Neuroticism has been shown to act as an important risk factor for major depressive disorder (MDD). Genetic and neuroimaging research has independently revealed biological correlates of neurotic personality including cortical alterations in brain regions of high relevance for affective disorders. Here we investigated the influence of a polygenic score for neuroticism (PGS) on cortical brain structure in a joint discovery sample of n = 746 healthy controls (HC) and n = 268 MDD patients. Findings were validated in an independent replication sample (n = 341 HC and n = 263 MDD). Subgroup analyses stratified for case-control status and analyses of associations between neurotic phenotype and cortical measures were carried out. PGS for neuroticism was significantly associated with a decreased cortical surface area of the inferior parietal cortex, the precuneus, the rostral cingulate cortex and the inferior frontal gyrus in the discovery sample. Similar associations between PGS and surface area of the inferior parietal cortex and the precuneus were demonstrated in the replication sample. Subgroup analyses revealed negative associations in the latter regions between PGS and surface area in both HC and MDD subjects. Neurotic phenotype was negatively correlated with surface area in similar cortical regions including the inferior parietal cortex and the precuneus. No significant associations between PGS and cortical thickness were detected. The morphometric overlap of associations between both PGS and neurotic phenotype in similar cortical regions closely related to internally focused cognition points to the potential relevance of genetically shaped cortical alterations in the development of neuroticism.

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This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5–1 and DA1151/5–2 to UD; SFB-TRR58, Projects C09 and Z02 to UD; FOR2107 KR3822/7–2, KO4291/3–1, and KR3822/5–1 to AK; JA1890/7–1 and JA1890/7–2 to AJ; NE2254/1-2 to IN; RI908/11-2 to MR; NO246/10-2 to MMN; HA7070/2-2 to TH; KI588/14-1 and KI588/14-2 to TK) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD) and the Deanery of the Medical Faculty of the University of Münster.

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Author notes

  1. These authors contributed equally: Bernhard T. Baune, Udo Dannlowski.


  1. Department of Psychiatry, University of Münster, Münster, Germany

    • Nils Opel
    • , Ronny Redlich
    • , Jonathan Repple
    • , Claas Kaehler
    • , Dominik Grotegerd
    • , Katharina Dohm
    • , Dario Zaremba
    • , Elisabeth J. Leehr
    • , Joscha Böhnlein
    • , Katharina Förster
    • , Christian Bürger
    • , Susanne Meinert
    • , Verena Enneking
    • , Daniel Emden
    • , Ramona Leenings
    • , Nils Winter
    • , Tim Hahn
    • , Volker Arolt
    •  & Udo Dannlowski
  2. Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, Australia

    • Azmeraw T. Amare
    •  & Bernhard T. Baune
  3. South Australian Academic Health Science and Translation Centre, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia

    • Azmeraw T. Amare
  4. Department of Mathematics and Computer Science, University of Münster, Münster, Germany

    • Claas Kaehler
  5. Institute of Clinical Radiology, University of Münster, Münster, Germany

    • Walter Heindel
    •  & Jochen Bauer
  6. Department of Psychiatry, University of Marburg, Marburg, Germany

    • David Wilhelms
    • , Simon Schmitt
    • , Andreas Jansen
    • , Axel Krug
    • , Igor Nenadic
    •  & Tilo Kircher
  7. Department of Genetic Epidemiology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

    • Marcella Rietschel
    •  & Stephanie Witt
  8. Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    • Andreas J. Forstner
    •  & Markus M. Nöthen
  9. Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia

    • Bernhard T. Baune


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All authors declare that they have no conflict of interest.

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Correspondence to Udo Dannlowski.

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