Alzheimer's disease

Exome

Receptor

Genome-wide association study

Disease

Bioinformatics

Biology

Gene

Genetic association

Genotype

TREM2

Mutation

Loss function

Internal medicine

Phenotype

Exome sequencing

Dementia

Myeloid cells

Single-nucleotide polymorphism

Genetics

Medicine

Nature Genetics

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.

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease