Investigating the role of tandem repeat variation in Alzheimer’s disease

Variation in tandem repeats (TRs), particularly large expansions of triplet repeats (eg. polyCAG), are known to cause a number of late-onset neurological diseases. Due to their repetitive and degenerate nature, variations in TRs are typically ignored by standard genome analysis pipelines. Furthermore, pathogenic repeat expansions typically span hundreds to thousands of bases, making variations in them difficult to detect in short read data. However, recently a number of specialized algorithms have been developed which enable expansions of short TRs (motif sizes 1-12bp) to be detected in short-read sequencing data. Our lab has also developed approaches that allow the copy number of repeats with larger motifs (motif size ranging from 12bp-200kb) to be estimated based on read depth. We hypothesize that variation in TR regions contributes to risk of AD, and will test two hypotheses:

1. That rare pathogenic expansions of TRs (either in the “full” or “pre-mutation” range) occur at increased frequency in AD patients compared to controls.
2. That length variation in TRs of all sizes represents a class of common genetic variation that may alter an individual’s susceptibility to AD.

In Aim 1, we will search for expansions of microsatellite repeats using tools such as ExpansionHunter, exSTRa and STRetch, that analyze WGS BAM files for signatures of expansion. We will look for loci with an excess of rare outlier genotypes in cases vs controls. If loci showing rare expansions in cases are identified, if possible, we would request aliquots of DNA from the specific individuals to perform long-read sequencing to validate the presence of potentially pathogenic repeat expansions. In Aim 2, we will use read depth approaches to estimate copy number of large TRs. We will compare estimated copy numbers of these repetitive regions in cases vs. controls to identify TR loci that show significant associations of copy number with AD compared to controls. Analysis will incorporate technical and biological covariates, such as principal components of WGS read depth data, ethnicity from SNV data, gender, etc, and will utilize a multiple testing correction for genome-wide analysis.

Some types of neurodegenerative diseases are known to be caused by a specific type of genetic mutation where a short piece of DNA becomes repeated hundreds of time. Termed “repeat expansions”, these types of mutation can be difficult to find using standard methods scientists use to sequence DNA. We believe that some cases of Alzheimer’s disease may also be caused by repeat expansions.
We will apply new analysis approaches that are specifically designed to find these repeat expansions in genome sequencing data, with the aim of finding novel types of genetic mutation that contribute to some cases of Alzheimer’s disease.