Cortical Surfaces Mediate the Relationship Between Polygenic Scores for Intelligence and General Intelligence

Author:

Lett Tristram A12,Vogel Bob O1ORCID,Ripke Stephan134,Wackerhagen Carolin1,Erk Susanne1,Awasthi Swapnil14,Trubetskoy Vassily14,Brandl Eva J1,Mohnke Sebastian1,Veer Ilya M1,Nöthen Markus M56,Rietschel Marcella7,Degenhardt Franziska56,Romanczuk-Seiferth Nina1,Witt Stephanie H7,Banaschewski Tobias8,Bokde Arun L W9,Büchel Christian10,Quinlan Erin B11,Desrivières Sylvane11,Flor Herta1213,Frouin Vincent14,Garavan Hugh15,Gowland Penny16,Ittermann Bernd17,Martinot Jean-Luc18,Martinot Marie-Laure Paillère19,Nees Frauke812,Papadopoulos-Orfanos Dimitri14,Paus Tomáš20,Poustka Luise21,Fröhner Juliane H22,Smolka Michael N22,Whelan Robert23,Schumann Gunter11,Tost Heike7,Meyer-Lindenberg Andreas7,Heinz Andreas1,Walter Henrik1,

Affiliation:

1. Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany

2. Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Campus Mitte, 10117 Berlin, Germany

3. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA

4. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

5. Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany

6. Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany

7. Central Institute of Mental Health, University of Heidelberg, 68159 Mannheim, Germany

8. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, 68159 Mannheim, Germany

9. Discipline of Psychiatry, School of Medicine and Trinity College, Institute of Neuroscience, College Green, Dublin 2, Ireland

10. University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany

11. Centre for Population Neuroscience and Stratified Medicine (PONS) and MRC-SGDP Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College De Crespigny Park, London, WC2R 2LS, UK

12. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany

13. Department of Psychology, School of Social Sciences, University of Mannheim, 68131 Mannheim, Germany

14. NeuroSpin, CEA, Université Paris-Saclay, F-91191 Gif-sur-Yvette, France

15. Departments of Psychiatry and Psychology, University of Vermont, 05405 Burlington, VT, USA

16. Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, NG7 2RD, UK

17. Physikalisch-Technische Bundesanstalt (PTB), Berlin, Germany

18. Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 “Neuroimaging & Psychiatry,” University Paris Sud, University Paris Descartes – Sorbonne Paris Cité; and Maison de Solenn, Paris, France

19. Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1000 “Neuroimaging & Psychiatry”, University Paris Sud, University Paris Descartes; Sorbonne Université; and AP-HP, Paris, France

20. Holland Bloorview Kids Rehabilitation Hospital and Departments of Psychology and Psychiatry, Bloorview Research Institute, University of Toronto, Toronto, Ontario, M6A 2E1, Canada

21. Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, 37075, Göttingen, Germany

22. Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany

23. School of Psychology and Global Brain Health Institute, Trinity College Dublin, College Green, Dublin 2, Ireland

Abstract

Abstract Recent large-scale, genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with general intelligence. The cumulative influence of these loci on brain structure is unknown. We examined if cortical morphology mediates the relationship between GWAS-derived polygenic scores for intelligence (PSi) and g-factor. Using the effect sizes from one of the largest GWAS meta-analysis on general intelligence to date, PSi were calculated among 10 P value thresholds. PSi were assessed for the association with g-factor performance, cortical thickness (CT), and surface area (SA) in two large imaging-genetics samples (IMAGEN N = 1651; IntegraMooDS N = 742). PSi explained up to 5.1% of the variance of g-factor in IMAGEN (F1,1640 = 12.2–94.3; P < 0.005), and up to 3.0% in IntegraMooDS (F1,725 = 10.0–21.0; P < 0.005). The association between polygenic scores and g-factor was partially mediated by SA and CT in prefrontal, anterior cingulate, insula, and medial temporal cortices in both samples (PFWER-corrected < 0.005). The variance explained by mediation was up to 0.75% in IMAGEN and 0.77% in IntegraMooDS. Our results provide evidence that cumulative genetic load influences g-factor via cortical structure. The consistency of our results across samples suggests that cortex morphology could be a novel potential biomarker for neurocognitive dysfunction that is among the most intractable psychiatric symptoms.

Funder

German Ministry for Education and Research

e:Med

Forschungsnetz AERIAL

NARSAD

BMBF

DFG

IMAGEN

ERC

ERANID

BRIDGET

IMAGEMEND

MATRICS

Innovative Medicine Initiative

Medical Research Council

Swedish Research Council Formas

National Institute for Health Research

Bundesministeriumfür Bildung und Forschung

Deutsche Forschungsgemeinschaft

Medical Research Foundation

ANR

Fondation pour la Recherche Médicale

Science Foundation Ireland

NIH

Publisher

Oxford University Press (OUP)

Subject

Cellular and Molecular Neuroscience,Cognitive Neuroscience

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