Common X‐Chromosome Variants Are Associated with Parkinson Disease Risk

Abstract

The objective of this study was to identify genetic variants on the X-chromosome associated with Parkinson disease (PD) risk. Methods: We performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the Xchromosome and focused on a European ancestry sample. We included 11,142 cases, 280,164 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with (1) PD risk in an independent replication with 1,561 cases and 2,465 controls and (2) putamen volume in 33,360 individuals from the UK Biobank. Results: In the discovery meta-analysis, we identified rs7066890 (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, p = 2.2 × 10 −9 ), intron of GPM6B, and rs28602900 (OR = 1.10, 95% CI = 1.07-1.14, p = 1.6 × 10 −8 ) in a high gene density region including RPL10, ATP6A1, FAM50A, and PLXNA3. The rs28602900 association with PD was replicated (OR = 1.16, 95% CI = 1.03-1.30, p = 0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in the Genotype-Tissue Expression Project. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses. Interpretation: We report the first XWAS of PD and identify 2 genome-wide significant loci. The rs28602900 association was replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10. These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk.

Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease

“…There are reports stating that certain Y chromosome genes show male-specific effects for potential dopaminergic loss. 29 Besides the differences in sex chromosomes in men and women, there are several other differences not directly assessed here that may likely contribute to sex differences in PD, including (1) differences in gene expression in cells and tissues on both autosomes and sex chromosomes, 30,31 (2) hormone production, and (3) the environment ) is observed between effect sizes from the male and female specific GWAS. Additional details can be found in Supplementary Table S2.…”

Exploring Uncharted Territory: Genetically Determined Sex Differences in Parkinson's Disease

“…Providing support to this observation, the same SNP was found to be associated with reduced brain volume of the putamen in UK Biobank data. Thus, with their results of the first XWAS in PD, Le Guen et al 18 present the first piece of the puzzle in genetic determination of sex differences in PD. Following up on their work, further XWAS might tease out additional effects by considering population stratification that is specific to the X chromosome, sex-specific imputation and quality control, and a wider spectrum of statistical tests that also allow (skewed) inactivation in females to be taken into account.…”

“…With their 2 studies on genetic sex differences in PD, Le Guen et al 18 and Blauwendraat et al 19 have pioneered an important area of PD research worthy of further exploration and extension to the investigation of related, currently unexplained observations, such as why the clinical presentation of PD differs in men and women 22 or why differences in the prevalence of PD between men and women increase even further with advancing age. 23 FIGURE 2: Agreement plot, according to Bland & Altman, 21 of effect sizes in males and females at 85 single nucleotide polymorphisms with genome-wide significance, as provided by Blauwendraat et al 19 (their supplementary table 2).…”

“…The present issue of the Annals of Neurology contains the first 2 studies devoted to sex-specific genetic risk factors for PD. The first study, by Le Guen et al, 18 focuses on the potential X-chromosomal contribution, hence based on the second model mentioned above, whereas the second study, by Blauwendraat et al, 19 explores possible autosomal risk factors, hence assuming models 1 and 3 (Fig 1).…”

“…It has also been attributed extraribosomal functions, for example in differentiation and development or signal transduction, and mutations in RPL10 cause an inherited developmental disorder grouped under the ribosomopathies. 20 Intriguingly, Le Guen et al 18 showed a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues. Providing support to this observation, the same SNP was found to be associated with reduced brain volume of the putamen in UK Biobank data.…”