# The molecular genetic analysis of human obesity

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $469,538

## Abstract

Project Summary
Obesity is an extremely costly health problem, largely unresponsive to current therapeutic and prophylactic
measures. Heritability estimates indicate that 30-50% of the likelihood of becoming obese is conveyed by
genes, and over 100 genes leading to susceptibility to obesity have been identified in rodents and humans.
However, the genes so far identified in the aggregate account for no more than ~5% of this risk. Genome
wide association studies for obesity are inherently designed to detect common alleles present in 5% or more of
the population. We hypothesize that some or most of the “missing heritability” for obesity is due to rare
variants. In Aim 1 we will sequence the exomes (and possibly entire genomes) of individuals and their families
in which severe, early-onset obesity is segregating. Multi-tiered bioinformatics filters and pathway analysis will
be used to examine the biological functions, molecular networks, and canonical energy homeostasis pathways
represented by the prioritized novel variants. In Aim 2–the implicated genes will be characterized in: 1.
hypothalamic neurons (and possibly other cell types) created from somatic cells of affected individuals as
compared to their isogenic controls (generated using CRISPR); 2. Mice manipulated by direct injection of
candidate gene constructs into the brain and mice segregating for knock-in alleles of the candidate gene.
These animals will be studied using sophisticated measures of energy homeostasis and food intake, including
studies of hedonic aspects of the quantity and quality of good intake. The stem cell-derived neurons will
enable study of the developmental, structural, cellular, biochemical/molecular and functional phenotypes of not
otherwise accessible for this type of analysis. Success in generating patient-specific hypothalamic neurons
from human iPSCs will create a cellular “reagent” likely to be extremely useful in molecular physiology and
drug discovery. The combining of three elements of analysis: exome sequencing/pathway analysis, iPSC-
derived hypothalamic neurons/other cells, and creation of animal models subjected to sophisticated metabolic
and behavioral phenotyping provides a powerful platform for the identification of novel molecular mechanisms
for human obesity.
.

## Key facts

- **NIH application ID:** 10000072
- **Project number:** 5R01DK052431-25
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Wendy K Chung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,538
- **Award type:** 5
- **Project period:** 1996-07-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000072

## Citation

> US National Institutes of Health, RePORTER application 10000072, The molecular genetic analysis of human obesity (5R01DK052431-25). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10000072. Licensed CC0.

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