Whole-genome sequencing reveals new Alzheimer's disease–associated rare variants in loci related to synaptic function and neuronal development

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Abstract

Introduction: Genome-wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole-genome sequencing (WGS) now permits genome-wide analyses to identify rare variants contributing to AD risk. Methods: We performed single-variant and spatial clustering–based testing on rare variants (minor allele frequency [MAF] ≤1%) in a family-based WGS-based association study of 2247 subjects from 605 multiplex AD families, followed by replication in 1669 unrelated individuals. Results: We identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2. Discussion: Downstream analyses of these novel loci highlight synaptic function, in contrast to common AD-associated variants, which implicate innate immunity and amyloid processing. These loci have not been associated previously with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of the exome.

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Prokopenko, D., Morgan, S. L., Mullin, K., Hofmann, O., Chapman, B., Kirchner, R., … Tanzi, R. E. (2021). Whole-genome sequencing reveals new Alzheimer’s disease–associated rare variants in loci related to synaptic function and neuronal development. Alzheimer’s and Dementia, 17(9), 1509–1527. https://doi.org/10.1002/alz.12319

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