The Role of X Chromosome in Alzheimer’s Disease Genetics

Abstract

AbstractImportanceThe X chromosome has remained enigmatic in Alzheimer’s disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.ObjectivesPerform the first large-scale X chromosome-wide association study (XWAS) of AD. Primary analyses are non-stratified, while secondary analyses evaluate sex-stratified effects.DesignMeta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer’s Disease Genetics Consortium (ADGC) and Alzheimer’s Disease Sequencing Project (ADSP), the UK Biobank (UKB), the Finnish health registry (FinnGen), and the US Million Veterans Program (MVP). Risk for AD evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024.SettingGenetic data available from high-density single-nucleotide polymorphism (SNP) microarrays and whole-genome sequencing (WGS). Summary statistics for multi-tissue expression and protein quantitative trait loci (QTL) available from published studies, enabling follow-up genetic colocalization analyses.Participants1,629,863 eligible participants were selected from referred and volunteer samples, of which 477,596 were excluded for analysis exclusion criteria. Number of participants who declined to participate in original studies was not available.Main Outcome and MeasuresRisk for AD (odds ratio; OR) with 95% confidence intervals (CI). Associations were considered at X-chromosome-wide (P-value<1e-5) and genome-wide (P-value<5e-8) significance.ResultsAnalyses included 1,152,284 non-Hispanic White European ancestry subjects (57.3% females), including 138,558 cases. 6 independent genetic loci passed X-chromosome-wide significance, with 4 showing support for causal links between the genetic signal for AD and expression of nearby genes in brain and non-brain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron ofSLC9A7(OR=1.054, 95%-CI=[1.035, 1.075]) and colocalization analyses prioritizing both theSLC9A7and nearbyCHST7genes.Conclusion and RelevanceWe performed the first large-scale XWAS of AD and identified the novelSLC9A7locus.SLC9A7regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid beta accumulation. Overall, this study significantly advances our knowledge of AD genetics and may provide novel biological drug targets.Key pointsQuestionDoes the X chromosome play a role in the genetics of Alzheimer’s Disease (AD)?FindingsIn a genetic meta-analysis across 1,152,284 individuals, several X chromosome loci were associated with AD. Four loci showed evidence of shared genetic associations between AD risk and regulation of nearby gene expression in brain tissue. The top association signal was intronic onSLC9A7and linked to its expression.MeaningWe performed the first large-scale X chromosome-wide association study of AD and prioritizedSLC9A7as a novel risk locus. This study significantly advances our knowledge of AD genetics and provides novel biological drug targets.