By Lucy Piper, medwireNews Reporter
medwireNews: SLC9A7 on the X chromosome has been pinpointed as a novel risk locus for Alzheimer’s disease (AD) in a genetic meta-analysis of over 1.15 million individuals.
“SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid β accumulation”, explain Michael Belloy (Washington University of Medicine, St Louis, Missouri, USA) and colleagues in JAMA Neurology.
They say that the “results provide initial insights into the role of the X chromosome in sex-related differences in AD prevalence and pathogenesis.”
For the chromosome-wide association study, the researchers analysed single-nucleotide microarrays and whole-genome sequencing data for 1,152,284 participants of non-Hispanic White, European ancestry, 57.7% of whom were women.
The participants were identified from case–control, family-based, and longitudinal AD genetic cohorts in 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.
AD was diagnosed in 138,558 patients, either clinically (n=15,081) or health registry (n=41,091) confirmed, and 82,386 were proxy cases, meaning they had a first-degree relative with AD or dementia.
The researchers found six independent gene loci that met X chromosome-wide significance for an association with AD risk (p<1 x 10–5). Two of these loci – NLGN4X and MID1 – were rare (minor allele frequency <1%). The remaining four loci – SLC9A7, ZNF28OC, ADGRG4, and MTM1 – were common and all showed colocalization for at least one nearby gene in brain tissue.
The strongest genetic signal for AD risk was intronic on SLC9A7, at a significant odds ratio of 1.03. This was linked to the expression of several genes in the brain tissue, most notably SLC9A7 and CHST7, the latter of which “may relate to promoting tau fibrillization and spreading,” the investigators propose.
They add that as the lead variant only had a small effect on AD risk and increased expression of SLC9A7 in the brain by just 8–22%, “more substantial reduction or pharmacological inhibition of SLC9A7 would prove to be an effective therapeutic strategy for AD.
In sensitivity analyses excluding data for proxy cases of AD, SLC9A7 again met X chromosome–wide significance for AD risk, alongside MTM1 loci. Further stratification according to sex, showed these two loci met X chromosome-wide significance in men and women, respectively.
Belloy et al also found that escape from random X chromosome inactivation, which occurs in one of the two X chromosomes in the cells of women to balance gene expression relative to men, did not occur for the SLC9A7 and MTM1 lead variants, but it did for NLGN4X, MIF1, ZNF280C and ARGRG4.
This finding may relate to “observations such as women appearing to show increased AD incidence at advanced ages and increased tau burden in the AD pathologic trajectory”, the team explains.
They add: “It may also be that these loci are relevant to resilience to AD rather than AD directly, such that they may relate to women appearing to survive longer with AD […], having more preserved brain structure despite elevated tau burden, and higher baseline cognitive reserve but reduced coping with AD pathology and more rapid cognitive decline across aging and AD.”
There was also evidence of a significant female-biased heterogeneity effect with the MID1 locus lead variant, which may indicate a hormone-related effect, the investigators note.
They conclude: “Altogether, these results suggest that X chromosome genetics likely play a role in AD sex differences and warrant further investigation, opening the door to sex-specific pathogenic pathways and associated drug targets.”
Commenting on the findings in a related editorial, Rachel Buckley and Mabel Seto, both from Brigham and Women’s Hospital in Boston, Massachusetts, USA, say that the “valuable work” of Belloy and co-workers will “pave the way for several future research directions.”
An important one will be “elucidating the synergistic role of APOEɛ4 and the X [chromosome],” to understand “why APOEɛ4 carriership exacerbates the risk for AD in women relative to men”, they highlight.
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JAMA Neurol 2024; doi:10.1001/jamaneurol.2024.2843
JAMA Neurol 2024; doi:10.1001/jamaneurol.2024.2831