Research shows the X chromosome has stayed mysterious in Alzheimer’s disease (AD). Yet it forms 5% of the genome and holds many genes that work in the brain. This makes it quite interesting as a possible source of unexplored genetic changes in AD.
Recent XWASs (large X chromosome–wide association studies) have shown promising results in cardiovascular disease, kidney disease, and Parkinson disease. These studies also revealed connections with other complex traits and brain imaging measures showing both sex-dependent and -independent links.
However, to our knowledge, no one has conducted such an XWAS for AD. This is interesting as X chromosomes possess a higher percentage of genes that show up in the brain and play a role in disabilities related to intellect.
This meta-analysis looked at genetic association studies in AD-related groups from several sources: 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. This group includes family-based, population based, case-control and long term based studies. Where they analysed the data for more than a year from Jan 2023 to March 2024.
This particular study included genetic data from a nucleotide variant microarrays and entire genome sequencing studies. Out of all 1,629,863 participants form the referred samples only 477,596 were left out due to the analysis exclusion criteria.
This study adhered to the Strengthening the Reporting of Genetic Association Studies reporting guideline. Participants or their caregivers gave written informed consent in the original studies.
Stanford University’s institutional review board exempted this study’s protocol. The board made this decision because the researchers analysed de-identified, off-the-shelf data. As a result, the study didn’t need additional informed consent.
Six separate genetic spots on the X chromosome showed strong links to Alzheimer’s disease (AD). Four of these spots had ties between AD genes and how nearby genes work in the brain and other tissues. One of these four spots stood out as important. Its main gene change was in SLC9A7 (odds ratio: 1.03; 95% confidence interval: 1.02-1.04).
More tests pointed to both SLC9A7 and CHST7 genes as key players. Four of the six spots seemed to avoid X chromosome shutdown, which affects AD risk.
This study helps us understand AD genetics better and might lead to new drug targets. It also starts to explain how the X chromosome plays a part in why AD affects men and women
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