In:
Nature Genetics, Springer Science and Business Media LLC, Vol. 54, No. 12 ( 2022-12), p. 1786-1794
Abstract:
Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70% 1 . The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants 2 . Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2 , SORL1 and ABCA7 , we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10 . Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.
Type of Medium:
Online Resource
ISSN:
1061-4036
,
1546-1718
DOI:
10.1038/s41588-022-01208-7
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2022
detail.hit.zdb_id:
1494946-5
SSG:
12
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