Integrating Genetic and Transcriptomic Data to Identify Genes Underlying Obesity Risk Loci

Overview

Journal medRxiv

Date 2024 Jun 21

PMID 38903089

Authors

Hanfei Xu

Shreyash Gupta

Ian Dinsmore

Abbey Kollu

Anne Marie Cawley

Mohammad Y Anwar

Hung-Hsin Chen

Lauren E Petty

Sudha Seshadri

Misa Graff

Piper Below

Jennifer A Brody

Geetha Chittoor

Susan P Fisher-Hoch

Nancy L Heard-Costa

Daniel Levy

Honghuang Lin

Ruth Jf Loos

Joseph B McCormick

Jerome I Rotter

Tooraj Mirshahi

Christopher D Still

Anita Destefano

L Adrienne Cupples

Karen L Mohlke

Kari E North

Anne E Justice

Ching-Ti Liu

Affiliations

Soon will be listed here.

Abstract

Genome-wide association studies (GWAS) have identified numerous body mass index (BMI) loci. However, most underlying mechanisms from risk locus to BMI remain unknown. Leveraging omics data through integrative analyses could provide more comprehensive views of biological pathways on BMI. We analyzed genotype and blood gene expression data in up to 5,619 samples from the Framingham Heart Study (FHS). Using 3,992 single nucleotide polymorphisms (SNPs) at 97 BMI loci and 20,692 transcripts within 1 Mb, we performed separate association analyses of transcript with BMI and SNP with transcript (P and P, respectively) and then a correlated meta-analysis between the full summary data sets (P). We identified transcripts that met Bonferroni-corrected significance for each omic, were more significant in the correlated meta-analysis than each omic, and were at least nominally associated with BMI in FHS data. Among 308 significant SNP-transcript-BMI associations, we identified seven genes (, , , , , , and ) in five association regions. Using an independent sample of blood gene expression data, we validated results for and . We tested for generalization of these associations in hypothalamus, nucleus accumbens, and liver and observed significant (P<0.05 & P<P & P<P) results for in nucleus accumbens and , , , , and in liver. The identified genes help link the genetic variation at obesity risk loci to biological mechanisms and health outcomes, thus translating GWAS findings to function.

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