioquia grant #2020 31455 TDO was supported by National Human Genome Research Institute of the National Institutes of Health under Award Number R35HG010692. DPL was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number T32HL007698 ETS was supported by FAPEMIG (Fundacao de Amparo a Pesquisa do Estado de Minas Gerais) RED 00314 16; Programa Nacional de Genomica e Saude de Precisao Genomas Brasil from the Brazilian Ministry of Health; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico CNPq CPZ was supported by International Research Grants Program award from the Parkinson s Foundation IFM was supported by Stanley Fahn Junior Faculty Award, an International Research Grants Program award from the Parkinson s Foundation, by a research grant from the American Parkinson s Disease Association, National Institutes of Health Grant R01 1R01NS112499 01A1, Michael J. Fox Foundation, ASAP GP2, and with resources and the use of facilities at the Veterans Affairs Puget Sound Health Care System. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Cleveland Clinic gave ethical approval for this work (IRB number is 19 340) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors