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.