A rare variant in <i>GPR156</i> associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice
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 <i>GPR156</i> (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 <i>Gpr156</i> 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
- Aris N. Economides (ORCID: https://orcid.org/0000-0002-6508-8942)
- Najaf Amin (ORCID: https://orcid.org/0000-0002-8944-1771)
- Evangelos Pefanis
- Joop de Jong (ORCID: https://orcid.org/0000-0002-7652-7509)
- Michael B. First (ORCID: https://orcid.org/0000-0002-8032-3947)
- Robert Breese
- Eli A. Stahl (ORCID: https://orcid.org/0000-0002-1192-0561)
- Erik G. Puffenberger (ORCID: https://orcid.org/0000-0002-6388-9148)
- Alan R. Shuldiner (ORCID: https://orcid.org/0000-0001-9921-4305)
- Karlla W. Brigatti (ORCID: https://orcid.org/0000-0002-9178-815X)
- Millie Young (ORCID: https://orcid.org/0000-0001-6014-5189)
- Lynn E. Macdonald (ORCID: https://orcid.org/0000-0002-2547-4523)
- Cristopher V. Van Hout (ORCID: https://orcid.org/0000-0001-9689-5344)
- Gorazd Rosoklija (ORCID: https://orcid.org/0000-0003-2711-1694)
- Bradley R. Miller (ORCID: https://orcid.org/0000-0003-4044-2412)
- Kevin A. Strauss (ORCID: https://orcid.org/0000-0002-6429-8657)
- Nicole Alessandri‐Haber
- John D. Overton (ORCID: https://orcid.org/0000-0001-7650-8634)
- Dadong Li (ORCID: https://orcid.org/0000-0003-0868-4884)
- Steven A. Kushner (ORCID: https://orcid.org/0000-0002-9777-3338)
- Jeffrey Staples (ORCID: https://orcid.org/0000-0002-9132-235X)
- Sander Markx (ORCID: https://orcid.org/0000-0002-7483-0352)
- Scott Mellis (ORCID: https://orcid.org/0009-0008-3991-2177)
- René Hen (ORCID: https://orcid.org/0000-0002-7763-4162)
- Silvio Alessandro Di Gioia (ORCID: https://orcid.org/0000-0002-7235-5682)
- Susannah Brydges (ORCID: https://orcid.org/0000-0002-3500-0313)
- Stephen Rayport (ORCID: https://orcid.org/0000-0001-9755-7486)
- Victor M. Luna (ORCID: https://orcid.org/0000-0002-6879-4308)
- Andrew J. Dwork (ORCID: https://orcid.org/0000-0002-9862-0384)
- Susan D. Croll (ORCID: https://orcid.org/0000-0002-3949-1877)
- David J. Carey (ORCID: https://orcid.org/0000-0001-6404-1950)
- Seung Yeon Ko
- Claudia Gonzaga‐Jauregui (ORCID: https://orcid.org/0000-0002-4667-3679)
- Kevin Elwood
- Nao Chuhma (ORCID: https://orcid.org/0000-0002-6846-3461)
- José Rojas (ORCID: https://orcid.org/0000-0001-5327-5508)
- Bin Ye (ORCID: https://orcid.org/0000-0003-1083-8432)
- Shane McCarthy
- Hilledna J. Gregoire
Institutions
- Clinic for Special Children (US)
- Regeneron (United States) (US)
- Erasmus MC (NL)
- Lancaster General Hospital (US)
- New York Psychoanalytic Society and Institute (US)
- University of Pennsylvania Health System (US)
- New York State Psychiatric Institute
- Geisinger Health System (US)
- Columbia University (US)
- Temple University (US)
- Universidad Nacional Autónoma de México (MX)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1073/pnas.2404754122
- Citations
- 1
- Primary Topic
- Neuropeptides and Animal Physiology
- Type
- article
- Field-Weighted Citation Impact
- 0.91