# Genome Wide Association Study for Childhood Obesity

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $594,204

## Abstract

ABSTRACT
In our original application for R01 HD056465 we hypothesized and proved that distillation of the genetic
component contributing to obesity is easier to determine in children, where environmental exposure has had
less of an impact due to a relatively short period of lifetime. During our first renewal, we successfully expanded
this programmatic line of research by identifying additional variants.
During the last funding cycles, we carried out a series of non-hypothesis-driven studies that were directed at
uncovering loci that predispose to childhood obesity by conducting various genome-wide based approaches.
For instance, employing a powered two-stage study design in a consortium setting, where cases were defined
as being in the ≥95th percentile of BMI, we identified novel association signals which we subsequently
replicated. This first NICHD funded study was ultimately published in Nature Genetics, with the subsequent
larger trans-ethnic study being more recently reported.
Intense genome-wide association studies (GWAS) efforts by the community have yielded key variants robustly
associated with measures of adiposity, both in children and adults. Interestingly, while macro-level gene sets
analysis of overall GWAS findings for adult waist-to-hip ratio (WHR) have implicated adipogenesis, comparable
analyses of adult BMI GWAS datasets implicate central nervous system (CNS) processes.
Despite these macro-level analyses, an important caveat of GWAS is that they only report genomic association
signals and not necessarily the precise localization of culprit genes. As such, GWAS have not strictly
represented an era of gene target discovery, rather it was simply a decade of signal discovery. One clear
example of this is with progress in understanding the obesity GWAS signal that resides within an intronic
region of FTO. Specifically, the signal is now known to influence the expression of nearby genes, IRX3, IRX5
and RFGRIP1L, rather than the `host' gene itself. These discoveries suggest that the FTO variant is actually an
enhancer embedded in one gene that influences the expression of other causal genes.
Since we already have dedicated infrastructure, namely the Center for Spatial and Functional Genomics at the
Children's Hospital of Philadelphia (CHOP), to conduct such `variant to gene mapping' efforts, our team is
poised to determine at scale how our reported childhood obesity loci affect the expression of specific genes in
neuronal relevant cells, namely neural precursors, microglia, astrocytes and hypothalamic neurons. This
involves the integration of high resolution `3D Genomics', `Assay for Transposase Accessible Chromatin
sequencing' (ATAC-seq), RNA-seq and CRISPR. This final step will enable us to fully infer effector genes.
Thus, the premise of this renewal is to uncover the correct functional context of the childhood obesity variants
identified by our GWAS in order to translate these discoveries into meaningful benefits for pediatric care.

## Key facts

- **NIH application ID:** 10115981
- **Project number:** 2R01HD056465-11A1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Struan F A Grant
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $594,204
- **Award type:** 2
- **Project period:** 2008-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115981

## Citation

> US National Institutes of Health, RePORTER application 10115981, Genome Wide Association Study for Childhood Obesity (2R01HD056465-11A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115981. Licensed CC0.

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