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

Alzheimers Dement. 2021 Sep;17(9):1509-1527. doi: 10.1002/alz.12319. Epub 2021 Apr 2.


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.

Keywords: Alzheimer's disease; LOAD; RVAS; family-based association study; neuronal development; rare variants; synaptic function; whole-genome sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Gene Frequency / genetics*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Ion Channels / genetics
  • Kinesins / genetics
  • Membrane Proteins / genetics
  • Microtubule-Associated Proteins / genetics
  • Proteins / genetics
  • Whole Genome Sequencing*


  • C2cd3 protein, human
  • Ion Channels
  • KIF2A protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • NALCN protein, human
  • Proteins
  • SEL1L protein, human
  • Kinesins