NEW YORK – By focusing on the X chromosome, a team from Washington University, Stanford University, and elsewhere has tracked down previously unappreciated contributors to Alzheimer's disease (AD) risk, including a locus in a SLC9A7 gene known for its role in Golgi secretory compartment pH homeostasis.
"Overall, this study advances our knowledge of AD genetics and may provide novel biological drug targets," corresponding author Michael Belloy from Washington University School of Medicine's NeuroGenomics and Informatics Center and his colleagues explained in JAMA Neurology on Monday, adding that "results obtained in the current study should serve as an anchor point for future X chromosome studies in AD."
After bringing together genotyping array or whole-genome sequencing data for participants from several prior population studies conducted in the US and Europe, longitudinal cohorts, family-based groups, and case-control analyses, the team performed an X chromosome-wide association meta-analysis involving nearly 1.2 million individuals, including 138,558 AD cases.
"[T]here have been recent initial successes with large X chromosome-wide association studies (XWASs) in cardiovascular disease, kidney disease, and Parkinson disease, as well as other complex traits and brain imaging measures, revealing both sex-dependent and -independent associations," the authors explained. "Yet, to our knowledge, no such XWAS has been conducted in AD, despite the X chromosome carrying a high proportion of genes that are expressed in the brain and relevant to intellectual disabilities."
Half a dozen genetic loci showed X chromosome-wide significant ties to AD, and by incorporating summary statistic data from past studies looking at gene expression and protein quantitative trait locus profiles across multiple tissue types, the researchers highlighted four AD-linked loci that appeared to coincide with the expression of neighboring genes in brain tissue or in tissues found in other parts of the body.
Based on the combined association, quantitative trait loci, and co-localization clues, the team went on to focus in on an apparent risk variant in an SLC9A7 intron that seems to influence the expression of that pH homeostasis-related gene.
Given the gene's expected influence on the environment in the Golgi secretory compartment and endosome, the investigators speculated that it may impact the AD-related accumulation of amyloid beta as individuals age — a notion backed up by a 2021 study in the journal eLife that linked a related gene called SLC9A6/NHE6 to AD trajectory and the formation of amyloid plaque deposits.
"Notably, SLC9A7 (also known as NHE7) is a paralog of SLC9A6 (also known as NHE6), previously implicated in experimental work as an X-linked AD-modifying gene," the authors reported, adding that SLC9A7 and SLC9A6 "are highly conserved genes that regulate pH homeostasis in Golgi secretory compartments and endosomes and might thus be expected to contribute to increased amyloid accumulation across aging when their expression levels are increased."
In a related editorial in JAMA Neurology, Brigham and Women's Hospital's Mabel Seto and Rachel Buckley noted that results of the new study "pave the way for several future research directions."
"Expanding studies to include even more diverse populations and age ranges will help validate and extend the current findings," Seto and Buckley explained, adding that future analyses on X-linked AD risk variants with potential ties to AD treatment or early diagnoses "could lead to significant advancements in AD treatment and prevention."