Frequency of Variants in Mendelian Alzheimer’s Disease Genes within the Alzheimer’s Disease Sequencing Project (ADSP)

Abstract

ABSTRACTObjectiveTo characterize the consequences of loss-of-function (LoF), predicted damaging missense (DM), and previously-reported clinically-relevant variants in three Mendelian Alzheimer’s disease (AD) genes – presenilin-2 (PSEN2), presenilin-1 (PSEN1), and amyloid precursor protein (APP) – within the participants from the Alzheimer’s Disease Sequencing Project (ADSP) whole genome sequence (WGS) and whole exome sequence (WES) data.MethodsWe identified rare variants (MAF <1%) previously-reported inPSEN2,PSEN1,andAPPin the available ADSP sample of 14,641 individuals with WGS and 16,849 individuals with WES available for research-use (Ntotal= 31,490). We additionally curated variants in these three genes from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as LoF and predicted DM variants in these genes.ResultsWe detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants inPSEN2, 25 inPSEN1, and 2 inAPP. Thirty-eight clinical variants with conflicting pathogenicity interpretation within ClinVar or across the databases were identified along with 12 additional LoF and 197 additional DM variants. The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed 78 individuals carrying at least one clinically-relevant variant, 79.5% were cases compared to 3.9% controls. In those with AD, we observed that the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6 ± 1.4 years earlier compared with non-carriers (p-value=7.8×10-57), and the average age of onset of AD is 5 years earlier in carriers of an additional LoF variant (n=5) compared with non-carriers.ConclusionThe ADSP data permit further characterization of previously-reported AD clinically-relevant variants. A 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 non-carriers. Furthermore, we observed additional LoF variants that potentially contribute to clinical presentation of AD.