Rare Variants in Alzheimer’s Disease and Other Dementias

Objectives
To identify genetic variants that are overrepresented in sporadic dementias when compared with controls.
To identify genetic variants that are found uniquely in apparently sporadic dementia cases.
To determine if rare variants identified in our cohorts of neurodegenerative disease are present in the ADSP controls.
Study Design
We have performed exome-sequencing in over 3,000 samples from a variety of neurodegenerative dementias. These data were generated using Illumina sequencing and called using GATK’s Best Practices v3.
In these samples, we have identified genetic variants that have either much lower frequency in controls and in publicly available databases of genetic data (gnomAD), or that are absent from these cohorts.
The proposed study design is largely a case-control study in ADSP data to replicate our findings as well as a simple lookup for rarer variants in cases and controls, where sample size isn’t enough to perform meaningful associations. We will perform single variant and gene-based associations using standard methods (fisher test/logistic regression and SKAT-O) using gender, age and principal components as covariates. These tests are either implemented in PLINK or can be performed in R.
To allow us to dissect the associations between genetic variants and phenotype we will require access to gender, age at onset, age at death (where available), Braak staging and CERAD scores for all cases in ADSP.
Funding
Funding for the study is currently from Van Andel Research Institute’s internal funds.

The main objective of the study is to identify genetic variants that cause or predispose to neurodegeneration. To accomplish this, we will analyze data previously generated for a variety of these conditions and use data from ADSP to replicate findings and improve our statistical power to detect these associations with disease. The identification of genetic variants, even if rare, that have a strong impact on dementia phenotypes will be of significant importance in advancing our understanding of disease biology. These variants will also be candidate targets for future diagnostic or therapeutic approaches for these diseases.