ALZHEIMER'S DISEASE SEQUENCING PROJECT: CASE-CONTROL ANALYSES

Abstract

Responding to a 2012 Presidential Initiative to fight Alzheimer's disease (AD), the National Institute on Aging (NIA) and National Human Genome Research Institute (NHGRI) jointly developed a project to analyze the genomes of well-characterized individuals with or without AD. This effort, the Alzheimer's Disease Sequencing Project (ADSP) has the overarching goals of identifying new (1) genes involved in AD, (2) genomic variation contributing to AD risk or protection, and (3) potential avenues for therapies and AD prevention. This presentation highlights findings from the ADSP Discovery Phase Case-Control Study, which analyzed whole exome sequence (WES) variation from unrelated participants of the Alzheimer's Disease Genetics Consortium (ADGC) and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We selected European-ancestry cases and dementia-free controls based on age, sex, APOE genotype, and pathology, along with additional unrelated cases from AD families and Caribbean Hispanic controls to enrich the risk profile and diversity of the study. We analyzed individual common variants (minor allele count > 10) using logistic regression and aggregated rare (minor allele frequency < 5%) functional variants into genes using SKAT-O with filters based on predicted functional impact or loss-of-function. All models included adjustment for sequencing center and population structure. Sensitivity analyses adjusted for age, sex, and APOE genotype. Analyses were performed separately by ancestry and were combined using seqMeta/R. Statistical significance was established using a Bonferroni correction. After QC, the analysis included 5,740 cases and 5,096 controls (218 cases and 177 controls were Hispanic) and approximately 1.5 million SNVs and 50,000 indels. Significant associations from single variant and gene-based tests included common and rare variants in several known AD risk genes (TREM2, MS4A6A, ABCA7, PILRA), as well as potentially novel findings in GAS2L2, OPRL1, ZNF655, NSF and a long non-coding RNA. Several of these findings show preliminary evidence of replication in ongoing efforts among independent WES and imputed datasets. WES association analyses of ADSP case-control data replicated several known AD genes and identified novel associations; efforts to replicate these findings and characterize the biological mechanisms of the identified genes in AD are currently underway.