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

Abstract

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Exome-wide age-of-onset analysis reveals exonic variants inERN1, TACR3andSPPL2Cassociated with Alzheimer’s disease

“…1A, Table S2, Model 1). Beneficial association of the missense variant rs7982 in CLU was not reported in the previous study of AD status using the same ADSP sample (Bis et al, 2018). We observed that the minor allele carriers of rs7982 had lower hazards consistently across a wide age interval (Fig.…”

“…Rare coding variants often show larger effect size and their biological consequences are more explicable, but its association analysis is complicated by insufficient statistical power. Although exome-wide association of AD has recently been explored using AD status (Bis et al, 2018;Cruchaga et al, 2014;Raghavan et al, 2018), our rationale is that more AD-related rare variants can be identified using analysis of age-of-onset of AD with a Cox model given emerging evidence from a previous study showing its advantage in terms of statistical power (He and Kulminski, 2019). We attempted to replicate significant findings in four other studies, with a meta-analysis sample size of about 20,000 subjects.…”

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

“…Given the rarity of most LSD-causing variants and allowing for the possibility of incomplete-and agedependent penetrance, definitive assessment of each gene for an association with PD risk will require very large case/control cohorts with sequencing. Based on recent studies in AD, 115 it now seems likely that sample sizes including more than 10,000 subjects will be necessary. Although studies of this scope may be possible in the near future, rather than focusing on individual genes where statistical power is more limited, we have pursued a complementary approach examining aggregate genetic risk among 54 LSD genes.…”

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

“…One study incorporating this dataset with others identified 19 loss‐of‐function variants of SORL1 in cases as opposed to one in controls and a collapsing test of loss‐of‐function ultrarare variants highlighted other genes including GRID2IP , WDR76 , and GRN (Raghavan et al., ). A subsequent study used variant‐based and gene‐based tests of association and followed up significant or suggestive results in other samples to implicate three novel genes, IGHG3 , AC099552.4 , and ZNF655 as well as novel and predicted functional genetic variants in genes previously associated with Alzheimer's disease (AD) (Bis et al., ). In the ADSP samples alone, five genes were exome‐wide significant: ABCA7 , TREM2 , CBLC , OPRL1 , and GAS2L2 .…”