Understanding Genetic Risk Factors for Alzheimer’s Disease in the Iceland Population

AGES Proposal
Objectives: To conduct a genome-wide association study of common and rare variants, including single nucleotide variants (SNVs), short insertion/deletions (indels), and structural variants (SVs), with Alzheimer’s Disease in an integrative analysis of ADSP and the Age/Gene-Environment Susceptibility (AGES) Study data

Analysis Plan:
1. QC plan for pooled samples from ADSP and AGES
1.1. Genotype Level QC
- Check read depth coverage and genotype quality for each genotype
- Change genotypes to missing if low quality (DP < 10 or GQ < 20)
- Allele balance heterozygosity (0.25 < ABhet < 0.75)
1.2. Sample Level QC
- Samples without AD status will be excluded
- Principal component analysis (PCA) with the reference populations in the 1000 Genomes Project to identify most similar population group
- Standard QC, remove samples with:
- Missingness > 1%
- Heterozygosity > 3 standard deviations from the mean het/hom ratio
- Relatedness values indicating duplicate samples
1.3. Variant Level QC
- Standard QC, remove variants with:
- Minor allele frequency threshold (see Association Tests)
- Missingness > 1%
- Low Hardy-Weinberg p-values (< 1e-10)
- Ti/Tv coefficients > 10 SD from the mean
- Keep variants with ABhet ratio between 0.3-0.7

2. General genetic quality analyses (non-phenotypic)
- Burden analysis using SKAT-O
- Identifying positive selection
- Identifying population bottlenecks and expansions (effective population size)

3. Primary Analysis
3.1 Available relevant phenotypes: Provided by The Icelandic Heart Association
3.2. Participants
- ADSP release 5 (R5) 58k samples with clear Alzheimer’s Disease status
- AGES subjects with clear Alzheimer’s Disease status
4. Potential Secondary Analyses: Copy Number Variation (CNV) and Structural Variant (SV) analyses if a novel SNV is found. CNVs/SVs are detected separately by Smoove and Manta and merged by Svimmer for each sample. Further merging for all samples can be done by Svimmer that provides the input of GraphTyper2 for joint genotyping.

Collaboration: This project will be a collaboration between University of Pennsylvania and The Icelandic Heart Association

This study aims to explore how genetic differences contribute to Alzheimer’s Disease by analyzing data integration of ADSP and the Age/Gene-Environment Susceptibility (AGES) Study. By studying various types of genetic changes—including small variations in DNA sequences and larger structural differences—this project seeks to identify genetic markers linked to Alzheimer’s.
The research team will employ advanced computational methods to ensure the data quality and analyze the relationship between specific genetic factors and Alzheimer’s. This includes examining rare mutations, evaluating their potential biological impact, and exploring pathways that might help explain the development of the disease.
This collaboration between the University of Pennsylvania and the Icelandic Heart Association represents an important step toward understanding the role of genetics in Alzheimer’s Disease in Iceland population and could provide insights for future treatments or interventions.