Alzheimer's Disease Genetics: mitochondrial, haplotype-based analyses, and genetic replication

Objectives

In our lab we are working on a variety of Alzheimer’s disease (AD) genetics research projects: mitochondrial genetics of AD, haplotype-based analyses in the nuclear genome, AD genetics in Pacific Islanders (PI), and replication of identified disease variants identified in our novel dataset (the Cache County Study). Our objectives include: 1) develop a large dataset of AD mitochondrial genomes (~60,000 total samples), 2) identify mitochondrial genetic variants associated with AD, 3) explore the relationship between mitochondrial inheritance of AD and the mitochondrial genome, 4) identify haplotypes that explain observed AD variants, 5) replicate variants we identify in samples from the Cache County Study, and 6) test PI-specific AD genetics variants for association in the races represented in the ADSP.

Study Design/Analysis Plan

1. Using our published approach, assemble, annotate, and deposit in NIAGAD whole mitochondrial genome sequences from the ADSP and a variety of sources.
2. Estimate haplotypes in the nuclear genome using ShapeIt and our own novel tool in development.
3. Using an evolutionary based method, TreeScanning, assess the effects of mitochondrial and nuclear haplotypes associated with AD status, including both risk and protective variation. We have published several papers using this approach to study the relationship between the mitochondrial genome and AD.
4. Also using TreeScanning, conduct association studies between mitochondrial haplotypes and maternal family history of AD.
5. Using standard statistical methods to replicate associations from the Cache County Study and PIs.
6. Use SNP data to estimate genetic variances.

Alzheimer’s disease (AD) is the most common form of dementia, is fatal, and causes a substantial burden to both affected individuals and loved ones. We seek to push the boundaries of our current understanding by identifying novel targets. Where a majority of approaches focus on single variants in the nuclear genome, we seek to identify mitochondrial-based targets and haplotypes responsible for influencing disease risk in the nuclear genome. We are sequencing whole genomes from the Cache County Study in large risk and protective pedigrees and will use these samples to confirm our findings.

In addition to the work described above, we are studying the AD genetics of Pacific Islanders (PIs). PIs are unrepresented in the ADSP. We will evaluate the genetics we discover in PIs in the populations represented in the ADSP and augment the ADSP with PI genomes.