Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnic diversity and systems approaches

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Project Summary/Abstract The goal of this two-year Research Diversity Supplement for the “Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnic diversity and systems approaches” parent award (U01AG058589) is to provide Dr. Nafikov with necessary skills to establish an independent research program in genetics of Alzheimer’s and other neurodegenerative diseases. Alzheimer’s disease (AD) is one of the leading causes of death in the elderly, cannot be cured or prevented, and is projected to impose a huge socioeconomic burden on our society by the middle of this century. Although significant efforts have been made to uncover the genetics of earlier-onset AD, the genetic basis of more common late-onset form of the disease awaits discovery. Thus, the overall objective of the current proposal is to identify new genes and/or biochemical pathways for late-onset AD (LOAD) using haplotype-based variant prioritization method developed by Dr. Nafikov and colleagues for pedigree-based analysis. Because haplotypes can allow evaluation of the joint effects of multiple rare genetic variants, recently implicated in complex diseases such as LOAD, the proposed analytical approach will test the role of these variants in the disease development. First, haplotype-based variant prioritization will be performed within already-defined linkage regions in families from the AD Sequencing Project (ADSP). A list of potential AD risk variants will be prioritized further using bioinformatics and omics integrative analyses. Second, replication analysis and integration of findings in all available ADSP samples will be performed using haplotype association analysis within genomic regions of interest in subgroups of the ADSP samples, followed by possible meta analyses across subgroups. Dr. Nafikov’s research activities will contribute to the following aims of the parent award: Aim 1: To fully characterize known AD loci and to identify novel protective and risk variants for AD by exploiting the full range of genetic variability revealed by WGS including single nucleotide polymorphisms, small insertion/deletions, and structural variants and Aim 3: To functionally characterize genes, gene networks, and systems, via bioinformatics and omics integrative analyses to identify putative therapeutic targets. The training activities for this award will take place at the University of Washington under the mentorship of Dr. Ellen Wijsman, who is internationally recognized experts in Statistical and Human Genetics. Dr. Nafikov has a background in biochemistry and statistics but will be trained in Human and Statistical Genetics. The training component of the award will include participation in seminars, conferences, and workshops on Statistical Genetics, Neurobiology, and Biology of Aging. 1