# Using polygenic scores to enhance both variant discovery, and understanding of functional consequences of genetic variation in IBD.

> **NIH NIH P01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $417,854

## Abstract

PROJECT 1:
The Inflammatory Bowel Diseases (IBD), Crohn's disease and ulcerative colitis are genetically complex
diseases in which the environment is also a significant contributor. More than 200 genetic variants have been
associated with the development of IBD and there have also been considerable insights of microbiome
associations with IBD. To date, most genetic studies have used platforms that are designed to capture
common genetic signals. We have shown that whole exome sequencing (WES) can identify rare variants that
add further to the understanding of the genetic structure of IBD. Our preliminary data also suggests that the
creation of polygenic gene risk scores (GRS) can add a powerful dimension to discovering additional genetic
signals and also to elucidating the complex relationship with the microbiome. In this proposal we will be
utilizing next generation sequencing approaches, single cell technology, together with novel genetic and
systems biology approaches to further understand the underlying causes of IBD. We will generate additional
WES data in IBD subjects selected as a consequence of their extreme phenotypes or GRS and enriching
populations either genetically or by extreme phenotype will likely enhance variant discovery further. We will
identify protective variants in healthy controls genetically `primed' to develop CD and also in UC subjects
genetically predisposed to severe disease. Genetic variation in genes of the NFkB pathway are enriched in
severe UC and we will extract monocytes from UC subjects with high and low NFkB GRSs and perform
RNAseq and single cell sequencing on these subjects to better understand the functional consequences of
these genetic variants. We will expand upon our striking observation that GRS has a profound effect on the
mucosal metabolome in both controls and IBD cases and we will extend these investigations to try and better
understand the ability of the serum metabolome to reflect the mucosal signature. Our preliminary data strongly
support the hypothesis that disease and pathway specific GRS will identify molecular extremes/clusters of IBD
subjects: facilitating novel variant discovery; elucidating functional effects consequent of IBD-associated
variants; and delineating genetic effects on host-microbiomal relationships.

## Key facts

- **NIH application ID:** 10019373
- **Project number:** 5P01DK046763-28
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Dermot Patrick McGovern
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,854
- **Award type:** 5
- **Project period:** 1997-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019373

## Citation

> US National Institutes of Health, RePORTER application 10019373, Using polygenic scores to enhance both variant discovery, and understanding of functional consequences of genetic variation in IBD. (5P01DK046763-28). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10019373. Licensed CC0.

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