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Original Investigation
June 23, 2021

Genetic Association Between Schizophrenia and Cortical Brain Surface Area and Thickness

Author Affiliations
  • 1NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  • 2School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
  • 3Centre for Lifespan Changes in Brain and Cognition (LCBC), Department of Psychology, University of Oslo, Oslo, Norway
  • 4Psychosis Studies, Institute of Psychiatry, Psychology and Neurosciences, King’s College London, London, United Kingdom
  • 5Population Neuroscience and Genetics Lab, University of California, San Diego, La Jolla
  • 6Center for Human Development, University of California, San Diego, La Jolla
  • 7Department of Psychology, University of Oslo, Oslo, Norway
  • 8Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
  • 9Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway
  • 10Department of Pharmacy, University of Oslo, Oslo, Norway
  • 11Department of Radiology, University of California, San Diego, La Jolla
  • 12Department of Psychiatry, University of California, San Diego, La Jolla
  • 13Department of Neurosciences, University of California San Diego, La Jolla
  • 14Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 15NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway
JAMA Psychiatry. Published online June 23, 2021. doi:10.1001/jamapsychiatry.2021.1435
Key Points

Question  To what extent is the genetic architecture of schizophrenia shared with cortical brain surface area and thickness?

Findings  In this genetic association study, data sets revealed that 94% of the genetic variants associated with total cortical surface area and all variants associated with average cortical thickness were also associated with the genetic risk of schizophrenia, despite nonsignificant genetic correlations.

Meaning  The amount of shared genetic variants between schizophrenia and cortical brain structure suggests overlapping molecular genetic mechanisms between cortical development and schizophrenia.


Importance  Schizophrenia is a complex heritable disorder associated with many genetic variants, each with a small effect. While cortical differences between patients with schizophrenia and healthy controls are consistently reported, the underlying molecular mechanisms remain elusive.

Objective  To investigate the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) and to identify shared genomic loci.

Design, Setting, and Participants  Independent genome-wide association study data on schizophrenia (Psychiatric Genomics Consortium and CLOZUK: n = 105 318) and SA and TH (UK Biobank: n = 33 735) were obtained. The extent of polygenic overlap was investigated using MiXeR. The specific shared genomic loci were identified by conditional/conjunctional false discovery rate analysis and were further examined in 3 independent cohorts. Data were collected from December 2019 to February 2021, and data analysis was performed from May 2020 to February 2021.

Main Outcomes and Measures  The primary outcomes were estimated fractions of polygenic overlap between schizophrenia, total SA, and average TH and a list of functionally characterized shared genomic loci.

Results  Based on genome-wide association study data from 139 053 participants, MiXeR estimated schizophrenia to be more polygenic (9703 single-nucleotide variants [SNVs]) than total SA (2101 SNVs) and average TH (1363 SNVs). Most SNVs associated with total SA (1966 of 2101 [93.6%]) and average TH (1322 of 1363 [97.0%]) may be associated with the development of schizophrenia. Subsequent conjunctional false discovery rate analysis identified 44 and 23 schizophrenia risk loci shared with total SA and average TH, respectively. The SNV associations of shared loci between schizophrenia and total SA revealed en masse concordant association between the discovery and independent cohorts. After removing high linkage disequilibrium regions, such as the major histocompatibility complex region, the shared loci were enriched in immunologic signature gene sets. Polygenic overlap and shared loci between schizophrenia and schizophrenia-associated regions of interest for SA (superior frontal and middle temporal gyri) and for TH (superior temporal, inferior temporal, and superior frontal gyri) were also identified.

Conclusions and Relevance  This study demonstrated shared genetic loci between cortical morphometry and schizophrenia, among which a subset are associated with immunity. These findings provide an insight into the complex genetic architecture and associated with schizophrenia.

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