Journal
ALZHEIMERS & DEMENTIA
Volume 17, Issue 9, Pages 1509-1527Publisher
WILEY
DOI: 10.1002/alz.12319
Keywords
Alzheimer' s disease; family‐ based association study; LOAD; neuronal development; rare variants; RVAS; synaptic function; whole‐ genome sequencing
Categories
Funding
- Cure Alzheimer's Fund
- National Institute for Health Research (NIHR) Sheffield Biomedical Research Centre (Translational Neuroscience)/NIHR Sheffield Clinical Research Facility
- Cure Alzheimer's Fund (Alzheimer's Disease Research Foundation)
- Boston University [P50AG08702]
- Columbia University [P50AG08702]
- Duke University [P30AG028377]
- Indiana University [P30AG010133]
- Massachusetts General Hospital [PO1 AG05138]
- Mayo Clinic, Rochester [PO1 AG05138]
- Mayo Clinic, Jacksonville [PO1 AG05138]
- Mount Sinai School of Medicine [PO1 AG05138]
- Northwestern University Medical School [P30AG010124]
- Oregon Health and Science University [P30AG010124]
- Rush University Medical Center [P30AG010124]
- University of Alabama at Birmingham [P30AG010124]
- David Geffen School of Medicine, University of California, Los Angeles [P30AG010124]
- University of Kentucky, Lexington [P30AG010124]
- University of Pennsylvania [P30AG010124]
- University of Pittsburgh [P30AG010124]
- University of Southern California [P30AG010124]
- University of Texas Southwestern Medical Center [P30AG010124]
- University of Washington [P30AG010124]
- Washington University School of Medicine [P30AG010124]
- [U24AG026395]
- [U24AG021886]
Ask authors/readers for more resources
Thirteen new candidate loci for AD were identified through rare variant analysis, highlighting synaptic function as a potential novel pathway for the disease.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available