Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

Risk for late-onset Alzheimer’s disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)> 0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimer’s Project (IGAP). Existing genotype data was imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P <10 −5 were meta-analyzed with the European Alzheimer’s Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF≥0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 ( P =2.33×10 −12 ), SHARPIN ( P =1.56×10 −9 ), and ATF5/SIGLEC11 ( P =1.03×10 −8 ), and newly significant associations without using AD proxy cases in MTSS1L/IL34 ( P =1.80×10 −8 ), APH1B ( P =2.10×10 −13 ), and CLNK ( P =2.24×10 −10 ). Rare variant (MAF<0.01) associations with genome-wide significance in stage 2 included multiple variants in APOE and TREM2 , and a novel association of a rare variant (rs143080277; MAF=0.0054; P =2.69×10 −9 ) in NCK2 , further strengthened with the inclusion of UKBB data in stage 3 ( P =7.17×10 −13 ). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.