Cell Reports (Aug 2023)
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
Affiliations
- Sarah N. Wright
- 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
- Brittany S. Leger
- 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
- Sara Brin Rosenthal
- Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
- Sophie N. Liu
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Tongqiu Jia
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Apurva S. Chitre
- Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA
- Oksana Polesskaya
- Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA
- Katie Holl
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Jianjun Gao
- Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA
- Riyan Cheng
- Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA
- Angel Garcia Martinez
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
- Anthony George
- Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY 14203, USA
- Alexander F. Gileta
- Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
- Wenyan Han
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
- Alesa H. Netzley
- Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA
- Christopher P. King
- Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY 14203, USA; Department of Psychology, University at Buffalo, Buffalo, NY 14260, USA
- Alexander Lamparelli
- Department of Psychology, University at Buffalo, Buffalo, NY 14260, USA
- Connor Martin
- Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY 14203, USA; Department of Psychology, University at Buffalo, Buffalo, NY 14260, USA
- Celine L. St. Pierre
- Department of Genetics, Washington University, St. Louis, MO 63110, USA
- Tengfei Wang
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
- Hannah Bimschleger
- Department of Psychiatry, University of California San Diego, La Jolla, CA 93093, USA
- Jerry Richards
- Clinical and Research Institute on Addictions, University at Buffalo, Buffalo, NY 14203, USA
- Keita Ishiwari
- 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
- Hao Chen
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
- Shelly B. Flagel
- Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA
- Paul Meyer
- Department of Psychology, University at Buffalo, Buffalo, NY 14260, USA
- Terry E. Robinson
- Department of Psychology, University of Michigan, Ann Arbor, MI 48109, USA
- Leah C. Solberg Woods
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Jason F. Kreisberg
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
- Trey Ideker
- 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; Corresponding author
- Abraham A. Palmer
- 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; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 8
p. 112873
Abstract
Summary: 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.
