STANFORD, CA — The X chromosome makes up 5% of the human genome and carries a high proportion of genes expressed in the brain. Yet, it is a relatively unexplored as a potential source of genetic variation in AD, according to a new study.
In response, Stanford University-led researchers performed the first large-scale X chromosome-wide association study (XWAS) of AD. Among the institutions participating were the National Center for PTSD, Behavioral Sciences Division at the VA Boston Healthcare System and the Center of Excellence for Stress and Mental Health at the VA San Diego Healthcare System.
The meta-analysis published in JAMA Neurology included genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the U.S. Alzheimer’s Disease Genetics Consortium, the Alzheimer’s Disease Sequencing Project, the UK Biobank, the Finnish health registry and the VA’s Million Veterans Program.1
The study team evaluated risk of AD through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Included were genetic data available from high-density single-nucleotide variant microarrays and whole-genome sequencing, as well as summary statistics for multi-tissue expression and protein quantitative trait loci, available from published studies. That enabled follow-up genetic colocalization analyses.
The researchers selected about 1.6 million eligible participants from referred and volunteer samples, 477,596 of whom were excluded for analysis exclusion criteria. Risk of AD was reported as odds ratios (ORs) with 95% CIs. Associations were considered at X chromosome-wide (P < 1 × 10-5) and genome-wide (P < 5 × 10-8) significance. Primary analyses are nonstratified, while secondary analyses evaluate sex-stratified effects.
The analyses included nearly 1.6 million participants of non-Hispanic white, European ancestry, 57.5% female; 138,558 of them had AD. Results indicated that 6 independent genetic loci passed X chromosome-wide significance, with 4 showing support for 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 of SLC9A7 (OR, 1.03; 95% CI, 1.02-1.04) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes,” the authors explained. “Of these 6 loci, 4 displayed evidence for escape from X chromosome inactivation with regard to AD risk.”
The report pointed out that the large-scale XWAS of AD identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid β accumulation.
“Overall, this study advances our knowledge of AD genetics and may provide novel biological drug targets,” the authors concluded. “The results further provide initial insights into elucidating the role of the X chromosome in sex-based differences in AD.”
- Belloy ME, Le Guen Y, Stewart I, Williams K, et. Al. Role of the X Chromosome in Alzheimer Disease Genetics. JAMA Neurol. 2024 Sep 9:e242843. doi: 10.1001/jamaneurol.2024.2843. Epub ahead of print. PMID: 39250132; PMCID: PMC11385320.