A rare variant in GPR156 associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice
Year: 2025
Type: article
Study design: Observational Study
Abstract: Major depressive disorder (MDD) is a leading cause of disability worldwide. Risk for MDD is heritable, and the genetic structure of founder populations enables investigation of rare susceptibility alleles with large effect. In an extended Old Order Mennonite family cohort, we identified a rare missense variant in GPR156 (c.1599G>T, p.Glu533Asp) associated with a two-fold increase in the relative risk of MDD. GPR156 is an orphan G protein–coupled receptor localized in the medial habenula, a region implicated in mood regulation. Insertion of a human sequence containing c.1599G>T into the murine Gpr156 locus induced medial habenula hyperactivity and abnormal stress-related behaviors. This work reveals a human variant that is associated with depression, implicates GPR156 as a target for mood regulation, and introduces informative murine models for investigating the pathophysiology and treatment of affective disorders.
Authors: Bradley R. Miller, Claudia Gonzaga-Jauregui, Karlla W. Brigatti, Job de Jong, Robert S. Breese, Seung Yeon Ko, Erik G. Puffenberger, Cristopher Van Hout, Millie Young, Victor M. Luna, Jeffrey Staples, Michael B. First, Hilledna J. Gregoire, Andrew J. Dwork, Evangelos Pefanis, Shane McCarthy, Susannah Brydges, Jose Rojas, Bin Ye, Eli Stahl, Silvio Alessandro Di Gioia, René Hen, Kevin Elwood, Gorazd Rosoklija, Dadong Li, Scott Mellis, David Carey, Susan D. Croll, John D. Overton, Lynn E. Macdonald, Aris N. Economides, Alan R. Shuldiner, Nao Chuhma, Stephen Rayport, Najaf Amin, Steven A. Kushner, Nicole Alessandri-Haber, Sander Markx, Kevin A. Strauss
Institutions: New York State Psychiatric Institute, Columbia University, Regeneron (United States), Universidad Nacional Autónoma de México, Clinic for Special Children, Temple University, Geisinger Health System, Erasmus MC, University of Massachusetts Chan Medical School, Lancaster General Hospital, University of Pennsylvania Health System
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Awards: G1284750487, Cellular Mechanisms of Antidepressant Action, Adult hippocampal neuroplasticity and depression, G248017920, Hippocampal neurogenesis, pattern separation & age-related cognitive impairments., 2-photon microscope for in vivo functional imaging of neuronal circuits, 1/5 Clinical Outcome Prediction of Psychosis from EHRs (COPPER), 5/5 Clinical Outcome Prediction of Psychosis from Electronic Health Records (COPPER), G904455231, G911393642
OpenAlex ID: W4409416047