A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment

Andrew J Schork; Hyejung Won; Vivek Appadurai; Ron Nudel; Mike Gandal; Olivier Delaneau; Malene Revsbech Christiansen; David M Hougaard; Marie Bækved-Hansen; Jonas Bybjerg-Grauholm; Marianne Giørtz Pedersen; Esben Agerbo; Carsten Bøcker Pedersen; Benjamin M Neale; Mark J Daly; Naomi R Wray; Merete Nordentoft; Ole Mors; Anders D Børglum; Preben Bo Mortensen; Alfonso Buil; Wesley K Thompson; Daniel H Geschwind; Thomas Werge

doi:10.1038/s41593-018-0320-0

A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment

Nat Neurosci. 2019 Mar;22(3):353-361. doi: 10.1038/s41593-018-0320-0. Epub 2019 Jan 28.

Authors

Andrew J Schork^{1

2}, Hyejung Won^{3

4

5

6

7}, Vivek Appadurai^{1

2}, Ron Nudel^{1

2}, Mike Gandal^{3

4

5}, Olivier Delaneau^{8

9

10}, Malene Revsbech Christiansen¹¹, David M Hougaard^{2

12}, Marie Bækved-Hansen^{2

12}, Jonas Bybjerg-Grauholm^{2

12}, Marianne Giørtz Pedersen^{2

13

14}, Esben Agerbo^{2

13

14}, Carsten Bøcker Pedersen^{2

13

14}, Benjamin M Neale^{15

16

17}, Mark J Daly^{15

16

17}, Naomi R Wray^{18

19}, Merete Nordentoft^{2

20

21}, Ole Mors^{2

22}, Anders D Børglum^{2

23

24}, Preben Bo Mortensen^{2

13

14

24}, Alfonso Buil^{1

2}, Wesley K Thompson^{1

2

25}, Daniel H Geschwind^{3

4

5

26}, Thomas Werge^{27

28

29}

Affiliations

¹ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
² The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark.
³ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁷ UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.
⁸ Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
⁹ Swiss Institute of Bioinformatics (SIB), University of Geneva, Geneva, Switzerland.
¹⁰ Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland.
¹¹ DTU Bioinformatics, Technical University of Denmark, Lyngby, Denmark.
¹² Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
¹³ NCRR - National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
¹⁴ Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark.
¹⁵ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
¹⁶ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁸ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
¹⁹ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
²⁰ Copenhagen Mental Health Center, Mental Health Services Capital Region of Denmark Copenhagen, Copenhagen, Denmark.
²¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²² Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
²³ Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
²⁴ Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.
²⁵ Division of Biostatistics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.
²⁶ Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
²⁷ Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. Thomas.Werge@regionh.dk.
²⁸ The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark. Thomas.Werge@regionh.dk.
²⁹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Thomas.Werge@regionh.dk.

Abstract

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain / embryology*
Brain / metabolism
Cohort Studies
Female
Gene Expression Regulation*
Genetic Loci
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Male
Mental Disorders / genetics*
Polymorphism, Single Nucleotide
Risk Factors

Abstract

Publication types

MeSH terms

Grants and funding