X-Chromosome-wide association study for Alzheimer’s disease

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To finally 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 four X-chromosome-wide significant loci (P ≤ 1.7 × 10 −6 ). Two signals locate in the FRMPD4 and DMD genes, while the two others are more than 300 kb away from the closest protein coding genes NLGN4X and GRIA3 . Overall, this XWAS found no common genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.