AUTHOR=Kim Myungsuk , Park Kye Won , Ahn Yeongseon , Lim Eun Bi , Kwak Soo Heon , Randy Ahmad , Song No Joon , Park Kyong Soo , Nho Chu Won , Cho Yoon Shin 

TITLE=Genetic association-based functional analysis detects HOGA1 as a potential gene involved in fat accumulation

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.951025

DOI=10.3389/fgene.2022.951025

ISSN=1664-8021

ABSTRACT=<p>Although there are a number of discoveries from genome-wide association studies (GWAS) for obesity, it has not been successful in linking GWAS results to biology. We sought to discover causal genes for obesity by conducting functional studies on genes detected from genetic association analysis. Gene-based association analysis of 917 individual exome sequences showed that <italic>HOGA1</italic> attains exome-wide significance (<italic>p</italic>-value &lt; 2.7 × 10<sup>–6</sup>) for body mass index (BMI). The mRNA expression of <italic>HOGA1</italic> is significantly increased in human adipose tissues from obese individuals in the Genotype-Tissue Expression (GTEx) dataset, which supports the genetic association of <italic>HOGA1</italic> with BMI. Functional analyses employing cell- and animal model-based approaches were performed to gain insights into the functional relevance of <italic>Hoga1</italic> in obesity. Adipogenesis was retarded when <italic>Hoga1</italic> was knocked down by siRNA treatment in a mouse 3T3-L1 cell line and a similar inhibitory effect was confirmed in mice with down-regulated <italic>Hoga1</italic>. <italic>Hoga1</italic> antisense oligonucleotide (ASO) treatment reduced body weight, blood lipid level, blood glucose, and adipocyte size in high-fat diet-induced mice. In addition, several lipogenic genes including <italic>Srebf1</italic>, <italic>Scd1</italic>, <italic>Lp1</italic>, and <italic>Acaca</italic> were down-regulated, while lipolytic genes <italic>Cpt1l</italic>, <italic>Ppara</italic>, and <italic>Ucp1</italic> were up-regulated. Taken together, <italic>HOGA1</italic> is a potential causal gene for obesity as it plays a role in excess body fat development.</p>