Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr 22;122(16):e2404754122.
doi: 10.1073/pnas.2404754122. Epub 2025 Apr 14.

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

Bradley R Miller #  1   2 , Claudia Gonzaga-Jauregui #  3   4 , Karlla W Brigatti #  5 , Job de Jong #  1   6 , Robert S Breese #  7 , Seung Yeon Ko #  1   2 , Erik G Puffenberger #  5 , Cristopher Van Hout  3   4 , Millie Young  5 , Victor M Luna  8 , Jeffrey Staples  3 , Michael B First  1 , Hilledna J Gregoire  1   2 , Andrew J Dwork  1 , Evangelos Pefanis  7 , Shane McCarthy  3 , Susannah Brydges  7 , Jose Rojas  7 , Bin Ye  3 , Eli Stahl  3 , Silvio Alessandro Di Gioia  3 , René Hen  1   2 , Kevin Elwood  9 , Gorazd Rosoklija  1 , Dadong Li  3 , Scott Mellis  7 , David Carey  9 , Susan D Croll  7 , John D Overton  3 , Lynn E Macdonald  7 , Aris N Economides  3   7 , Alan R Shuldiner  3 , Nao Chuhma  6 , Stephen Rayport  6 , Najaf Amin  10   11 , Steven A Kushner  1   2 , Nicole Alessandri-Haber #  7 , Sander Markx #  1   6 , Kevin A Strauss #  5   12   13
Affiliations

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

Bradley R Miller et al. Proc Natl Acad Sci U S A. .

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.

Keywords: GPR156; genetics; major depressive disorder; medial habenula; orphan G protein-coupled receptor.

PubMed Disclaimer

Conflict of interest statement

Competing interests statement:J.S., S.M., J.D.O., A.R.S., R.S.B., S.B., A.N.E., E.L.P., J.R., B.Y., D.L., E.S., S.A.D.G., S.M., S.D.C., L.E.M., N.A.-H. are full-time employees of the Regeneron Genetics Center or Regeneron Pharmaceuticals Inc. and receive salary and stock options as part of compensation. C.G.-J. and C.V.H. were full-time employees of the Regeneron Genetics Center at the time of study and received salary and stock options as part of compensation., C.G.-J., N.A.-H., R.B., S.C., J.R., and S.B. are inventors on patent US-20230123787-A1. C.G.-J. is an inventor on patent US-2020231651-A1.

Similar articles

See all similar articles

References

    1. World Health Organization, Depression and Other Common Mental Disorders: Global Health Estimates (World Health Organization, 2017) https://apps.who.int/iris/handle/10665/254610.
    1. Bromet E., et al. , Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 9, 90 (2011). - PMC - PubMed
    1. Kessler R. C., Bromet E. J., The epidemiology of depression across cultures. Annu. Rev. Public Health 34, 119–138 (2013). - PMC - PubMed
    1. Insel T. R., Disruptive insights in psychiatry: Transforming a clinical discipline. J. Clin. Invest. 119, 700–705 (2009). - PMC - PubMed
    1. Malhi G. S., et al. , Primary prevention of mood disorders: A primary concern that requires urgent action. J. Am. Acad. Child Adolesc. Psychiatry 57, 629–631 (2018). - PubMed

Substances

LinkOut - more resources