Genetic risk for bipolar disorder and schizophrenia predicts structure and function of the ventromedial prefrontal cortex

Genetic risk for bipolar disorder and schizophrenia predicts structure and function of the ventromedial prefrontal cortex

J Psychiatry Neurosci 2021;46(4):E441-E450 | PDF | Appendix

Christoph Abé, PhD; Predrag Petrovic, MD, PhD; William Ossler, MD; William H. Thompson, PhD; Benny Liberg, MD, PhD; Jie Song, PhD; Sarah E. Bergen, PhD; Carl M. Sellgren, MD, PhD; Peter Fransson, PhD; Martin Ingvar, MD, PhD; Mikael Landén, MD, PhD

Background: Bipolar disorder is highly heritable and polygenic. The polygenic risk for bipolar disorder overlaps with that of schizophrenia, and polygenic scores are normally distributed in the population. Bipolar disorder has been associated with structural brain abnormalities, but it is unknown how these are linked to genetic risk factors for psychotic disorders.

Methods: We tested whether polygenic risk scores for bipolar disorder and schizophrenia predict structural brain alterations in 98 patients with bipolar disorder and 81 healthy controls. We derived brain cortical thickness, surface area and volume from structural MRI scans. In post-hoc analyses, we correlated polygenic risk with functional hub strength, derived from resting-state functional MRI and brain connectomics.

Results: Higher polygenic risk scores for both bipolar disorder and schizophrenia were associated with a thinner ventromedial prefrontal cortex (vmPFC). We found these associations in the combined group, and separately in patients and drug-naive controls. Polygenic risk for bipolar disorder was correlated with the functional hub strength of the vmPFC within the default mode network.

Limitations: Polygenic risk is a cumulative measure of genomic burden. Detailed genetic mechanisms underlying brain alterations and their cognitive consequences still need to be determined.

Conclusion: Our multimodal neuroimaging study linked genomic burden and brain endophenotype by demonstrating an association between polygenic risk scores for bipolar disorder and schizophrenia and the structure and function of the vmPFC. Our findings suggest that genetic factors might confer risk for psychotic disorders by influencing the integrity of the vmPFC, a brain region involved in self-referential processes and emotional regulation. Our study may also provide an imaging–genetics vulnerability marker that can be used to help identify individuals at risk for developing bipolar disorder.


Submitted Aug. 21, 2020; Revised Dec. 28, 2020; Accepted Feb. 14, 2021

Acknowledgements: We thank the patients who participated in this study. We also thank the staff at the St. Göran bipolar affective disorder unit, including study coordinators, nurses and data managers.

Affiliations: From the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Abé, Petrovic, Ossler, Thompson, Liberg, Fransson, Ingvar, Landén); the Department of Psychology, Stanford University, Stanford, California, USA (Thompson); the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Song, Bergen); the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (Sellgren); Karolinska University Hospital, Department of Neuroradiology, Stockholm, Sweden (Ingvar); and the Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the Gothenburg University, Sweden (Landén).

Data availability: Data access and codes can be obtained on reasonable request.

Funding: This work was supported by the Swedish Medical Research Council (grant no. 2018-02653; to ML), the Swedish Foundation for Strategic Research (grant no. KF10-0039; to ML), the Swedish Brain Foundation (to ML), the Swedish Federal Government under the LUA/ALF agreement (grant nos. ALF20170019 and ALFGBG-71680; to ML), and the Barbro and Bernard Osher Foundation (to MI). Funding sources were not involved in study design, collection, analysis, or interpretation of data, nor in the writing of the report or decision to submit the paper for publication. PP was supported by the Swedish Research Foundation (Vetenskapsrådet; VR; 2019-01253 and 2014-30186-113005-199, ALF Medicine (20160039 and 20140306), the Swedish Brain Foundation (Hjärnfonden; FO2016-0083), Marianne och Marcus Wallenbergs Stiftelse (MMW2014.0065) and Karolinska Institutet (2-70/2014-97).

Competing interests: Dr. Landén reports grants from the Swedish Medical Research Council, the Swedish Foundation for Strategic Research and the Swedish Federal Government during the conduct of the study. No other competing interests declared.

Contributors: P. Petrovic and M. Landén designed the study. C. Sellgren, M. Ingvar and M. Landén acquired the data, which C. Abé, P. Petrovic, W. Ossler, W. Thompson, B. Liberg, J. Song, S. Bergen and P. Fransson analyzed. C. Abé, P. Petrovic, W. Ossler, B. Liberg, J. Song and M. Landén wrote the article, which P. Petrovic, W. Thompson, B. Liberg, S. Bergen, C. Sellgren, P. Fransson, M. Ingvar and M. Landén reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BYNC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

DOI: 10.1503/jpn.200165

Correspondence to: C. Abé, Department of Clinical Neuroscience, Karolinska Institutet, Nobels väg 9, 17177 Stockholm, Sweden; christoph.abe@ki.se