Genome-Wide Meta-Analysis of Late-Onset Alzheimer's Disease Using Rare Variant Imputation in 324,809 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer's Project (IGAP)
Adam C Naj,
Maria Carolina Dalmasso,
Sven J. van der Lee,
Brian W. Kunkle,
Yuk Yee Leung,
John J Farrell,
Badri N. Vardarajan,
Pavel P. Kuksa,
Jennifer E. Phillips-Cremins,
Kara L Hamilton-Nelson,
William S Bush,
Li San Wang,
Jennifer E Below,
Cornelia van Duijn,
Jonathan L. Haines,
Anita L. DeStefano,
Margaret A. Pericak-Vance,
The International Genomics of Alzheimer's Project
Posted 24 Mar 2021
medRxiv DOI: 10.1101/2021.03.14.21253553
Posted 24 Mar 2021
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 were 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=2.33x10-12), SHARPIN (P=1.56x10-9), and ATF5/SIGLEC11 (P=1.03[mult]10-8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80x10-8), APH1B (P=2.10x10-13), and CLNK (P=2.24x10-10). 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=2.69x10-9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17x10-13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.
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