Weiqiu Cheng1, Oleksandr Frei1, Dennis van der Meer1,2, Yunpeng Wang3, Kevin S O'Connell1, Yunhan Chu1, Shahram Bahrami1, Alexey A Shadrin1, Dag Alnæs1, Guy F L Hindley1,4, Aihua Lin1, Naz Karadag1, Chun-Chieh Fan5,6, Lars T Westlye1,7, Tobias Kaufmann1,8, Espen Molden9,10, Anders M Dale11,12,13, Srdjan Djurovic14,15, Olav B Smeland1, Ole A Andreassen1. 1. NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 2. School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands. 3. Centre for Lifespan Changes in Brain and Cognition (LCBC), Department of Psychology, University of Oslo, Oslo, Norway. 4. Psychosis Studies, Institute of Psychiatry, Psychology and Neurosciences, King's College London, London, United Kingdom. 5. Population Neuroscience and Genetics Lab, University of California, San Diego, La Jolla. 6. Center for Human Development, University of California, San Diego, La Jolla. 7. Department of Psychology, University of Oslo, Oslo, Norway. 8. Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany. 9. Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. 10. Department of Pharmacy, University of Oslo, Oslo, Norway. 11. Department of Radiology, University of California, San Diego, La Jolla. 12. Department of Psychiatry, University of California, San Diego, La Jolla. 13. Department of Neurosciences, University of California San Diego, La Jolla. 14. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 15. NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
Abstract
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.
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.
Authors: Weiqiu Cheng; Dennis van der Meer; Nadine Parker; Guy Hindley; Kevin S O'Connell; Yunpeng Wang; Alexey A Shadrin; Dag Alnæs; Shahram Bahrami; Aihua Lin; Naz Karadag; Børge Holen; Sara Fernandez-Cabello; Chun-Chieh Fan; Anders M Dale; Srdjan Djurovic; Lars T Westlye; Oleksandr Frei; Olav B Smeland; Ole A Andreassen Journal: Mol Psychiatry Date: 2022-09-13 Impact factor: 13.437
Authors: Eun-Jin Cheon; Carrie E Bearden; Daqiang Sun; Christopher R K Ching; Ole A Andreassen; Lianne Schmaal; Dick J Veltman; Sophia I Thomopoulos; Peter Kochunov; Neda Jahanshad; Paul M Thompson; Jessica A Turner; Theo G M van Erp Journal: Psychiatry Clin Neurosci Date: 2022-02-26 Impact factor: 12.145
Authors: Dennis van der Meer; Tobias Kaufmann; Alexey A Shadrin; Carolina Makowski; Oleksandr Frei; Daniel Roelfs; Jennifer Monereo-Sánchez; David E J Linden; Jaroslav Rokicki; Dag Alnæs; Christiaan de Leeuw; Wesley K Thompson; Robert Loughnan; Chun Chieh Fan; Lars T Westlye; Ole A Andreassen; Anders M Dale Journal: Sci Adv Date: 2021-12-15 Impact factor: 14.136
Authors: Gökberk Alagöz; Barbara Molz; Else Eising; Dick Schijven; Clyde Francks; Jason L Stein; Simon E Fisher Journal: Proc Natl Acad Sci U S A Date: 2022-09-26 Impact factor: 12.779