X-chromosome-wide association study for Alzheimer’s disease.

The IANEC has participated in this important international study to understand the role of the X chromosome on Alzheimer’s disease (AD).

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on AD. To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

In conclusion, this XWAS found no common genetic risk factor for AD on the non-pseudoautosomal region of the X-chromosome but identified suggestive signals with moderate impact on AD risk, which warrant further investigations. In particular, future analyses of sequencing data will help to address some of the technical issues described above, and will allow to study the impact of X-chromosome rare variants or structural variants on AD risk.

Additionally, extending XWAS to AD-related phenotypes, such asognitive decline, AD pathology or AD biomarkers, would further delineate the impact of X-chromosome genetic variations on the processes leading to AD. Lastly, insights into the contribution of the X-chromosome to AD or AD-related phenotypes will be provided by additional studies of the impact of X-chromosome biology beyond genetic variations, for example gene expression or epigenetic alterations, including parental imprinting.

Further information:

https://www.nature.com/articles/s41380-024-02838-5