Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease

Jacob Bergstedt; Joëlle A Pasman; Ziyan Ma; Arvid Harder; Shuyang Yao; Nadine Parker; Jorien L Treur; Dirk J A Smit; Oleksandr Frei; Alexey A Shadrin; Joeri J Meijsen; Qing Shen; Sara Hägg; Per Tornvall; Alfonso Buil; Thomas Werge; Jens Hjerling-Leffler; Thomas D Als; Anders D Børglum; Cathryn M Lewis; Andrew M McIntosh; Unnur A Valdimarsdóttir; Ole A Andreassen; Patrick F Sullivan; Yi Lu; Fang Fang

doi:10.1038/s44161-024-00488-y

Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease

Nat Cardiovasc Res. 2024;3(6):754-769. doi: 10.1038/s44161-024-00488-y. Epub 2024 Jun 17.

Authors

Jacob Bergstedt^#¹, Joëlle A Pasman^#², Ziyan Ma^#², Arvid Harder², Shuyang Yao^{2

3}, Nadine Parker⁴, Jorien L Treur⁵, Dirk J A Smit⁵, Oleksandr Frei^{4

6}, Alexey A Shadrin^{4

7}, Joeri J Meijsen⁸, Qing Shen^{1

9

10}, Sara Hägg², Per Tornvall¹¹, Alfonso Buil⁸, Thomas Werge^{8

12}, Jens Hjerling-Leffler³, Thomas D Als^{13

14

15}, Anders D Børglum^{14

15}, Cathryn M Lewis^{16

17}, Andrew M McIntosh^{18

19}, Unnur A Valdimarsdóttir^{1

20

21}, Ole A Andreassen^{4

7}, Patrick F Sullivan^{2

22

23}, Yi Lu^#², Fang Fang^#¹

Affiliations

¹ Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³ Department Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
⁴ Centre for Precision Psychiatry, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Oslo, Norway.
⁵ Genetic Epidemiology, Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁶ Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
⁷ K.G. Jebsen Centre for Neurodevelopmental Disorders, University of Oslo and Oslo University Hospital, Oslo, Norway.
⁸ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
⁹ Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine, Shanghai, China.
¹⁰ Institute for Advanced Study, Tongji University, Shanghai, China.
¹¹ Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹² Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹³ Department of Molecular Medicine (MOMA), Molecular Diagnostic Laboratory, Aarhus University Hospital, Aarhus, Denmark.
¹⁴ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
¹⁵ Center for Genomics and Personalized Medicine, Aarhus, Denmark.
¹⁶ Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
¹⁷ Department of Medical and Molecular Genetics, King's College London, London, UK.
¹⁸ Centre for Clinical Brain Sciences, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
¹⁹ Centre for Genomics and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
²⁰ Centre of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
²¹ Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Boston, MA USA.
²² Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.
²³ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.

^# Contributed equally.

Abstract

Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Here we show that CVDs share most of their genetic risk factors with MDD. Multivariate genome-wide association analysis of shared genetic liability between MDD and atherosclerotic CVD revealed seven loci and distinct patterns of tissue and brain cell-type enrichments, suggesting the involvement of the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic and psychosocial or lifestyle risk factors. Our data indicated causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and showed that the causal effects were partly explained by metabolic and psychosocial or lifestyle factors. The distinct signature of MDD-atherosclerotic CVD comorbidity suggests an immunometabolic subtype of MDD that is more strongly associated with CVD than overall MDD. In summary, we identified biological mechanisms underlying MDD-CVD comorbidity and modifiable risk factors for prevention of CVD in individuals with MDD.

Keywords: Cardiovascular diseases; Genetics research; Genome-wide association studies.

Abstract

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