A rare variant in <i>GPR156</i> associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (39)
Bradley R. Miller
Department of Psychiatry, Columbia University
Claudia Gonzaga-Jauregui
Regeneron Genetics Center
Karlla W. Brigatti
Clinic for Special Children
Job de Jong
Department of Psychiatry, Columbia University
Robert S. Breese
Regeneron Pharmaceuticals Inc. Tarrytown
Seung Yeon Ko
Department of Psychiatry, Columbia University
Erik G. Puffenberger
Clinic for Special Children
Cristopher Van Hout
Regeneron Genetics Center
Millie Young
Clinic for Special Children
Victor M. Luna
Department of Neural Sciences, Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University
Jeffrey Staples
Michael B. First
Department of Psychiatry, Columbia University
Hilledna J. Gregoire
Department of Psychiatry, Columbia University
Andrew J. Dwork
Evangelos Pefanis
Regeneron Pharmaceuticals Inc. Tarrytown
Shane McCarthy
Tree of Life Programme, Wellcome Sanger Institute
Susannah Brydges
Regeneron Pharmaceuticals Inc. Tarrytown
Jose Rojas
Regeneron Pharmaceuticals Inc. Tarrytown
Bin Ye
Eli Stahl
Silvio Alessandro Di Gioia
Regeneron Genetics Center
René Hen
Department of Psychiatry, Columbia University
Kevin Elwood
Geisinger Health System
Gorazd Rosoklija
Department of Psychiatry, Columbia University
Dadong Li
Scott Mellis
Regeneron Pharmaceuticals Inc. Tarrytown
David Carey
Geisinger Health System
Susan D. Croll
Regeneron Pharmaceuticals Inc. Tarrytown
John D. Overton
Lynn E. Macdonald
Regeneron Pharmaceuticals Inc. Tarrytown
Aris N. Economides
Connective Tissue Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals
Alan R. Shuldiner
Nao Chuhma
Division of Molecular Therapeutics, New York State Psychiatric Institute
Stephen Rayport
Division of Molecular Therapeutics, New York State Psychiatric Institute
Najaf Amin
Department of Psychiatry, Erasmus University Medical Center
Steven A. Kushner
Nicole Alessandri-Haber
Regeneron Pharmaceuticals Inc. Tarrytown
Sander Markx
Department of Psychiatry, Columbia University
Kevin A. Strauss
Clinic for Special Children