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

Abstract

BackgroundSex 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.ObjectiveThe objective of this study was to perform the first X‐chromosome–wide association study for PD risk in a Latin American cohort.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.

Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci

“…We estimated the number of haplotype blocks on the X chromosome to be 6296 in the LBD cohort (Supplementary Figure). Based on this, the Bonferroni threshold for significance was set to 7.94 × 10 −6 (=0.05/6296), as is the standard for XWAS 17 .…”

“…Genetic associations for neurodegenerative diseases differ across ethnic and racial groups 52 , and female sex has been associated with a higher LBD risk in people identifying as African American or Hispanic 53 . The future availability of diverse cohorts of people affected by Lewy body disorders, together with new frameworks for analyzing admixed populations 17 , will allow a better understanding of the genetic underpinnings of this disease spectrum.…”

Comparing the effect of imputation reference panel composition in four distinct Latin American cohorts

“…The X chromosome was limited to the non-pseudoautosomal region. We followed data cleaning steps outlined in XWAS [41,42] , which includes removing any individuals failing a sex check (on LD pruned data), and SNPs with different missingness or MAF between males and females. Finally, we filtered SNPs to exclude those with a MAC ≤ 1, missingness greater than 5%, and SNPs with a HWE test p-value < 1×10 -6 using plink 2.0 [32] .…”

Levodopa-induced dyskinesia: interplay between the N-methyl-D-aspartic acid receptor and neuroinflammation

“…As populations are aging, the global numbers of people with PD are increasing, placing a heavy financial and emotional burden on individuals, families, and society at large ( 30 , 31 ). L-DOPA is currently recognized as a drug that offers good symptom control in patients with PD, but most patients will develop LID after long-term application, with mechanisms that are complex and not yet understood.…”