Variants near X‐Chromosome Genes NLGN4X and PTCHD1 are Significantly Associated with Alzheimer’s Disease Risk

Abstract Background Genome‐wide association studies (GWAS) for AD have identified numerous associated loci but have been focused only on the autosomes. We sought to identify novel AD‐associated genes on X‐Chromosome (X‐Chr). Method We evaluated the association of AD with X‐Chr variants in GWAS datasets assembled by the Alzheimer Disease Genetics Consortium including 26,322 non‐Hispanic White (NHW) individuals using logistic regression models with covariates for age, sex and principal components of ancestry. The number of independent SNPs in X‐Chr was calculated by linkage disequilibrium pruning yielding a study‐wide significance threshold of P<7.58×10 −7 . Genes near SNPs surpassing this threshold were further evaluated by expression quantitative trait locus (eQTL) in the BRAINEAC database and differential gene expression analyses using RNA‐seq data obtained from autopsied brains contained (GEO: GSE44772 and GSE33000). We also tested association of AD with missense or splicing variants with minor allele count (MAC)≥10 in the same genes using GENESIS and whole exome sequencing (WES) data obtained by the Alzheimer Disease Sequencing Project (ADSP) for 11,172 NHWs. Result We identified novel associations with variants near NLGN4X (rs34056759; minor allele frequency [MAF] = 0.15, OR = 1.15, P = 5.14×10 −7 ) and PTCHD1 (rs5970663; MAF = 0.30, OR = 1.13, P = 8.26×10 −7 ). The rs5970663 risk allele C was significantly associated with increased expression of PTCHD1 in the medulla region, and PTCHD1 expression was significantly higher in AD cases than in controls in the prefrontal cortex (P<2.1×10 −8 ) and visual cortex (P<2.3×10 −4 ). Rs34056759 was not associated with NLGN4X expression, but NLGN4X expression was significantly lower in AD cases compared to controls in the prefrontal cortex (P<8.7×10 −7 ). A rare PTCHD1 variant (rs201933353; MAF = 0.001) was nominally associated with AD among 6,318 women (OR = 3.72, P = 0.06). Conclusion We identified novel associations of AD with X‐Chr variants near NLGN4X and PTCHD1, loci that were previously associated with autism spectrum disorder. We plan to replicate, fine‐map, and annotate the candidate loci identified in this study using large whole genome sequencing ADSP datasets.