Most discoveries of the genetic basis of Alzheimer disease (AD) were made in Caucasians of European ancestry (EAs) and required samples between 10,000 and 75,000 subjects to detect them. We and others have demonstrated that risk variants for AD can be identified in ethnic groups of a more homogeneous genetic background using samples comprising several thousand or fewer subjects. Studies of non-EA populations also afford the opportunity to discover variants that are rare or display a smaller effect size in EAs due to modification by other genes and environmental factors. We will direct our efforts to Koreans, a population which has a high prevalence of AD, but, like other East Asian populations, have not been included in large DNA sequencing studies and for whom little is known about the genetic basis of AD other than association with APOE. They have maintained a distinct genetic profile that reflects a unique component resulting from genetic drift and new mutations during the last two millennia. We will leverage the genetic architecture of Koreans to promote discovery of AD-related genes and variants by studying rare and common genetic variation, and the impact of AD- associated variants on gene expression. To accomplish our scientific goals, we will study AD cases and controls who are ascertained and followed longitudinally at the National Center for Research on Dementia at Chosun University located in the southwestern city of Gwangju, Republic of Korea, and obtain from each participant a blood specimen and phenotypic data including clinical exam, demographic, medical history and lifestyle information. In addition, most subjects will undergo an extensive neuropsychological test battery developed specifically for Koreans and a brain MRI scan. The cohort will comprise an unrelated group of 2,000 AD cases and 2,000 elderly controls ascertained from existing patient registries and prospectively identified subjects all of whom will have GWAS data available generated using a microarray designed for Koreans. DNA specimens from all subjects will be whole genome sequenced (WGS). WGS data will be processed using pipelines established by the Alzheimer Disease Sequencing Project. We will conduct a genome-wide association study for AD using methods for single variant and gene-based tests based on models that adjust for age, sex and population substructure. Top-findings will be replicated in datasets of other ethnicities assembled by the Genomics Center for Alzheimer Disease for the Alzheimer Disease Sequencing Project using trans-ethnic analysis and approaches that focus on variants affecting protein structure, transcription, and gene expression. Next we will perform a GWAS for age at onset and brain imaging and cognitive endophenotypes. Finally, we will identify gene targets of the top-ranked SNPs by performing expression quantitative trait locus analysis using public datasets containing genotype and gene expression data in brain and other tissues, and establish functional connections among the top-ranked SNPs and genes using pathway analysis and co-expression network analysis. We expect this project will identify novel targets for development of new drugs to treat or retard mechanisms leading to AD.
The collective findings from this project aimed at identifying risk and protective genetic factors for Alzheimer disease (AD) in Koreans, coupled with genetic analyses of age at onset of symptoms, measures of cognitive functioning in multiple domains and structural brain changes assessed by magnetic resonance imaging, will permit us to develop new hypotheses about pathogenic mechanisms, identify proteins as targets for drug development, and provide genetic and cognitive markers for use in risk assessment and profiling subjects for clinical trials.
