Associations of schizophrenia risk genes ZNF804A and CACNA1C with schizotypy and modulation of attention in healthy subjects

Tina Meller; Simon Schmitt; Frederike Stein; Katharina Brosch; Johannes Mosebach; Dilara Yüksel; Dario Zaremba; Dominik Grotegerd; Katharina Dohm; Susanne Meinert; Katharina Förster; Ronny Redlich; Nils Opel; Jonathan Repple; Tim Hahn; Andreas Jansen; Till F M Andlauer; Andreas J Forstner; Stefanie Heilmann-Heimbach; Fabian Streit; Stephanie H Witt; Marcella Rietschel; Bertram Müller-Myhsok; Markus M Nöthen; Udo Dannlowski; Axel Krug; Tilo Kircher; Igor Nenadić

doi:10.1016/j.schres.2019.04.018

Associations of schizophrenia risk genes ZNF804A and CACNA1C with schizotypy and modulation of attention in healthy subjects

Schizophr Res. 2019 Jun:208:67-75. doi: 10.1016/j.schres.2019.04.018. Epub 2019 May 7.

Authors

Tina Meller¹, Simon Schmitt², Frederike Stein², Katharina Brosch², Johannes Mosebach³, Dilara Yüksel⁴, Dario Zaremba⁵, Dominik Grotegerd⁵, Katharina Dohm⁵, Susanne Meinert⁵, Katharina Förster⁵, Ronny Redlich⁵, Nils Opel⁵, Jonathan Repple⁵, Tim Hahn⁵, Andreas Jansen⁶, Till F M Andlauer⁷, Andreas J Forstner⁸, Stefanie Heilmann-Heimbach⁹, Fabian Streit¹⁰, Stephanie H Witt¹⁰, Marcella Rietschel¹⁰, Bertram Müller-Myhsok¹¹, Markus M Nöthen⁹, Udo Dannlowski⁵, Axel Krug², Tilo Kircher², Igor Nenadić²

Affiliations

¹ Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg and University Hospital Marburg, UKGM, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), Hans-Meerwein-Str. 6, 35032 Marburg, Germany. Electronic address: [email protected].
² Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg and University Hospital Marburg, UKGM, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), Hans-Meerwein-Str. 6, 35032 Marburg, Germany.
³ Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg and University Hospital Marburg, UKGM, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
⁴ Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg and University Hospital Marburg, UKGM, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany; SRI International, Center for Health Sciences, Bioscience Division, 333 Ravenswood Avenue, 94025 Menlo Park, CA, USA.
⁵ Department of Psychiatry and Psychotherapy, Westfälische Wilhelms-Universität Münster, Albert-Schweitzer-Campus 1, Building A9, 48149 Münster, Germany.
⁶ Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg and University Hospital Marburg, UKGM, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), Hans-Meerwein-Str. 6, 35032 Marburg, Germany; Core-Facility BrainImaging, Faculty of Medicine, Philipps-Universität Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
⁷ Max-Planck-Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
⁸ Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany; Institute of Human Genetics, Philipps-Universität Marburg, Baldingerstraße, 35033 Marburg, Germany; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Institute of Medical Genetics and Pathology, University Hospital Basel, Schönbeinstr. 40, 4056 Basel, Switzerland.
⁹ Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany.
¹⁰ Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J5, 68159 Mannheim, Germany.
¹¹ Max-Planck-Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377 Munich, Germany; Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.

PMID: 31076262
DOI: 10.1016/j.schres.2019.04.018

Abstract

Schizotypy is a multidimensional risk phenotype distributed in the general population, constituting of subclinical, psychotic-like symptoms. It is associated with psychosis proneness, and several risk genes for psychosis are associated with schizotypy in non-clinical populations. Schizotypy might also modulate cognitive abilities as it is associated with attentional deficits in healthy subjects. In this study, we tested the hypothesis that established genetic risk variants ZNF804A rs1344706 and CACNA1C rs1006737 are associated with psychometric schizotypy and that schizotypy mediates their effect on attention or vice versa. In 615 healthy subjects from the FOR2107 cohort study, we analysed the genetic risk variants ZNF804A rs1344706 and CACNA1C rs1006737, psychometric schizotypy (schizotypal personality questionnaire-brief SPQB), and a neuropsychological measure of sustained and selective attention (d2 test). ZNF804A rs1344706 C (non-risk) alleles were significantly associated with higher SPQ-B Cognitive-Perceptual subscores in women and with attention deficits in both sexes. This schizotypy dimension also mediated the effect of ZNF804A on attention in women, but not in men. CACNA1C rs1006737-A showed a significant sex-modulated negative association with Interpersonal schizotypy only in men, and no effect on attention. Our multivariate model demonstrates differential genetic contributions of two psychosis risk genes to dimensions of schizotypy and, partly, to attention. This supports a model of shared genetic influence between schizotypy and cognitive functions impaired in schizophrenia.

Keywords: Attention; Cognition; Psychosis; Schizophrenia risk variants; Schizotypy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Attention Deficit Disorder with Hyperactivity / genetics*
Cognitive Dysfunction / genetics*
Cohort Studies
Europe
Female
Humans
Male
Middle Aged
Psychotic Disorders / genetics
Schizophrenia / genetics
Schizotypal Personality Disorder / genetics*
Young Adult