Beata Stepniak1, Sergi Papiol2, Christian Hammer1, Anna Ramin1, Sarah Everts1, Lena Hennig1, Martin Begemann1, Hannelore Ehrenreich3. 1. Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. 2. Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. 3. Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. Electronic address: ehrenreich@em.mpg.de.
Abstract
BACKGROUND: Schizophrenia is caused by a combination of genetic and environmental factors, as first evidenced by twin studies. Extensive efforts have been made to identify the genetic roots of schizophrenia, including large genome-wide association studies, but these yielded very small effect sizes for individual markers. In this study, we aimed to assess the relative contribution of genome-wide association study-derived genetic versus environmental risk factors to crucial determinants of schizophrenia severity: disease onset, disease severity, and socioeconomic measures. METHODS: In this parallel analysis, we studied 750 male patients from the Göttingen Research Association for Schizophrenia (GRAS) dataset (Germany) with schizophrenia for whom both genome-wide coverage of single-nucleotide polymorphisms and deep clinical phenotyping data were available. Specifically, we investigated the potential effect of schizophrenia risk alleles as identified in the most recent large genome-wide association study versus the effects of environmental hazards (ie, perinatal brain insults, cannabis use, neurotrauma, psychotrauma, urbanicity, and migration), alone and upon accumulation, on age at disease onset, age at prodrome, symptom expression, and socioeconomic parameters. FINDINGS: In this study, we could show that frequent environmental factors become a major risk for early schizophrenia onset when accumulated (prodrome begins up to 9 years earlier; p=2·9×10(-10)). In particular, cannabis use-an avoidable environmental risk factor-is highly significantly associated with earlier age at prodrome (p=3·8×10(-20)). By contrast, polygenic genome-wide association study risk scores did not have any detectable effects on schizophrenia phenotypes. INTERPRETATION: These findings should be translated to preventive measures to reduce environmental risk factors, since age at onset of schizophrenia is a crucial determinant of an affected individual's fate and the total socioeconomic cost of the illness. FUNDING: German Research Foundation (Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain), Max Planck Society, Max Planck Förderstiftung, EXTRABRAIN EU-FP7, ERA-NET NEURON.
BACKGROUND:Schizophrenia is caused by a combination of genetic and environmental factors, as first evidenced by twin studies. Extensive efforts have been made to identify the genetic roots of schizophrenia, including large genome-wide association studies, but these yielded very small effect sizes for individual markers. In this study, we aimed to assess the relative contribution of genome-wide association study-derived genetic versus environmental risk factors to crucial determinants of schizophrenia severity: disease onset, disease severity, and socioeconomic measures. METHODS: In this parallel analysis, we studied 750 male patients from the Göttingen Research Association for Schizophrenia (GRAS) dataset (Germany) with schizophrenia for whom both genome-wide coverage of single-nucleotide polymorphisms and deep clinical phenotyping data were available. Specifically, we investigated the potential effect of schizophrenia risk alleles as identified in the most recent large genome-wide association study versus the effects of environmental hazards (ie, perinatal brain insults, cannabis use, neurotrauma, psychotrauma, urbanicity, and migration), alone and upon accumulation, on age at disease onset, age at prodrome, symptom expression, and socioeconomic parameters. FINDINGS: In this study, we could show that frequent environmental factors become a major risk for early schizophrenia onset when accumulated (prodrome begins up to 9 years earlier; p=2·9×10(-10)). In particular, cannabis use-an avoidable environmental risk factor-is highly significantly associated with earlier age at prodrome (p=3·8×10(-20)). By contrast, polygenic genome-wide association study risk scores did not have any detectable effects on schizophrenia phenotypes. INTERPRETATION: These findings should be translated to preventive measures to reduce environmental risk factors, since age at onset of schizophrenia is a crucial determinant of an affected individual's fate and the total socioeconomic cost of the illness. FUNDING: German Research Foundation (Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain), Max Planck Society, Max Planck Förderstiftung, EXTRABRAIN EU-FP7, ERA-NET NEURON.
Authors: Jennifer L Cecilione; Lance M Rappaport; Shannon E Hahn; Audrey E Anderson; Laura E Hazlett; Jason R Burchett; Ashlee A Moore; Jeanne E Savage; John M Hettema; Roxann Roberson-Nay Journal: Twin Res Hum Genet Date: 2018-02 Impact factor: 1.587
Authors: Hana Janova; Sahab Arinrad; Evan Balmuth; Marina Mitjans; Johannes Hertel; Mohamad Habes; Robert A Bittner; Hong Pan; Sandra Goebbels; Martin Begemann; Ulrike C Gerwig; Sönke Langner; Hauke B Werner; Sarah Kittel-Schneider; Georg Homuth; Christos Davatzikos; Henry Völzke; Brian L West; Andreas Reif; Hans Jörgen Grabe; Susann Boretius; Hannelore Ehrenreich; Klaus-Armin Nave Journal: J Clin Invest Date: 2017-12-18 Impact factor: 14.808
Authors: Jai L Shah; Sinan Guloksuz; Vincent Paquin; Lotta-Katrin Pries; Margreet Ten Have; Maarten Bak; Nicole Gunther; Ron de Graaf; Saskia van Dorsselaer; Bochao D Lin; Kristel R van Eijk; Gunter Kenis; Alexander Richards; Michael C O'Donovan; Jurjen J Luykx; Bart P F Rutten; Jim van Os Journal: Soc Psychiatry Psychiatr Epidemiol Date: 2022-08-01 Impact factor: 4.519
Authors: Beata Stepniak; Anne Kästner; Giulia Poggi; Marina Mitjans; Martin Begemann; Annette Hartmann; Sandra Van der Auwera; Farahnaz Sananbenesi; Dilja Krueger-Burg; Gabriela Matuszko; Cornelia Brosi; Georg Homuth; Henry Völzke; Fritz Benseler; Claudia Bagni; Utz Fischer; Alexander Dityatev; Hans-Jörgen Grabe; Dan Rujescu; Andre Fischer; Hannelore Ehrenreich Journal: EMBO Mol Med Date: 2015-12 Impact factor: 12.137