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)
Naj A., Leonenko G., Jian X., Grenier-Boley B., Dalmasso MC., Bellenguez C., Sha J., Zhao Y., van der Lee S., Sims R., Chouraki V., Bis J., Kunkle B., Holmans P., Leung YY., Farrell J., Chesi A., Chen H-H., Vardarajan B., Benchek P., Barral S., Lee C-Y., Kuksa P., Haut J., Lee E., Li M., Zhang Y., Grant S., Phillips-Cremins J., Comic H., Pitsillides A., Xia R., Hamilton-Nelson K., Kuzma A., Valladares O., Fulton-Howard B., Dupuis J., Bush W., Wang L-S., Below J., Farrer L., van Duijn C., Mayeux R., Haines J., DeStefano A., Pericak-Vance M., Ramirez A., Seshadri S., Amouyel P., Williams J., Lambert J-C., Schellenberg G.
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.