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

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

doi:10.1073/pnas.2404754122

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

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^*

^*Corresponding author for this work

Columbia University
Regeneron Pharmaceuticals, Inc.
Universidad Nacional Autónoma de México
Clinic for Special Children
New York State Psychiatric Institute
Temple University
Geisinger Medical Center
Penn Medicine-Lancaster General Hospital
University of Massachusetts Medical School

Research output: Contribution to journal › Article › Academic › peer-review

1 Citation (Scopus)

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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.

Original language	English
Article number	e2404754122
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	122
Issue number	16
DOIs	https://doi.org/10.1073/pnas.2404754122
Publication status	Published - 14 Apr 2025

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© 2025 the Author(s).

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A rare variant in GPR156 associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in miceFinal published version, 2.13 MBLicence: CC BY-NC-ND

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Miller, B. R., Gonzaga-Jauregui, C., Brigatti, K. W., de Jong, J., Breese, R. S., Ko, S. Y., Puffenberger, E. G., Van Hout, C., Young, M., Luna, V. M., Staples, J., First, M. B., Gregoire, H. J., Dwork, A. J., Pefanis, E., McCarthy, S., Brydges, S., Rojas, J., Ye, B., ... Strauss, K. A. (2025). A rare variant in GPR156 associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice. Proceedings of the National Academy of Sciences of the United States of America, 122(16), Article e2404754122. https://doi.org/10.1073/pnas.2404754122

@article{c75847ca65264117b0ede6f986725b0c,

title = "A rare variant in GPR156 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.",

author = "Miller, \{Bradley R.\} and Claudia Gonzaga-Jauregui and Brigatti, \{Karlla W.\} and \{de Jong\}, Job and Breese, \{Robert S.\} and Ko, \{Seung Yeon\} and Puffenberger, \{Erik G.\} and \{Van Hout\}, Cristopher and Millie Young and Luna, \{Victor M.\} and Jeffrey Staples and First, \{Michael B.\} and Gregoire, \{Hilledna J.\} and Dwork, \{Andrew J.\} and Evangelos Pefanis and Shane McCarthy and Susannah Brydges and Jose Rojas and Bin Ye and Eli Stahl and \{Di Gioia\}, \{Silvio Alessandro\} and Ren{\'e} Hen and Kevin Elwood and Gorazd Rosoklija and Dadong Li and Scott Mellis and David Carey and Croll, \{Susan D.\} and Overton, \{John D.\} and Macdonald, \{Lynn E.\} and Economides, \{Aris N.\} and Shuldiner, \{Alan R.\} and Nao Chuhma and Stephen Rayport and Najaf Amin and Kushner, \{Steven A.\} and Nicole Alessandri-Haber and Sander Markx and Strauss, \{Kevin A.\}",

note = "Publisher Copyright: {\textcopyright} 2025 the Author(s).",

year = "2025",

month = apr,

day = "14",

doi = "10.1073/pnas.2404754122",

language = "English",

volume = "122",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Miller, BR, Gonzaga-Jauregui, C, Brigatti, KW, de Jong, J, Breese, RS, Ko, SY, Puffenberger, EG, Van Hout, C, Young, M, Luna, VM, Staples, J, First, MB, Gregoire, HJ, Dwork, AJ, Pefanis, E, McCarthy, S, Brydges, S, Rojas, J, Ye, B, Stahl, E, Di Gioia, SA, Hen, R, Elwood, K, Rosoklija, G, Li, D, Mellis, S, Carey, D, Croll, SD, Overton, JD, Macdonald, LE, Economides, AN, Shuldiner, AR, Chuhma, N, Rayport, S, Amin, N, Kushner, SA, Alessandri-Haber, N, Markx, S & Strauss, KA 2025, 'A rare variant in GPR156 associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 122, no. 16, e2404754122. https://doi.org/10.1073/pnas.2404754122

A rare variant in GPR156 associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice. / Miller, Bradley R.; Gonzaga-Jauregui, Claudia; Brigatti, Karlla W. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 122, No. 16, e2404754122, 14.04.2025.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - A rare variant in GPR156 associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice

AU - Miller, Bradley R.

AU - Gonzaga-Jauregui, Claudia

AU - Brigatti, Karlla W.

AU - de Jong, Job

AU - Breese, Robert S.

AU - Ko, Seung Yeon

AU - Puffenberger, Erik G.

AU - Van Hout, Cristopher

AU - Young, Millie

AU - Luna, Victor M.

AU - Staples, Jeffrey

AU - First, Michael B.

AU - Gregoire, Hilledna J.

AU - Dwork, Andrew J.

AU - Pefanis, Evangelos

AU - McCarthy, Shane

AU - Brydges, Susannah

AU - Rojas, Jose

AU - Ye, Bin

AU - Stahl, Eli

AU - Di Gioia, Silvio Alessandro

AU - Hen, René

AU - Elwood, Kevin

AU - Rosoklija, Gorazd

AU - Li, Dadong

AU - Mellis, Scott

AU - Carey, David

AU - Croll, Susan D.

AU - Overton, John D.

AU - Macdonald, Lynn E.

AU - Economides, Aris N.

AU - Shuldiner, Alan R.

AU - Chuhma, Nao

AU - Rayport, Stephen

AU - Amin, Najaf

AU - Kushner, Steven A.

AU - Alessandri-Haber, Nicole

AU - Markx, Sander

AU - Strauss, Kevin A.

PY - 2025/4/14

Y1 - 2025/4/14

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105003616421

U2 - 10.1073/pnas.2404754122

DO - 10.1073/pnas.2404754122

M3 - Article

C2 - 40228124

AN - SCOPUS:105003616421

SN - 0027-8424

VL - 122

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 16

M1 - e2404754122

ER -

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

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