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F2–01–02: Study of rare variants in Alzheimer's disease
Author(s) -
Sims Rebecca
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.04.126
Subject(s) - genetics , biology , genetic association , single nucleotide polymorphism , genome wide association study , snp , trem2 , population , genetic variation , missing heritability problem , genotype , gene , medicine , receptor , myeloid cells , environmental health
Background:Commonvariation within ten genes (APOE, CLU, CR1, PICALM,BIN1, ABCA7,MS4Agene cluster, EPHA1, CD2AP and CD33), and rare variation in one gene (TREM2) are known to increase susceptibility to late-onset AD (LOAD). Despite the recent success in identifying genetic risk loci for AD, much of the genetic heritability of AD remains unexplained. Additionally, aside from APOE and TREM2, each variant is associated with low risk and is noncoding, making it difficult to link the identified variants to a molecular function. While common variation in LOAD has been extensively studied, rare variant identification through next generation sequencing is expensive meaning that investigators are not able to utilise suitably powered samples to comprehensively test rare variants across the genome for association with complex disease. This study utilises the Illumina Humanexome Beadchip, designed using 12,000 exome sequences and the 1000 genomes project, to assay 247,870 predominantly low frequency, coding variants.Methods:This study comprised a total sample of 8154 Alzheimer’s disease cases, 4222 elderly controls and 29000 population controls. The study was conducted in two stages. Stage one genotyped 5762 cases and 2488 elderly controls on the Illumina HumanExome v1.0 Beadchip, and utilised approximately 29,000 population controls from the UK HumanExome Chip collaboration. Stage 2 genotyped 2392 cases and 1734 elderly controls on the Illumina HumanExome v1.1 Beadchip. All genotyping was performed at Life & Brain GmbH, Bonn, Germany. SNP calling was performed using both GenTrain and zCall algorithms. Quality control included standard protocols implemented by the UK HumanExome Chip collaboration. Statistical analyses included single variant analysis as well as analyses, which combined association evidence such as all SNPs within a gene (Moskvina et al. 2011). Such genewide analyses have been shown to give robust results in other disorders, and are more suitably powered to distinguish complex association with multiple rare variants. Results:Will be presented at AAIC 2013. Conclusions: Our analyses utilise a well powered sample to identify novel low frequency loci that have been missed by the common variant GWAS. Identification of these loci will further elucidate the genetic architecture of AD and implicate functional variants for molecular investigation.