The overarching aim of the proposed work is to merge, in our investigation of the genetic bases of SRD, the two prevalent hypotheses used to study genetic foundations of complex common traits/disorders-the common disorder-common variant (CDCV) and the common disorder-rare variant (CDRV) hypotheses. To achieve this merge. Project VI is designed as a two-stage study. The first stage will focus on sequencing DNA from 60 study participants (30 SRD+ and 30 SRD-individuals of African descent). The overarching objective of this effort will be to identify group-specific patterns of variation in the genomic DNA sequence. This identification will be carried out by means of whole-genome paired-end sequencing, performed in a staggered fashion, so that informative analyses of multiple freezes are possible. The second stage will verify and clarify the results ofthe first stage. Specifically, the expected result ofthe first-stage analyses will be the identification of groups of candidate genes or candidate functional elements for SRD, which will be further investigated in subsequent analyses of large, independent samples of SRD probands and their families (total n~3,000). Through both stages of the investigation, we will attempt to correlate the "genomotype" of SRD with the SRD diagnosis itself and its componential facets.
This project is designed to contribute to the ongoing investigation of the genetic bases of SRD. It capitalizes on new theoretical and technological developments in the field of genetics and genomics and focuses on a subsample of individuals with SRD currently underrepresented in the field, that is, African-American probands with SRD and their families.
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