Analysis of 470,000 exome-sequenced UK Biobank participants identifies genes containing rare variants which confer dementia risk
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Background
Previous studies have reported that rare coding variants in a handful of genes have major effects on risk of Alzheimer’s disease (AD). A recent exome wide association study (ExWAS) of dementia in a subset of the UK Biobank cohort implicated a number of genes, including five which were novel. Here we report a similar analysis, carried out on the full cohort of 470,000 exome-sequenced participants.
Methods
A score was assigned to each participant depending on individual and/or parental diagnosis of dementia. Regression analysis including APOE ε3 and ε4 doses as covariates was applied to gene-wise tests for association with loss of function (LOF) and nonsynonymous variants. 45 tests using different pathogenicity predictors were applied to the first cohort of 200,000 participants. Subsequently the 100 genes showing strongest evidence for association were analysed in the second cohort of 270,000 participants, using only the best-performing predictor for each gene.
Results
Three genes achieved statistical significance, TREM2, SORL1 and ABCA7 . The five genes reported as novel in the ExWAS did not produce any appreciable evidence for association in this study. The effects and frequencies of variants in different functional categories were characterised for these genes.
Conclusions
Rare coding variants in a small number of genes have important effects on dementia risk. Further study of individual variant effects might elucidate mechanisms of pathogenesis. Incorporating rare variant effects for individual risk assessment might become important if preventative treatments for dementia become available.
