CHROMOSOME X-WIDE ASSOCIATION STUDY IDENTIFIES A NEW LOCUS FOR LATE-ONSET ALZHEIMER’S DISEASE ON XQ25

Abstract

Despite the collective evidence pointing to a possible role for X-linked genes, no association study has clearly addressed their contribution to Alzheimer's Disease (AD) or AD-related biomarkers. We aim to perform the first comprehensive X chromosome-wide association study (XWAS) of late-onset AD. We performed an XWA mega-analysis by combining 12987 Northwestern Europeans (NWE) from thirteen independent datasets, followed by replication using a cohort of 531 Southeastern Europeans (SEE). All the subjects analyzed belong to datasets included in the Stage 1 subset of the Alzheimer's Disease Genetics Consortium, which has been described in previous studies. The datasets were accessed via dbGAP and NIAGADS and independently quality controlled using X-chromosome specific procedures implemented in XWAS 1.1. X-chromosome imputation was performed using the Haplotype Reference Consortium r1.1. panel. XWA testing was carried out by logistic regression in males and females, separately, and the results were combined using the Stouffer's method implemented in XWAS 1.1. Gene-based analysis was performed using VEGAS2 software. In the XWA mega-analysis, we identified two novel loci reaching genome-wide significance threshold (rs112930037, near DCAF12L2, MAF=0.20, P=1.8x10-10; rs147122766, in the premature ovarian failure critical region, MAF=0.26, P=1.5x10-9). The top XWAS-hit rs112930037, near DCAF12L2, was successfully replicated in the SEE cohort (P=0.018). rs112930037 increases risk for LOAD in both males and in females (males OR=1.216, P=0.011; females OR=1.314, P=6.0x10-10). Gene-based analysis failed to reveal genes associated with LOAD. Our study reveals the existence of an X-linked locus for LOAD on Xq25 DCAF12L2, which is one of the only two known retrogenes on the X chromosome and widely expressed in the brain. The parent gene DCAF12, located on 9p13.3 (a frontotemporal dementia linkage region), encodes a WD repeat-containing protein that interacts with the COP9 signalosome. Recent studies reveal that members of the COP9 signalosome were associated with several neurological disorders, including AD. By interacting with its parent gene DCAF12L2 may influence COP9 signalosome activity, thereby playing a role in dendritic morphogenesis as previously described in the Drosophila literature. Further studies will address the functional impact of genetic variation at the Xq25 locus in influencing susceptibility to LOAD. Two novel X-linked loci reach genome-wide significance in the Northwestern European cohort. The solid red line indicates the threshold for genome-wide significance (P < 5 x 10-8), and the blue line represents the threshold for suggestive hits (P < 1 x 10-5). XWAS top hit rs112930037 is located near DCAF12L2. The solid diamond represents the top ranked SNP in the region, based on two-sided P values. Pairwise correlation (r2) between the top SNP and the other SNPs in the region is indicated by color.