Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer’s Disease Sequencing Project

Abstract

Background/Aims: The Alzheimer’s Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer’s disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as “pathogenic” in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. Results/Conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

“…The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced (WGS) family-based dataset [34,35]. This dataset includes 197 individuals sequenced in 42 EA families and 351 individuals in 67 CH families.…”

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

“…Additionally, three individual variants were exome‐wide significant: rs75932628 in TREM2 ( p = 4.8 × 10 −12 ), rs2405442 in PILRA ( p = 1.7 × 10 −7 ), and a novel variant at 7:154,988,675 AC099552.4 ( p = 1.2 × 10 −7 ). Another study focussed on a panel of 35 known dementia genes using variants thought likely to be consequential based on ClinVar, literature review, and predicted effect (Blue et al., ). Using gene‐based analyses in the ADSP case‐control sample, TREM2 was significant at p = 1.8 × 10 −11 and APOE was significant at p = 0.0069, while ARSA , CSF1R , PSEN1 , and MAPT were less strongly implicated although were still significant at p < 0.05.…”

Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

“…Of genes with SLPs above 3, a number have previously been implicated by sequencing studies, consisting of TREM2, ABCA7, SORL1 and PSEN1 (Blue et al, 2018;Guerreiro et al, 2013;Kim, 2018;Patel et al, 2019;Raghavan et al, 2018). PIK3R1 codes for a key component of the PI3K/Akt/GSK-3β signalling pathway and in neuronally differentiated PC12 cells activation of this pathway is neuroprotective against Aβ25-35-induced apoptosis and tau hyperphosphorylation (Cheng et al, 2018).…”

“…Additionally, three individual variants were exome-wide significant: rs75932628 in TREM2 (p = 4.8 × 10 −12 ), rs2405442 in PILRA (p = 1.7 × 10 −7 ), and a novel variant at 7:154,988,675 AC099552.4 (p = 1.2 × 10 −7 ). Another study focussed on a panel of 35 known dementia genes using variants thought likely to be consequential based on ClinVar, literature review and predicted effect (Blue et al, 2018). Using gene-based analyses in the ADSP case-control sample, TREM2 was significant at p = 1.8 × 10 -11 and APOE was significant at p = 0.0069 while ARSA, CSF1R, PSEN1 and MAPT were less strongly implicated although were still significant at p < 0.05.…”