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

Authors: Dmitry Prokopenko, Sarah L. Morgan, Kristina Mullin, Oliver Hofmann, Brad Chapman, Rory Kirchner, Sandeep Amberkar, Inken Wohlers, Christoph Lange, Winston Hide, Lars Bertram, Rudolph E. Tanzi


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.

Source: Alzheimer's & Dementia, 2021