26 - ESTIMATED DNA METHYLATION GESTATIONAL AGE IN NEWBORN MONOZYGOTIC TWINS ASSOCIATE WITH LATER PSYCHIATRIC DISORDERS BETWEEN CON/DISCORDANT PAIRS

Abstract

Background Neonate developmental state at birth has previously been associated with later occurring psychiatric disease. As a novel possible measure of neonate epigenetic developmental state, we investigate the association between Accelerated Gestational Age (AccGA) and later occurring psychiatric disorder in six neuropsychiatric illnesses: Schizophrenia (SZ), Bipolar Disorder (BD), Major Depressive Disorder (MDD), Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and Anorexia (ANX), in a cohort of dis/concordant Monozygotic (MZ) twins. Methods Neonatal dried blood spots, of 548 MZ twins (274 pairs) born between 1981 and 2005 were obtained from the Danish Neonatal Screening Biobank. The samples were analysed on the Illumina Infinium HumanMethylation 450k BeadChip. Estimated DNA methylation gestational age (EstGA) was calculated from 148 CpG probes across the array (described by Knight et al. 2016). Residual values of the linear fit between EstGA and actual gestational age, were used as measures of the in-cohort AccGA. We applied a linear mixed model for the twin pedigree structure - regressing AccGA against the six neuropsychiatric disorders and sex, while Twin Pair ID served as random effect in the twin model. Statistical significance was reached at p-value Results The EstGA correlated well with the actual gestational age (pearson r=0.86), and the AccGA correlated between twin-cotwin (Pearson r=0.67). Within the full cohort BD (N=7) and ANX (N=44) patients had significantly (p-val=0.007 and p-val=0.024) elevated AccGAs over healthy cotwins and cohort (0.967+/-0.356 and 0.310+/-0.137 weeks, respectively). For SZ (N=18) the opposite was observed (pval=0.005) with lowered AccGA (-0.585+/-0.206 weeks). Neither MDD, ASD nor ADHD were significantly associated with AccGA. Within Twin pair analysis of BD (N=6 pairs) and SZ (N=17 pairs), revealed the same significant (p-val=0.016, p-val=0.022, respectively) difference as observed above (1.185+/-0.341 and -0.697+/-0.275, respectively), while ANX (N=40 pairs) showed the same tendency although not significantly (p-val=0.053, 0.235+/-0.118). This association was independent of twin-cotwin birth weight percentile differences (Pearson r=0.0002, Not significant). Discussion We found significant AccGA differences within con/discordant MZ twin pairs and cohort of at least three main psychiatric disorders - detectable already at birth. AccGA has previously been correlated with birth weight percentile. Twin-cotwin differences of AccGA was however not explained by birth weight percentile differences, suggesting that the within pair differences caught by the estimator describes other aspects of neonate development, independent of weight. Our findings suggest that gestational age estimation, as assessed by the 148 CpG probes, in MZ twin pairs, can indicate a not previously reported epigenetic link to later psychiatric illness, this should be further investigated.