SGCG rs679482 Associates With Weight Loss Success in Response to an Intensively Supervised Outpatient Program Majid Nikpay, 1 Paulina Lau, 2 Sébastien Soubeyrand, 2 Katey L. Whytock, 3 Kaitlyn Beehler, 2 Chantal Pileggi, 4 Sujoy Ghosh, 5 Mary-Ellen Harper, 4 Robert Dent, 6 and Ruth McPherson 1,2,7 Diabetes 2020;69:2017–2026 | https://doi.org/10.2337/db20-0219 Weight loss in response to energy restriction is highly vari- able, and identi fication of genetic contributors can provide insights into underlying biology. Leveraging 1000 Genomes imputed genotypes, we carried out genome-wide associa- tion study (GWAS) analysis in 551 unrelated obese subjects of European ancestry who participated in an intensively supervised weight loss program with replication of prom- ising signals in an independent sample of 1,331 obese subjects who completed the program at a later date. By single nucleotide polymorphism–based and sib-pair analy- sis, we show that that weight loss is a heritable trait, with estimated heritability (h 2 5 0.49) within the range reported for obesity. We find rs679482, intronic to SGCG (sarcoglycan g), highly expressed in skeletal muscle, to concordantly associate with weight loss in discovery and replication samples reaching GWAS signi ficance in the combined meta-analysis (b520.35, P 5 1.7 3 10 212 ). Located in a region of open chromatin, rs679482 is predicted to bind DMRT2, and allele-speci fic transcription factor binding analysis indicates preferential binding of DMRT2 to rs679482-A. Concordantly, rs679482-A impairs native re- pressor activity and increases basal and DMRT2-mediated enhancer activity. These findings confirm that weight loss is a heritable trait and provide evidence by which a novel variant in SGCG, rs679482, leads to impaired diet response. Obesity is a complex phenotype (1), and energy intake, physical activity, non–exercise-associated energy expendi- ture, and genetic factors contribute to different degrees in a given individual. Weight loss variability in response to a variety of interventions is well-documented (2,3) and is in part a heritable trait (4). Bouchard et al. (5) demon- strated elegantly that identical twin pairs exhibit very high concordance for weight loss in response to exercise—in contrast to marked variability among dizygotic twin pairs. Hatoum et al. (6) reported that a 15q26.1 locus near ST8SIA2 and SLCO3A1 was significantly associated with weight loss after Roux-en-Y gastric bypass (RYGB). More recently, Heianza et al. (7) demonstrated that a common copy number variant in the amylase gene cluster confers greater weight loss in response to diet. In the Look AHEAD (Action for Health in Diabetes) trial, McCaffery et al. (8) used the Illumina CARe iSelect (IBC) chip to identify single nucleotide polymorphisms (SNPs) at the ABCB11 and TNFRSF11A loci that associated with weight loss at year 1. Also in support of the hypothesis that weight loss post– bariatric surgery is not simply a function of dietary com- pliance, Hatoum et al. (9) found that first-degree relatives exhibit similar weight loss in response to RYGB compared with unrelated or, more interestingly, cohabitating indi- viduals. Furthermore, we recently reported that weight loss in response to dietary intervention was highly corre- lated with weight loss following RYGB (10). To investigate the biology underlying these differences, we have extensively characterized a large cohort of obese subjects enrolled in the Weight Management Clinic at The Ottawa Hospital. In support of the hypothesis that weight 1 Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada 2 Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada 3 Translational Research Institute for Metabolism and Diabetes, AdventHealth, Orlando, FL 4 Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada 5 Duke-NUS Medical School, Singapore, Singapore 6 Weight Management Clinic, The Ottawa Hospital, Ottawa, Canada 7 Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada Corresponding author: Ruth McPherson, rmcpherson@ottawaheart.ca Received 3 March 2020 and accepted 7 June 2020 This article contains supplementary material online at https://doi.org/10.2337/ figshare.12448796. © 2020 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals .org/content/license. Diabetes Volume 69, September 2020 2017 GENETICS/GENOMES/PROTEOMICS/METABOLOMICS Downloaded from http://diabetesjournals.org/diabetes/article-pdf/69/9/2017/431386/db200219.pdf by guest on 19 February 2022