Genetic Association Study of Alzheimer’s Disease with Whole-Genome and Whole-Exome Sequence Data

Objective of the proposed research: Recent studies have found that single nucleotide polymorphism (SNPs) and copy number variations (CNVs) can both play significant roles in missing heritability of Alzheimer’s Disease (AD). In this project, we propose to conduct a comprehensive investigation on both variant types and understand their contributions in AD risk.
Study design: We will use the whole-genome (WGS) and whole-exome (WES) sequence data in the Alzheimer's Disease Sequencing Project (ADSP) and conduct case-control association analyses of SNPs and CNVs.
Analysis plan: Using the ADSD sequence data, we will start with CNV detection and characterization of CNV sequence features (e.g., microhomology, non-template insertions, and segmental duplications) to understand potential mechanisms of CNV formation. Next, we will study the association of AD status with SNPs and CNVs (common and rare) using standard association methods and adjusting for population structure (PS) and ages of onset. We will also develop and apply new methods using kernel and regularized regressions to assure efficient modeling of joint SNP-CNV effects from common and rare variants. We will perform ethnic-specific and ethnic-combined association analyses. We will use principle-component-based methods to adjust for PS, but also explore the efficacy of other PS adjustment methods. Finally, we will conduct biological annotation on identified risk variants.
Collaborators: The team includes researchers from University of Pennsylvania (UPenn) and North Carolina State University (NCSU). UPenn researchers include Gerard Schellenberg (PI: Professor of Pathology and Laboratory Medicine), Li-San Wang (PI: Professor of Pathology and Laboratory Medicine), Wan-Ping Lee (PI: Research Assistant Professor of Pathology and Laboratory Medicine), Adam Naj (Assistant Professor of Biostatistics and Epidemiology) and Yuk Yee Leung (Research Assistant Professor of Pathology and Laboratory Medicine).

Copy number variants (CNVs) are DNA regions that have gains (duplications) or losses (deletions). CNVs affect a considerable number of base pairs in the human genome. Unlike single-nucleotide polymorphisms (SNPs) that has been broadly studied in diseases, CNVs were not intensively discovered. The large-scale Alzheimer’s Disease Sequencing Project (ADSP) provides a systematic way to capture nearly all genomic variations and to study the genetic basis of Alzheimer’s Disease (AD). In this project, using the data of affected and unaffected samples from ADSP, we propose to conduct a comprehensive investigation on both variant types (SNPs and CNVs) and study their contributions in AD risk and etiology. We will start with CNV genotyping, followed by conducting standard association analysis of AD with SNPs and CNVs. We will also develop and apply new analytical methods for efficient modeling of joint SNP-CNV effects from common and rare variants. Finally, we will conduct functional annotation on identified risk variants to uncover possible biological mechanisms.