# Search for obesity-associated genes with protective effects on metabolic health

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $581,636

## Abstract

Obesity is a major risk factor for a number of metabolic and cardiovascular complications. However, a
substantial proportion of obese individuals are protected from cardiometabolic complications, despite their
excess adiposity (the so-called metabolically healthy obese, MHO). Conversely, not all normal weight
individuals are metabolically healthy, despite being lean (the metabolically obese normal weight, MONW). The
physiological mechanisms that determine why some obese individuals are protected, and why some normal
weight individuals are at risk, are poorly understood, because clinical studies are often too small and methods
to test presumed pathways involved are too invasive. Identifying genes and the pathways in which they are
implicated provides an alternative strategy to elucidate the biology that underlies the MHO and MONW.
 Genome-wide association studies (GWAS) have so far identified >300 loci for obesity traits. However, these
loci have provided only limited insight into the mechanisms that link obesity and its complications, because the
GWAS examine each trait in isolation and ignore the fact that obesity is a heterogeneous clinical condition.
 Therefore, we propose to [1] perform a multi-trait genome-wide search for obesity-increasing loci with
protective effects on cardiometabolic traits and vice versa, [2] prioritize candidate genes within identified loci,
and [3] functionally characterize prioritized candidate genes in model systems.
 Specifically, we apply two complementary discovery approaches. In the first approach (Aim 1a), we perform
multi-trait correlated meta-analyses that combine summary statistics of adiposity and cardiometabolic GWAS
from large-scale genetic consortia and the UK Biobank (Ntotal~840,000). We aim to identify SNPs
simultaneously associated with increased adiposity and a favorable cardiometabolic risk profile, and vice
versa. In the second approach (Aim 1b), we use individual-level data from the UKBiobank (N~500,000) to
perform GWAS on new outcomes derived from the difference between a cardiometabolic and an adiposity trait.
Next, we prioritize the most likely candidate genes in identified loci and the most relevant tissues using
functional annotation pipelines (Aim 2a) and high-throughput screens in transgenic CRISPR-Cas9-based
zebrafish model systems (Aim 2b). Lastly, we investigate the functional impact of prioritized genes using
CRISPR-Cas9 in human-induced pluripotent stem cells (hiPSCs) differentiated into relevant cell types (Aim 3a)
and tissue-specific transcriptomic analyses in transgenic zebrafish model systems (Aim 3b).
 Our focus on obesity-associated loci with protective effects on health (and vice versa) is unique and targets
a biology that has not been accessed with single-trait GWAS. Our approaches that use model systems to
prioritize and characterize genes are innovative and will provide the critical insights needed for in-depth follow-
up in murine models and clinical studies. Some identified...

## Key facts

- **NIH application ID:** 9977175
- **Project number:** 5R01DK107786-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ruth JF Loos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $581,636
- **Award type:** 5
- **Project period:** 2017-09-20 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977175

## Citation

> US National Institutes of Health, RePORTER application 9977175, Search for obesity-associated genes with protective effects on metabolic health (5R01DK107786-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977175. Licensed CC0.

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