# Discovery and CRISPR validation of genetic factors associated with antipsychotic-induced weight gain and cardiometabolic risk

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $730,623

## Abstract

PROJECT SUMMARY/ABSTRACT
Antipsychotic-induced weight gain (AIWG) is of significant public health importance in mentally ill populations,
potentially addressable with personalized, precision medicine. Antipsychotic medications increase body weight,
thereby increasing cardiometabolic risk (CMR) conditions like type 2 diabetes and cardiovascular disease,
conditions associated with accelerated cellular aging. This has contributed to a 10 to 15-year mortality gap
between mentally ill individuals and the general population. Antipsychotic medications are commonly used at all
ages, but are associated with differential patterns of fat gain, whereby children gain more and older adults gain
less. Numerous genome-wide association studies (GWAS) have identified key genetic factors associated with
AIWG, but are limited by the use of indirect measures of body fat, like weight or body mass index (BMI), that are
less well correlated with metabolic disease risk. Additionally, existing research does not fully address age-related
differences in AIWG. In response to NIH PA-17-088 “Secondary Analyses of Existing Cohorts, Data Sets and
Stored Biospecimens to Address Clinical Aging Research Questions,” we propose a novel approach applying
population-based genetics, existing biospecimen with linked clinical data including precisely-measured adiposity
and insulin sensitivity, and advanced molecular tools to identify and functionally validate key genetic
determinants of AIWG and CMR across the age-span. This approach leverages 1) existing population-level data
from large biobanking initiatives and epidemiological studies inclusive of approximately 15,000 individuals with
genetic and relevant phenotypic data, 2) existing clinical and biospecimen data from NIH funded randomized
clinical trials or RCTs characterizing the metabolic effects of antipsychotics in children, adults and older adults
with direct and precise measures of body fat, together with data from approximately 600 individuals with genetic
data and additional biomarkers of metabolic risk, and 3) CRISPR based in vitro drug exposure, followed by
cellular functional assays to characterize molecular mechanisms impacted by antipsychotic. Additional sources
of existing data will be available upon funding, including data on approximately 3000 individuals from large
industry funded RCTs, data on up to 250,000 individuals from the Psychiatric Genetics Consortium (PGC, see
letter of support), and data from more than 2,000 individuals from the Dutch Bipolar Cohort Study (see letter of
support) will also be used for independent validation and replication. This study will combine unbiased genomic
methods, including array-based genotyping, GWAS and GWAS meta-analysis, CRISPR-based gene
inhibition/activation screens (CRISPRi/a), and functional molecular and cellular studies on prioritized variants of
interest, combined with unique clinical data to identify genetic factors and generate predictive models of weight
related physi...

## Key facts

- **NIH application ID:** 10350672
- **Project number:** 5R01MH122686-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Anne Justice
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $730,623
- **Award type:** 5
- **Project period:** 2021-02-12 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10350672

## Citation

> US National Institutes of Health, RePORTER application 10350672, Discovery and CRISPR validation of genetic factors associated with antipsychotic-induced weight gain and cardiometabolic risk (5R01MH122686-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10350672. Licensed CC0.

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