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O3‐13‐05: Rare coding mutations identified by targeted sequencing of Alzheimer's disease loci detected in genome‐wide association studies
Author(s) -
Vardarajan Badri N.,
Ghani Mahdi,
Kahn Amanda,
Sheikh Stephanie,
Sato Christine,
Barral Sandra,
Lee Joseph H.,
Cheng Rong,
Reitz Christiane,
Lantigua Rafael,
Reyes-Dumeyer Dolly,
Medrano Martin,
Jimenez-Velazquez Ivonne Z.,
Rogaeva Ekaterina,
St George-Hyslop Peter,
Mayeux Richard
Publication year - 2015
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.2015.07.313
Subject(s) - genetics , biology , disease , genome wide association study , genetic association , gene , mutation , polymorphism (computer science) , allele , single nucleotide polymorphism , genotype , medicine
Background:Rapid advancement of next-generation sequencing (NGS) technology has facilitated the search for genetic factors that influence disease risk. Recent studies identified independent rare variants with large effects on risk of late-onset Alzheimer’s disease (LOAD) (Guerreiro et al. 2013; Cruchaga et al. 2013). Here, we report a genome-wide rare variant association analysis using an optimized composite memory score (ADNI-MEM) as phenotype and whole-genome sequencing (WGS). Methods: 757 non-Hispanic Caucasian participants from a WGS data set (Illumina HiSeq2000; N1⁄4815) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort were used. Short-read sequences were processed using NGS analysis pipeline with BWA and GATK. Exonic variants, annotated by ANNOVAR, were mapped to genes using the dbSNP annotation file and assigned to each of 19,795 autosomal genes according to position. ADNI-MEM scores were calculated using item-level data (Crane et al. 2012). Genome-wide gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results:A total of 15,737 genes were found to have 5 rare exonic variants (MAF<0.05). Using a