# Constructing multi-omics regulatory networks for functional variant annotation

> **NIH NIH R03** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $335,000

## Abstract

PROJECT SUMMARY
Over the past decade, thousands of genome-wide association studies (GWAS) have been performed, greatly
improving our understanding of the genetic origins of complex diseases. A large number of variants have been
associated with individual traits, but a complete understanding of complex disease remains elusive, due in
large part to two unsolved challenges. First, a majority of associated variants are noncoding and distant from
the nearest gene, complicating their interpretation. Second, the observed heritability of many complex diseases
far exceeds the portion which can be explained by GWAS-discovered variants, largely because of the
combined effects of rare variants unprobed by current techniques and common variants falling below
significance thresholds of existing GWAS methods. As whole-genome sequencing and rare variant discovery
become increasingly prevalent, frameworks for functionally annotating rare variants and associating them with
disease-associated driver genes and pathways will become increasingly important. A wealth of public
epigenetic data exists, including collections of chromatin modification profiles and 3D structure data from
various Common Fund sources as well as external consortia. In combination with whole-genome sequencing
data, these datasets offer great potential to further our understanding of diseases across the spectrum from
Mendelian to complex diseases.
As members of the ENCODE Project, we have developed the Registry of candidate cis-Regulatory Elements
(cCREs), a collection of nearly a million candidate enhancers, promoters, and insulators in the human genome
with activity profiles in more than 800 human cell types. In parallel, we collaborated with Prof. Xihong Lin on
the development of variant-Set Test for Association using Annotation infoRmation (STAAR), a framework for
performing rare-variant association tests using functional annotations and a dynamic weighting scheme. Here
we aim to extend the Registry of cCREs to include gene regulatory networks, including gene-enhancer links,
3D chromatin neighborhoods, co-expressed gene networks, and biochemical pathways, drawing on data from
the Common Fund, including GTEx and the 4DNucleome Project, and other public sources (Aim 1). We then
aim to extend GWAS and the STAAR methodology to incorporate these higher-order features to identify novel
gene regulatory network associations with disease-associated rare variants (Aim 2). In this study, we will focus
on three human congenital disorders, cleft lip/palate (CLP), congenital diaphragmatic hernia (CDH), and
ventricular septal defect (VSD), as these disorders have extensive whole-genome sequencing data by the
Gabriella Miller Kids First Pediatric Research Consortium. We will validate our results using Knockout Mouse
Phenotyping Program (KOMP2). In summary, we will discover new disease-gene associations, produce a
framework broadly applicable to existing and future whole-genome sequencing datasets, and improv...

## Key facts

- **NIH application ID:** 10112018
- **Project number:** 1R03OD030608-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Zhiping Weng
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,000
- **Award type:** 1
- **Project period:** 2020-09-18 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112018

## Citation

> US National Institutes of Health, RePORTER application 10112018, Constructing multi-omics regulatory networks for functional variant annotation (1R03OD030608-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10112018. Licensed CC0.

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