Abstract
BACKGROUND: While several risk factors for schizophrenia have been identified, their individual impacts are rather small. The relative independent and cumulative impacts of multiple risk factors on disease risk and age of onset warrant further investigation. STUDY DESIGN: We conducted a register-based case-control study including all individuals receiving a schizophrenia spectrum disorder in Denmark from 1973 to 2018 (N = 29,142), and a healthy control sample matched 5:1 on age, sex, and parental socioeconomic status (N = 136,387). Register data included parental history of psychiatric illness, birth weight, gestational age, season of birth, population density of birthplace, immigration, paternal age, and Apgar scores. Data were analysed using logistic regression and machine learning. RESULTS: Parental history of psychiatric illness (OR = 2.32 [95%CI 2.21-2.43]), high paternal age (OR = 1.30 [1.16-1.45]), and low birth weight (OR = 1.28 [1.16-1.41]) increased the odds of belonging to the patient group. In contrast, being a second-generation immigrant (OR = 0.65 [0.61-0.69]) and high population density of the birthplace (OR = 0.92 [0.89-0.96]) decreased the odds. The findings were supported by a decision tree analysis where parental history, paternal age, and birth weight contributed most to diagnostic classification (ACC(test) = 0.69, AUC(test) = 0.59, p < 0.001). Twenty percent of patients were child-onset cases. Here, female sex (OR = 1.82 [1.69-1.97]) and parental psychiatric illness (OR = 1.62 [1.49-1.77]) increased the odds of receiving the diagnosis <18 years. CONCLUSION: Multiple early factors contribute independently to a higher psychosis risk, suggesting cumulative effects leading to symptom onset. Routine assessments of the most influential risk factors could be incorporated into clinical practise. Being female increased the risk of diagnosis during childhood, suggesting sex differences in the developmental trajectories of the disorder.