Gender-specific associations between polygenic scores and age-specific risk of psychiatric disorders

Background Polygenic scores (PGS) have been used to quantify genetic liability for psychiatric disorders, but it remains unclear how these scores are associated with age- and gender-specific risk of diagnosis. Aims To examine associations between disorder-specific PGS and age- and gender-specific risk of psychiatric diagnoses across major psychiatric disorders. Method We conducted a population-based case–cohort study using the Danish iPSYCH2015 sample, including individuals born in Denmark between 1981 and 2008 and followed for psychiatric diagnoses from 1994 to 2015. Cases comprised individuals diagnosed with major depressive disorder (MDD; N = 30 905), schizophrenia spectrum disorders (SCZ; N = 12 703), bipolar disorder ( N = 3169), attention-deficit hyperactivity disorder ( N = 25 167) or autism spectrum disorder (ASD; N = 15 677), alongside a randomly sampled subcohort ( N = 52 765). Disorder-specific PGS were the exposures. Gender- and age-specific hazard ratios for first hospital-based diagnoses were estimated using Cox proportional hazards models. Results All PGS were associated with risk of all disorders regardless of age. For MDD, the highest association per 1 s.d. increase in PGS was observed at ages 17–19 (males: hazard ratio 1.56; 95% CI 1.45–1.69; females: hazard ratio 1.48; 95% CI 1.40–1.57). SCZ-PGS showed marked gender differences, with the strongest association with SCZ diagnosis at ages 20–22 years for males (hazard ratio 1.71; 95% CI 1.54–1.90) and 17–19 years for females (hazard ratio 1.29; 95% CI 1.16–1.44). ASD–PGS associations were strongest in males at ages 4–6 (hazard ratio 1.51; 95% CI 1.44–1.61) and 7–9 years (hazard ratio 1.55; 95% CI 1.47–1.65), and in females at ages 13–15 years (hazard ratio 1.60; 95% CI 1.41–1.82). Gender differences were evident across disorders. The PGS–schizophrenia association was stronger in males, whereas for childhood-onset disorders, associations were stronger in females but emerged at older ages. Conclusions Polygenic burden for psychiatric disorders tends to be more strongly associated with risk of diagnosis at younger ages, with gender-specific patterns. Future genetic research should consider both age at diagnosis and potential gender differences.