Extensive search for variants that protect or elevate the risk of Alzheimer's Disease

Objectives: The aim of our analyses of the Alzheimer’s Disease Sequence Project (ADSP) cohort data is to improve the identification of reliable gene-drug targets to develop effective therapeutic medicines to prevent or slow-down the progression of Alzheimer’s disease in patients. Study design: Our goal is to identify novel and reliable gene-targets to develop effective therapeutic medicines to prevent or slow-down the human burden caused by Alzheimer’s disease. To identify variants that confer risk or provide protection to Alzheimer’s disease it is essential to obtain deep sequencing (whole-genome and whole-exome) in families with high penetrant variants and in case-control populations. We will capitalize on the Discovery Phase and Extension Phase cohorts that includes WGS data in families by performing family-based association analyses. Additionally, we will perform case-control association analyses on the whole-exome sequence data from the Discovery Phase Case/Control, Extension Case/Control, FUS1, and FUS2 cohorts. Analysis Plan: We plan to analyze the WGS and WES data with several phenotype-variant analysis approaches. We will perform common variant, rare variant gene-based (i.e. stop-gain, frameshift, putatively deleterious non-synonymous, and splice-site variants), pathway-based analysis, and sex-stratified analysis. We plan to perform association analysis with a dichotomous outcome (i.e. affected/unaffected) and with neuropathology quantitative measures (where available). We have expertise in several analyses software to perform the proposed analysis; they include PLINK, PLINKSeq, MENDELSCAN, and varianttools.
We plan to analyze the ADSP cohort and other Alzheimer's disease cohorts independently (i.e. UKBB) and to combine the summary statistics (Odds ratio and p-values) by meta-analysis. The planned research is consistent with the data use limitations/restrictions for the requested dataset(s), and we promise to follow all regulations within. Our proposed research will support all conditions specified in the Data Use Agreements associated with the study and will not violate relevant privacy or consent policies.

The aim of our analyses of the Alzheimer’s Disease Sequence Project (ADSP) cohort data is to unravel the genetic architecture of AD with an objective to identify reliable gene-drug targets through various family-based and population-based statistical analyses, followed by prioritizing molecular targets and to develop effective therapeutic medicines to prevent or slow-down the progression of Alzheimer’s disease in patients.