A rare variant in GPR156 associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice

• 成果类型: Article
• 署名作者: Millera, Bradley R.; Gonzaga-Jaureguic, Claudia; Brigattie, Karlla W.; de Jonga, Job; Breeseg, Robert S.; Ko, Seungyeon; Puffenbergere, Erik G.; Van Houtc, Cristopher; Younge, Millie; Lunah, Victor M.; Staplesc, Jeffrey; First, Michael B.; Gregoirea, Hilledna J.; Dworka, Andrew J.; Pefanisg, Evangelos; Mccarthyc, Shane; Brydges, Susannah; Rojasg, Jose; Yec, Bin; Stahlc, Eli; Di Gioiac, Silvio Alessandro; Hena, Rene; Elwoodi, Kevin; Rosoklijaa, Gorazd; Lic, Dadong; Mellisg, Scott; Careyi, David; Crollg, Susan D.; Overtonc, John D.; Macdonaldg, Lynn E.; Economidesc, Aris N.; Shuldinerc, Alan R.; Chuhmaf, Nao; Rayportf, Stephen; Aminj, Najaf; Kushnera, Steven A.; Haberg, Nicole Alessandri-; Markx, Sander; Strauss, Kevin A.
• 署名单位: Columbia University; New York State Psychiatry Institute; Regeneron; Universidad Nacional Autonoma de Mexico; New York State Psychiatry Institute; Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple University; Geisinger Health System; Erasmus University Rotterdam; Erasmus MC; Erasmus University Rotterdam; Erasmus MC; University of Massachusetts System; University of Massachusetts Worcester; University of Massachusetts System; University of Massachusetts Worcester
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13140
• DOI: 10.1073/pnas.2404754122
• 发表日期: 2025-04-22
• 关键词: behavioral despair; lateral habenula; mood disorders; MODEL; population; ANXIETY; medicine; insights; disease; targets

摘要

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 Gpr156locus 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.