Molecular characterization of the stress network in individuals at risk for schizophrenia

Mandy Meijer; Arlin Keo; Judith M C van Leeuwen; Oleh Dzyubachyk; Onno C Meijer; Christiaan H Vinkers; Ahmed Mahfouz

doi:10.1016/j.ynstr.2021.100307

Molecular characterization of the stress network in individuals at risk for schizophrenia

Neurobiol Stress. 2021 Feb 10:14:100307. doi: 10.1016/j.ynstr.2021.100307. eCollection 2021 May.

Authors

Mandy Meijer^{1

2

3}, Arlin Keo^{1

4}, Judith M C van Leeuwen^{5

6}, Oleh Dzyubachyk⁷, Onno C Meijer², Christiaan H Vinkers^{8

9}, Ahmed Mahfouz^{1

4

10}

Affiliations

¹ Leiden Computational Biology Center, Leiden University Medical Center, 2333 ZA, Leiden, the Netherlands.
² Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, 2333 ZA, Leiden, the Netherlands.
³ Department of Human Genetics, Cognition and Behaviour, Donders Institute for Brain, Radboud University Medical Center, 6525 GA, Nijmegen, the Netherlands.
⁴ Delft Bioinformatics Lab, Delft University of Technology, 2628 XE, Delft, the Netherlands.
⁵ University Medical Center Utrecht, Department of Psychiatry, Utrecht, the Netherlands.
⁶ Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ Department of Radiology, Division of Medical Image Processing, Leiden University Medical Center, 2333 ZA, Leiden, the Netherlands.
⁸ Department of Psychiatry, Amsterdam UMC (location VUmc)/GGZ InGeest, 1081 HV, Amsterdam, the Netherlands.
⁹ Department of Anatomy and Neurosciences, Amsterdam UMC (location VUmc), 1081 HV, Amsterdam, the Netherlands.
¹⁰ Department of Human Genetics, Leiden University Medical Center, 2333ZA, Leiden, the Netherlands.

Abstract

The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of aberrant neural stress sensitivity in individuals at risk for schizophrenia. Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 201 differentially expressed genes in cortex-specific brain regions differentially activated by stress in individuals with low (healthy siblings of schizophrenia patients) or high (healthy controls) stress sensitivity. These genes are associated with stress-related psychiatric disorders (e.g. schizophrenia and anxiety) and include markers for specific neuronal populations (e.g. ADCYAP1, GABRB1, SSTR1, and TNFRSF12A), neurotransmitter receptors (e.g. GRIN3A, SSTR1, GABRB1, and HTR1E), and signaling factors that interact with the corticosteroid receptor and hypothalamic-pituitary-adrenal axis (e.g. ADCYAP1, IGSF11, and PKIA). Overall, the identified genes potentially underlie altered stress reactivity in individuals at risk for schizophrenia and other psychiatric disorders and play a role in mounting an adaptive stress response in at-risk individuals, making them potentially druggable targets for stress-related diseases.

Keywords: Molecular correlates; Stress network; Stress reactivity; Stress sensitivity; Stress-related diseases.