Genome-wide association studies of human and rat BMI converge on synapse, epigenome, and hormone signaling networks

Sarah N Wright; Brittany S Leger; Sara Brin Rosenthal; Sophie N Liu; Tongqiu Jia; Apurva S Chitre; Oksana Polesskaya; Katie Holl; Jianjun Gao; Riyan Cheng; Angel Garcia Martinez; Anthony George; Alexander F Gileta; Wenyan Han; Alesa H Netzley; Christopher P King; Alexander Lamparelli; Connor Martin; Celine L St Pierre; Tengfei Wang; Hannah Bimschleger; Jerry Richards; Keita Ishiwari; Hao Chen; Shelly B Flagel; Paul Meyer; Terry E Robinson; Leah C Solberg Woods; Jason F Kreisberg; Trey Ideker; Abraham A Palmer

doi:10.1016/j.celrep.2023.112873

Genome-wide association studies of human and rat BMI converge on synapse, epigenome, and hormone signaling networks

Cell Rep. 2023 Aug 29;42(8):112873. doi: 10.1016/j.celrep.2023.112873. Epub 2023 Jul 31.

Authors

Sarah N Wright¹, Brittany S Leger², Sara Brin Rosenthal³, Sophie N Liu⁴, Tongqiu Jia⁴, Apurva S Chitre⁵, Oksana Polesskaya⁵, Katie Holl⁶, Jianjun Gao⁵, Riyan Cheng⁵, Angel Garcia Martinez⁷, Anthony George⁸, Alexander F Gileta⁹, Wenyan Han⁷, Alesa H Netzley¹⁰, Christopher P King¹¹, Alexander Lamparelli¹², Connor Martin¹¹, Celine L St Pierre¹³, Tengfei Wang⁷, Hannah Bimschleger⁵, Jerry Richards⁸, Keita Ishiwari¹⁴, Hao Chen⁷, Shelly B Flagel¹⁵, Paul Meyer¹², Terry E Robinson¹⁶, Leah C Solberg Woods¹⁷, Jason F Kreisberg⁴, Trey Ideker¹⁸, Abraham A Palmer¹⁹

Affiliations

¹ Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Program in Bioinformatics and Systems Biology, University of California San Diego, La Jolla, CA 92093, USA.
² Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA; Program in Biomedical Sciences, University of California San Diego, La Jolla, CA 93093, USA.
³ Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁵ Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA.
⁶ Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁷ Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
⁸ Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY 14203, USA.
⁹ Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
¹⁰ Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY 14203, USA; Department of Psychology, University at Buffalo, Buffalo, NY 14260, USA.
¹² Department of Psychology, University at Buffalo, Buffalo, NY 14260, USA.
¹³ Department of Genetics, Washington University, St. Louis, MO 63110, USA.
¹⁴ Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY 14203, USA; Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY 14203, USA.
¹⁵ Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁶ Department of Psychology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁷ Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
¹⁸ Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: tideker@ucsd.edu.
¹⁹ Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: aap@ucsd.edu.

Abstract

A vexing observation in genome-wide association studies (GWASs) is that parallel analyses in different species may not identify orthologous genes. Here, we demonstrate that cross-species translation of GWASs can be greatly improved by an analysis of co-localization within molecular networks. Using body mass index (BMI) as an example, we show that the genes associated with BMI in humans lack significant agreement with those identified in rats. However, the networks interconnecting these genes show substantial overlap, highlighting common mechanisms including synaptic signaling, epigenetic modification, and hormonal regulation. Genetic perturbations within these networks cause abnormal BMI phenotypes in mice, too, supporting their broad conservation across mammals. Other mechanisms appear species specific, including carbohydrate biosynthesis (humans) and glycerolipid metabolism (rodents). Finally, network co-localization also identifies cross-species convergence for height/body length. This study advances a general paradigm for determining whether and how phenotypes measured in model species recapitulate human biology.

Keywords: BMI; CP: Genomics; GWAS; body mass index; cross-species; gene networks; genome-wide association studies; heterogeneous stock rat; network; network co-localization; rat.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Body Mass Index*
Body Size
Gene Regulatory Networks*
Genome-Wide Association Study
Humans
Mice
Rats
Species Specificity

Abstract

Publication types

MeSH terms

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