Shi-Heng Wang1, Po-Chang Hsiao2, Ling-Ling Yeh3, Chih-Min Liu4, Chen-Chung Liu4, Tzung-Jeng Hwang4, Ming H Hsieh4, Yi-Ling Chien4, Yi-Ting Lin4, Yen-Tsung Huang5, Chia-Yen Chen6, Sharon D Chandler7, Stephen V Faraone8, Benjamin Neale6, Stephen J Glatt8, Ming T Tsuang7, Hai-Gwo Hwu9, Wei J Chen10. 1. Departments of Public Health and Occupational Safety and Health, College of Public Health, China Medical University, Taichung, Taiwan. 2. Institute of Epidemiology and Preventive Medicine, College of Public Health, Taipei, Taiwan. 3. Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan. 4. Department of Psychiatry, College of Medicine and National Taiwan University Hospital, Taipei, Taiwan. 5. Institute of Statistical Science, Academia Sinica, Taipei, Taiwan. 6. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 7. Center for Behavioral Genomics, Department of Psychiatry and Institute for Genomic Medicine, University of California San Diego, La Jolla, California. 8. Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Medical Genetics Research Center, State University of New York Upstate Medical University, Syracuse, New York. 9. Department of Psychiatry, College of Medicine and National Taiwan University Hospital, Taipei, Taiwan; Institute of Brain and Mind Sciences, College of Medicine, Taipei, Taiwan. 10. Institute of Epidemiology and Preventive Medicine, College of Public Health, Taipei, Taiwan; Department of Public Health, College of Public Health, Taipei, Taiwan; Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: wjchen@ntu.edu.tw.
Abstract
BACKGROUND: Whether paternal age effect on schizophrenia is a causation or just an association due to confounding by selection into late parenthood is still debated. We investigated the association between paternal age and early onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia as empirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium. METHODS: Among 2923 sporadic schizophrenia cases selected from the Schizophrenia Trio Genomic Research in Taiwan project, 1649 had parents' genotyping data. The relationships of paternal schizophrenia PRS to paternal age at first birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model of patients' early onset of schizophrenia (≤18 years old) on paternal age was conducted. RESULTS: Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset of schizophrenia (odds ratio per 10-year increase in paternal age = 1.28, p = .007) after adjusting for maternal age, sex, and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, a U-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting for both paternal and maternal schizophrenia PRS, the association of paternal age with patients' early onset of schizophrenia remained (odds ratio = 1.29, p = .04). CONCLUSIONS: The association between paternal age and early onset of schizophrenia was not confounded by parental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Our findings support an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring.
BACKGROUND: Whether paternal age effect on schizophrenia is a causation or just an association due to confounding by selection into late parenthood is still debated. We investigated the association between paternal age and early onset of schizophrenia in offspring, controlling for both paternal and maternal predisposition to schizophrenia as empirically estimated using polygenic risk score (PRS) derived from the Psychiatric Genomics Consortium. METHODS: Among 2923 sporadic schizophrenia cases selected from the SchizophreniaTrio Genomic Research in Taiwan project, 1649 had parents' genotyping data. The relationships of paternal schizophrenia PRS to paternal age at first birth (AFB) and of maternal schizophrenia PRS to maternal AFB were examined. A logistic regression model of patients' early onset of schizophrenia (≤18 years old) on paternal age was conducted. RESULTS: Advanced paternal age over 20 years exhibited a trend of an increasing proportion of early onset of schizophrenia (odds ratio per 10-year increase in paternal age = 1.28, p = .007) after adjusting for maternal age, sex, and age. Older paternal AFB also exhibited an increasing trend of paternal schizophrenia PRS. Additionally, a U-shaped relationship between maternal AFB and maternal schizophrenia PRS was observed. After adjusting for both paternal and maternal schizophrenia PRS, the association of paternal age with patients' early onset of schizophrenia remained (odds ratio = 1.29, p = .04). CONCLUSIONS: The association between paternal age and early onset of schizophrenia was not confounded by parental PRS for schizophrenia, which partially captures parental genetic vulnerability to schizophrenia. Our findings support an independent role of paternal age per se in increased risk of early onset of schizophrenia in offspring.