TARGET SEQUENCING ASSOCIATED WITH MULTIPLEX SNP GENOTYPING REVEALED NOVEL CAUSAL AND RISK RARE CODING VARIANTS OF ALZHEIMER’S DISEASE

Abstract

Recent advances in sequencing technology have made it possible to identify rare coding variants that conferring a larger effect in polygenic diseases. However, the contribution of rare coding variants is rarely studied in Alzheimer's disease (AD). Here in this study, we accessed the impact of rare coding variants of dementia related genes on both familial and sporadic AD patients. First, we conducted a targeted sequencing among 75 FAD index case with a gene panel of 112 genes. After collapsing rare coding variants (minor allele frequency≤1%) of the GWAS loci, we genotyped them in an independent group of 487 AD case and 463 age, ancestry matched controls. As a result, we detected three novel mutations in PSEN1, PSEN2, and PLD3 genes. The rs74642146 in SORL1 gene, and a missense mutation in ABCA7 gene were highly significant in sporadic AD cases, and the rs200820365 in TREM2 is significant in AD families compared with the control group. We conclude that rare coding variants in TREM2, SORL1 and ABCA7 are strong risk factors for AD. Target sequencing of AD-related genes is an efficient way to find novel causative and risk variants.