SU4: GENOME-WIDE EXAMINATION OF PARENT-OF-ORIGIN EFFECTS IN CHILDREN WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER

Abstract

Background Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common and most heritable childhood-onset neuropsychiatric disorders, characterized by multifaceted genetics. To date, genetic studies of ADHD focused on additive effects only, explaining just a fraction of its heritability. Thus, we aimed at examining parent of origin effects (POE) together with maternal and additive effects, providing novel insight into the complex genetic architecture of ADHD. Methods We compiled parent-offspring data collected through the Psychiatric Genomics Consortium and the Norwegian Mother and Child Cohort, consisting of 2060 trios and 328 duos. Additional parent-offspring data is being added. ADHD was diagnosed based on DSM-IV, ICD-10 and child behavior checklist. POE, maternal and additive genetic effects are being evaluated using multinomial modelling implemented in EMIM software. We explored our signals in the light of known imprinted genes (POE) and the largest ADHD Genome-Wide Association Study (GWAS) in children (N=17666). Gene based analyses are being performed using MAGMA software. Heritability estimates and genetic correlations of the examined effects are being calculated using LD score regression. Results Our preliminary results indicate the presence of non-additive genetic effects in the development of ADHD. Our preliminary strongest imprinting signal is located in CALD1 locus (rs11980823, effect=0.77, SE=0.14, P=1.21E-07). This gene also revealed strong association signal in the previously reported large-scale childhood ADHD GWAS (rs79846815, P=2.03E-06). CALD1 plays essential an role in nerve regeneration, a function previously implicated in a number of neuropsychiatric disorders. Our preliminary gene-based analyses of the known imprinted genes revealed strong association with TP73 locus (P=0.0034), encoding a transcription factor implicated in disorders of nervous system (e.g. neuroblastoma). Additional hits were noted in the non-coding RNA genes, adding to the recent observations in neuropsychiatric genetics of gene regulation playing a pivotal role in the development of disorders of mental health. Discussion In conclusion, this is the first and the largest genome-wide parent-offspring study in ADHD, exploring its non-additive genetic effects by detecting and distinguishing between POE (imprinting), maternal and child effects. As we increase our sample size, we will provide estimates of such effects as well as those of their heritability and genetic correlations.