PhD Scientific Days 2021

Budapest, 7-8 July 2021

MH_I_P: Mental Health Sciences I. Posters

Circadian Clock Gene ARNTL Affects Depression Directly and Also Via Perseverative Negative Thinking

Nora Eszlari1,2, Bence Bruncsics3, Andras Millinghoffer2,3,4, Gabor Hullam3,5, Peter Petschner1,5, Xenia Gonda2,5,6, Gerome Breen7,8, Peter Antal3,4, Gyorgy Bagdy1,2,5, John Francis William Deakin9,10, Gabriella Juhasz1,5,11
1 Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary;
2 NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary;
3 Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary;
4 Abiomics Europe Ltd. Zólyomi út 23, Budapest 1118, Hungary
5 MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary;
6 Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
7 Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom;
8 UK National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust, London, United Kingdom;
9 Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, United Kingdom;
10 Manchester Mental Health and Social Care Partnership, Manchester, United Kingdom;
11 SE-NAP 2 Genetic Brain Imaging Migraine Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction
Perseverative negative thinking, such as rumination on past stress, predicts future depression, which makes it a promising candidate in prevention. Or recent study (Eszlari et al, submitted for publication) revealed circadian clock gene ARNTL in the background of rumination, if controlling for depression.
Aims
Our present aim was to explore the role of ARNTL variants in depression, and the potential mediating role of rumination in these associations.
Methods
Our sample consisted of 72,395 participants of the UK Biobank database. Rumination was measured by the question "Do you worry too long after an embarrassing experience?", and depression was assessed by lifetime depression based on interview, and by depressive symptoms of the past two weeks. Regression models were run in Plink v1.9, with each of 256 ARNTL variants as predictor, for each of the two depression phenotypes as outcome, to search for significant variants that had also been significant for rumination in similar models. In case of such a shared variant, mediating role of rumination was tested in its association with depression, in Mplus v7.4.
Results
No variant survived Bonferroni correction for lifetime depression. However, rs3816360 survived correction for both current depression and rumination. Hypothesising direct and indirect effects within the same model, rs3816360 significantly affected current depression, both directly and as mediated by rumination.
Conclusion
Rs3816360 within ARNTL has a high regulatory potential, and has been implicated in rapid cycling of bipolar and schizoaffective patients. Our results extend its relevance to perseverative negative thinking and depression, pointing to the potential of circadian clock gene ARNTL as a promising drug target in multimorbid conditions.
Funding
ÚNKP-20-4-II-SE-9 New National Excellence Program of The Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund; 2017-1.2.1-NKP-2017-00002; 2019-2.1.7-ERA-NET-2020-00005 under the frame of ERAPERMED.

University and Doctoral School

Semmelweis University, Doctoral School of Mental Health Sciences