Frequency of variants in Mendelian Alzheimer's disease genes within the Alzheimer's Disease Sequencing Project

BackgroundPrior studies examined variants within presenilin-2 (<i>PSEN2</i>), presenilin-1 (<i>PSEN1</i>), and amyloid precursor protein (<i>APP</i>) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer's Disease Sequencing Project (ADSP).ObjectiveTo characterize previously-reported clinically-relevant variants and DM variants in <i>PSEN2, PSEN1, APP</i> within the participants from the ADSP.MethodsWe identified rare variants (MAF < 1%) in <i>PSEN2</i>, <i>PSEN1,</i> and <i>APP</i> in 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available (N_total= 31,490). We additionally curated variants from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as predicted DM variants in these genes.ResultsWe detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants in <i>PSEN2</i>, 25 in <i>PSEN1</i>, and 2 in <i>APP</i>. The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed that 79.5% of the variant carriers were cases compared to 3.9% were controls. In those with AD, the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6 ± 1.4 years earlier compared with noncarriers (p = 7.8 × 10^-57). Additionally, we identified 197 rare variants (MAF < 1%) within ADSP participants not reported in known clinical databases.ConclusionsA small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to noncarriers.