Role of the X Chromosome in Alzheimer Disease Genetics

作者：Michaël E. Belloy, Yann Le Guen, Ilaria Stewart, Kennedy Williams, Joachim Herz, Richard Sherva, Rui Zhang, Victoria C. Merritt, Matthew S. Panizzon, Richard L. Hauger, J. Michael Gaziano, Mark W. Logue, Valerio Napolioni, Michael D. Greicius · 发表于：JAMA Neurology · 年份：2024 · DOI：10.1001/jamaneurol.2024.2843 · 被引用次数：28 · 研究领域：Genetic Associations and Epidemiology、Alzheimer's disease research and treatments、Dementia and Cognitive Impairment Research

Importance: The X chromosome has remained enigmatic in Alzheimer 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. Objectives: To perform the first large-scale X chromosome-wide association study (XWAS) of AD. Design, Setting, and Participants: This was a meta-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, the Alzheimer's Disease Sequencing Project, the UK Biobank, the Finnish health registry, and the US Million Veterans Program. Risk of AD was evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Genetic data available from high-density single-nucleotide variant microarrays and whole-genome sequencing and summary statistics for multitissue expression and protein quantitative trait loci available from published studies were included, enabling follow-up genetic colocalization analyses. A total of 1 629 863 eligible participants were selected from referred and volunteer samples, 477 596 of whom were excluded for analysis exclusion criteria. The number of participants who declined to participate in original studies was not available. Main Outcome and Measures: Risk of AD, reported as odds ratios (ORs) with 95% CIs. Associations were cons...