Protective variant for hippocampal atrophy identified by whole exome sequencing

Abstract

We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets.

FIGURE

Association of whole-exome sequencing–identified variant rs3796529 in a larger sample of 315 Alzheimer’s Disease Neuroimaging Initiative Phase 1 subjects by surface-based analysis (SurfStat) of cortical thickness at baseline. Statistical maps of SurfStat were thresholded using random field theory (RFT) correction with a corrected significance level of 0.05. Left hemisphere is shown on the left and P is the RFT-corrected p-value.