Chromosome X-wide association study in case control studies of pathologically confirmed Alzheimer’s disease in a European population

Simmonds, Emily, Leonenko, Ganna ORCID: https://orcid.org/0000-0001-8025-661X, Yaman, Umran, Bellou, Eftychia, Myers, Amanda, Morgan, Kevin, Brookes, Keeley, Hardy, John, Salih, Dervis and Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483 2024. Chromosome X-wide association study in case control studies of pathologically confirmed Alzheimer’s disease in a European population. Translational Psychiatry 14 (1) , 358. 10.1038/s41398-024-03058-9

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Abstract

Although there are several genome-wide association studies available which highlight genetic variants associated with Alzheimer’s disease (AD), often the X chromosome is excluded from the analysis. We conducted an X-chromosome-wide association study (XWAS) in three independent studies with a pathologically confirmed phenotype (total 1970 cases and 1113 controls). The XWAS was performed in males and females separately, and these results were then meta-analysed. Four suggestively associated genes were identified which may be of potential interest for further study in AD, these are DDX53 (rs12006935, OR = 0.52, p = 6.9e-05), IL1RAPL1 (rs6628450, OR = 0.36, p = 4.2e-05; rs137983810, OR = 0.52, p = 0.0003), TBX22 (rs5913102, OR = 0.74, p = 0.0003) and SH3BGRL (rs186553004, OR = 0.35, p = 0.0005; rs113157993, OR = 0.52, p = 0.0003), which replicate across at least two studies. The SNP rs5913102 in TBX22 achieves chromosome-wide significance in meta-analysed data. DDX53 shows highest expression in astrocytes, IL1RAPL1 is most highly expressed in oligodendrocytes and neurons and SH3BGRL is most highly expressed in microglia. We have also identified SNPs in the NXF5 gene at chromosome-wide significance in females (rs5944989, OR = 0.62, p = 1.1e-05) but not in males (p = 0.83). The discovery of relevant AD associated genes on the X chromosome may identify AD risk differences and similarities based on sex and lead to the development of sex-stratified therapeutics.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Springer Nature [academic journals on nature.com]
Date of First Compliant Deposit:	5 September 2024
Date of Acceptance:	22 August 2024
Last Modified:	03 Oct 2024 14:23
URI:	https://orca.cardiff.ac.uk/id/eprint/171830

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