Elevated DNA Methylation Gestational Age is associated with the Risk of Later Bipolar Disorder and Anorexia Nervosa in Twins

Background: Foetal development indicates the risk of later disease, but has only been associated with few psychiatric disorders. An aggregated molecular marker of development - DNA methylation based estimates of gestational age (DNAmGA) adjusted for GA, can be indicative of foetal health and development. Twins have the same chronological GA and monozygotic (MZ) twins share genetic liability. We leveraged this to examine whether DNAmGA in neonates associate with later psychiatric disorder, independent of chronological GA, maternal characteristics, genetic influences, and shared environmental factors. Method: We estimated DNAmGA in 260 MZ and 396 dizygotic (DZ) twin pairs, later diagnosed with schizophrenia, bipolar disorder, affective/depressive mood disorder, autism spectrum disorder, attention deficit hyperactivity disorder or anorexia. DNAmGA was tested for association with psychiatric outcome by mean discordant twin differences and by linear mixed model (LMM), adjusting for relatedness and potential confounders. Results: We found elevated DNAmGA to associate with anorexia between discordant DZ and MZ twins (0.74 weeks, 95%CI[0.34:1.14] and 0.28 weeks, 95%CI[0.04:0.53], respectively), and with bipolar disorder between discordant MZ twins (0.85 weeks, 95%CI[0.16:1.53]). Elevated DNAmGA associated significantly with both in the LMM analysis (0.56 weeks, 95%CI[0.32:0.83] and 0.89 weeks, 95%CI[0.32:1.51], respectively). Conclusions: Elevated DNAmGA is associated with two later onset psychiatric disorders in twins, and thus supports a developmental origin of disease. This association was not confounded by variation in conventional measures of foetal development nor genetic liability. We therefore propose that a novel molecular marker of development, can differentiate between later psychiatric outcome in newborn twins.

Anxiety at age 15 predicts psychiatric diagnoses and suicidal ideation in late adolescence and young adulthood: results from two longitudinal studies

Background Anxiety disorders in adolescence have been associated with several psychiatric outcomes. We sought to describe the prospective relationship between various levels of adolescent anxiety and psychiatric diagnoses (anxiety-, bipolar/psychotic-, depressive-, and alcohol and drug misuse disorders) and suicidal ideation in early adulthood while adjusting for childhood attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental coordination disorder (DCD). Furthermore, we aimed to estimate the proportion attributable to the various anxiety levels for the outcomes. Methods We used a nation-wide population-based Swedish twin study comprising 14,106 fifteen-year-old twins born in Sweden between 1994 and 2002 and a replication sample consisting of 9211 Dutch twins, born between 1985 and 1999. Adolescent anxiety was measured with parental and self-report. Psychiatric diagnoses and suicidal ideation were retrieved from the Swedish National Patient Register and via self-report. Results Adolescent anxiety, of various levels, predicted, in the Swedish National Patient Register, anxiety disorders: hazard ratio (HR) = 4.92 (CI 3.33–7.28); depressive disorders: HR = 4.79 (3.23–7.08), and any psychiatric outcome: HR = 3.40 (2.58–4.48), when adjusting for ADHD, ASD, and DCD. The results were replicated in the Dutch data. The proportion of psychiatric outcome attributable to adolescent anxiety over time (age 15–21) was 29% for any psychiatric outcome, 43–40% for anxiety disorders, and 39–38% for depressive disorders. Conclusion Anxiety in adolescence constitutes an important risk factor in the development of psychiatric outcomes, revealing unique predictions for the different levels of anxiety, and beyond the risk conferred by childhood ADHD, ASD, and DCD. Developmental trajectories leading into psychiatric outcomes should further empirically investigated.