IDENTIFICATION OF POLYGENIC ADAPTATION IN ATTENTION-DEFICIT/HYPERACTIVITY DISORDER USING GWAS DATA

Background During the human Diaspora out of Africa, Anatomically Modern Humans (AMH) adapted to the new environments they encountered. On top, adaptation process could have been fueled by interbreeding with homo archaic species -such as Neanderthal and Denisovan- present at that time in Eurasia. In this context of natural adaptation, Attention-Deficit/Hyperactivity Disorder (ADHD) poses an interesting evolutionary paradox: despite being associated with significant impairment, morbidity and increased rates of mortality, it is a highly prevalent phenotype. Being a highly heritable trait, several selective hypotheses have been proposed to explain the prevalence of this phenotype. In the present study, we have analysed the signatures of recent polygenic selection and the effect of archaic inbreeding in ADHD. Methods Databases: i) The effect size estimates of millions of SNPs reported at a GWAS meta-analysis on ADHD conducted by the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) and the Psychiatric Genomics Consortium (PGC) on approximately 20 K patients and 35 K controls. ii) The SDS statistic for detecting recent selection estimated in the UK10K dataset. iii) Genotypes reported at archaic European anatomically modern humans individuals (ranging from ~2 kilo years ago (kya) to ~45 kya. iv) The sequenced Altai Neanderthal genome. v) Map of Neanderthal introgression haplotypes in current humans. Analyses: The presence of signatures of recent polygenic adaptation of ADHD in UK10K samples was estimated by means of the SDS statistic. For ancestral human samples, regression analysis was conducted between the time of each sample and the average ADHD genetic score (GS) by SNP. For the Altai Neanderthal sample, average ADHD GS was compared with the one observed with ancestral human samples. The map of introgressed Neanderthal alleles was used for estimating the effect of introgressed Neanderthal alleles in ADHD in current humans. Results Our results suggest that current North European populations show signatures of recent ( Discussion Overall, our results are compatible with a thrifty-gene-like hypothesis such as the hunter-farmer theory, where some phenotypes related to ADHD (e.g. hyperactivity, impulsivity) may have been beneficial in the past as hunters but the change of lifestyle during the last 45 kya towards farmers would have provided them as detrimental in the new environment.