Targeted analysis of non-coding variants in Alzheimer’s Disease

Background
The gene progranulin is critical for maintenance of brain health. Progranulin is thought to regulate components of the autophagic/lysosomal pathway. Normal expression of progranulin is needed to prevent neurodegenerative disease caused by aberration in this pathway. Mutations that disrupt the function of progranulin cause Frontotemporal Dementia, while mutations that reduce progranulin expression are thought to increase risk for the development of Alzheimer’s disease. However, mutations that reduce progranulin expression remain to be fully characterized.

Objectives
This research project seeks to evaluate the effect of variation in progranulin’s regulatory regions on the risk of developing Alzheimer’s disease. In doing so, we hope to uncover novel Alzheimer’s risk variants and broaden the current understanding of the role of progranulin in Alzheimer’s disease.

Study Design
The first phase of this study involves the computational prediction of thousands of variants with the potential to alter progranulin expression. Briefly, transcription factor ChIP-seq data and transcription factor binding site sequence information has been utilized to identify regions within the progranulin gene where variation is expected to alter transcription factor binding. Variation in these transcriptionally active ‘regulatory’ sites is expected to modify progranulin expression. We will query these regulatory sites in Alzheimer’s patient and control genomes to identify novel variants that are associated with increased or decreased risk of Alzheimer’s. Variants of interest will be further characterized to determine the effect of the variant on progranulin expression.

Analysis Plan
We will assess enrichment of the most common variants (MAF > 0.005) by chi-squared test. Since most of the variants are thought to be rare, enrichment for these variants will be assessed using a rare variant association test called the Optimized Sequence Kernel Association Test (SKAT-O). Our primary analysis will assess whether any variants are enriched in case or control populations. Subsequently, we intend to evaluate if any variants are capable of modifying age of onset or symptom severity.

Maintenance of brain health during aging is a complicated process, involving many players. One such player is a protein called progranulin. Progranulin works to regulate components of the waste disposal system inside brain cells. Without enough functional progranulin, the waste builds up in brain cells and causes dementia. In fact, progranulin mutations are a common genetic cause of Frontotemporal Dementia. Furthermore, some progranulin mutations are thought to increase risk for the development of Alzheimer’s disease. Despite progranulin’s important role in maintaining brain health during aging, we still do not know much about the role of progranulin mutations in Alzheimer’s. To address this knowledge gap, we intend to perform the most comprehensive search to date for progranulin mutations that increase risk for Alzheimer’s. Any progranulin mutations that appear to increase risk for Alzheimer’s will be characterized further. Ultimately, this study seeks to expand our current understanding of the role of progranulin in the development of Alzheimer’s disease.