Identification of genetic risk factors for Inflammatory Bowel Disease in a Hispanic cohort

The objective of the proposed research is to elucidate the genetic risk factors for Inflammatory Bowel Disease (IBD) in a Hispanic cohort. In order to fulfill this objective, we are requesting access to whole genome sequence (WGS) data for 500 Hispanic controls which were sequenced by the National Human Genome Research Institute as part of the Alzheimer Disease Sequencing Project Discovery Case-Control Based Extension Study. More specifically, these data will be combined with WGS data from our Hispanic cohort of ~1600 IBD cases and ~900 controls ascertained through the Crohn's and Colitis Center at the University of Miami in Miami, Florida and Cedars Sinai Medical Center in Los Angeles, California. Drs. Jacob McCauley and Maria Abreu will serve as the primary investigators for this application at the University of Miami and Dr. Dermot McGovern will serve as the primary investigator at Cedars Sinai Medical Center. The use of these data by the noted not-for-profit organizations will be limited to biomedical purposes as related to IBD, in accordance with data use limitations.

The analyses to be conducted in this combined Hispanic sample of ~1600 IBD cases and ~1400 controls include case-control association for replication of single variant IBD associations previously identified in European populations as well as assessment for homogeneity of effect size across populations. Polygenic risk scores will be utilized to test for cumulative variant associations with IBD. Fine-mapping of single variant associations will be done using several parallel approaches. Firstly, trans-ethnic meta-analysis with summary statistics from published European and African American studies will be conducted. Linkage disequilibrium (LD) structure around associated variants will be assessed using knowledge of replication and information on LD from ancestral source populations. Secondly, the Bayesian FINEMAP algorithm will also be considered. Additional analyses will include admixture mapping for identification of novel signals and gene-based tests for cumulative association of rare variants.

The objective of the proposed research is to elucidate the genetic risk factors for Inflammatory Bowel Disease (IBD) in a Hispanic cohort. This project combines whole genome sequence data from 500 Hispanic controls which were sequenced as part of the Alzheimer Disease Sequencing Project with ~1600 IBD patient and ~900 control samples which were ascertained by the Crohn’s and Colitis Center at the University of Miami and Cedars Sinai Medical Center. To facilitate our objective, several analyses will be conducted in this combined sample of ~1600 IBD patients and ~1400 controls. First, we will identify DNA segments that contain a genetic variant that occurs more often in IBD patients than in healthy controls. These segments may be novel to Hispanics or have been identified previously in populations of European ancestry. These DNA segments can be large and often the exact location of the predisposing variant within each segment is unclear. Therefore, additional analyses will be done to narrow the width of these DNA segments and identify the predisposing variant(s) within each segment.