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Attention-deficit/hyperactivity disorder (ADHD) is an impairing neurodevelopmental condition highly prevalent in current populations. Several hypotheses have been proposed to explain this paradox, mainly in the context of the Paleolithic versus Neolithic cultural shift but especially within the framework of the mismatch theory. This theory elaborates on how a particular trait once favoured in an ancient environment might become maladaptive upon environmental changes. However, given the lack of genomic data available for ADHD, these theories have not been empirically tested. We took advantage of the largest GWAS meta-analysis available for this disorder consisting of over 20,000 individuals diagnosed with ADHD and 35,000 controls, to assess the evolution of ADHD-associated alleles in European populations using archaic, ancient and modern human samples. We also included Approximate Bayesian computation coupled with deep learning analyses and singleton density scores to detect human adaptation. Our analyses indicate that ADHD-associated alleles are enriched in loss of function intolerant genes, supporting the role of selective pressures in this early-onset phenotype. Furthermore, we observed that the frequency of variants associated with ADHD has steadily decreased since Paleolithic times, particularly in Paleolithic European populations compared to samples from the Neolithic Fertile Crescent. We demonstrate this trend cannot be explained by African admixture nor Neanderthal introgression, since introgressed Neanderthal alleles are enriched in ADHD risk variants. All analyses performed support the presence of long-standing selective pressures acting against ADHD-associated alleles until recent times. Overall, our results are compatible with the mismatch theory for ADHD but suggest a much older time frame for the evolution of ADHD-associated alleles compared to previous hypotheses. ; We acknowledge the support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d'Empresa i Coneixement, the co-funding by the Spanish Ministry of Science and Innovation with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program. O.L. gratefully acknowledges the financial support from Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness) - RYC-2013-14797, BFU2015-68759-P and PGC2018-098574-B-I00, Generalitat de Catalunya (Government of Catalonia) - GRC 2017 SGR 937, EC | EU Horizon 2020 Research and Innovation Programme (Personalising Health and Care) - 667302 and EC | EU Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie Action: Innovative Training Networks, ITN) - 643051. P.E.-C. gratefully acknowledges the financial support from the Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants) - FI_B1_00113. I.M. gratefully acknowledges the financial support from the Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants) - GRC 2014 SGR 615. A.D.B. and D.D. were supported by the Lundbeck Foundation (grant numbers R102-A9118 and R155-2014-1724). High-performance computer capacity for handling and statistical analysis of iPSYCH and PGC data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine, Aarhus University and Central Region Denmark, and Centre for Integrative Sequencing, iSEQ, Aarhus University (grant to A.D.B.). S.V.F. was supported by the European Union's Seventh Framework Programme for Research, Technological Development and Demonstration under grant agreement - 602805, the European Union's Horizon 2020 Research and Innovation Programme under grant agreements 667302 & 728018 and NIMH grants 5R01MH101519 and U01 MH109536-01. B.C. gratefully acknowledges the financial support from Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness) - SAF2015-68341-R and RTI2018-100968-B-100, Generalitat de Catalunya | Agaur (Government of Catalonia) - GRC 2017 SGR 738, EC | EU Horizon 2020 Research and Innovation Programme (Personalising Health and Care) - 667302, EC | EU Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie Action: Innovative Training Networks, ITN) - 643051 and EC | EU Horizon 2020 Research and Innovation Proramme (Sustainable Food Security - Resilient and Resource - Efficient Value Chains) - 728018. ; Peer reviewed

Attention-deficit/hyperactivity disorder (ADHD) is an impairing neurodevelopmental condition highly prevalent in current populations. Several hypotheses have been proposed to explain this paradox, mainly in the context of the Paleolithic versus Neolithic cultural shift but especially within the framework of the mismatch theory. This theory elaborates on how a particular trait once favoured in an ancient environment might become maladaptive upon environmental changes. However, given the lack of genomic data available for ADHD, these theories have not been empirically tested. We took advantage of the largest GWAS meta-analysis available for this disorder consisting of over 20,000 individuals diagnosed with ADHD and 35,000 controls, to assess the evolution of ADHD-associated alleles in European populations using archaic, ancient and modern human samples. We also included Approximate Bayesian computation coupled with deep learning analyses and singleton density scores to detect human adaptation. Our analyses indicate that ADHD-associated alleles are enriched in loss of function intolerant genes, supporting the role of selective pressures in this early-onset phenotype. Furthermore, we observed that the frequency of variants associated with ADHD has steadily decreased since Paleolithic times, particularly in Paleolithic European populations compared to samples from the Neolithic Fertile Crescent. We demonstrate this trend cannot be explained by African admixture nor Neanderthal introgression, since introgressed Neanderthal alleles are enriched in ADHD risk variants. All analyses performed support the presence of long-standing selective pressures acting against ADHD-associated alleles until recent times. Overall, our results are compatible with the mismatch theory for ADHD but suggest a much older time frame for the evolution of ADHD-associated alleles compared to previous hypotheses. ; We acknowledge the support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d'Empresa i Coneixement, the co-funding by the Spanish Ministry of Science and Innovation with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program. O.L. gratefully acknowledges the financial support from Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness) - RYC-2013-14797, BFU2015-68759-P and PGC2018-098574-B-I00, Generalitat de Catalunya (Government of Catalonia) - GRC 2017 SGR 937, EC | EU Horizon 2020 Research and Innovation Programme (Personalising Health and Care) - 667302 and EC | EU Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie Action: Innovative Training Networks, ITN) - 643051. P.E.-C. gratefully acknowledges the financial support from the Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants) - FI_B1_00113. I.M. gratefully acknowledges the financial support from the Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants) - GRC 2014 SGR 615. A.D.B. and D.D. were supported by the Lundbeck Foundation (grant numbers R102-A9118 and R155-2014-1724). S.V.F. was supported by the European Union's Seventh Framework Programme for Research, Technological Development and Demonstration under grant agreement - 602805, the European Union's Horizon 2020 Research and Innovation Programme under grant agreements 667302 & 728018 and NIMH grants 5R01MH101519 and U01 MH109536-01. B.C. gratefully acknowledges the financial support from Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness) - SAF2015-68341-R and RTI2018-100968-B-100, Generalitat de Catalunya | Agaur (Government of Catalonia) - GRC 2017 SGR 738, EC | EU Horizon 2020 Research and Innovation Programme (Personalising Health and Care) - 667302, EC | EU Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie Action: Innovative Training Networks, ITN) - 643051 and EC | EU Horizon 2020 Research and Innovation Proramme (Sustainable Food Security - Resilient and Resource - Efficient Value Chains) - 728018

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. ; Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)). ; European Union LSHM-CT-2006-037761 PIAP-GA-2008-218251 HEALTH-F2-2009-223423 National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) 01GS08144 01GS08147 National Institute of Mental Health R01 MH078075 N01 MH900001 MH074027 Centre of Excellence for Complex Disease Genetics of the Academy of Finland 213506 129680 Biocentrum Helsinki Foundation Faculty of Medicine, University of Helsinki Stanley Medical Research Institute Danish Council for Strategic Research 2101-07-0059 H. Lundbeck A/S Research Council of Norway 163070/V50 South-East Norway Health Authority 2004-123 Medical Research Council Ministerio de Sanidad y Consumo, Spain PI081522 Xunta de Galicia 08CSA005208PR Swedish Research Council Wellcome Trust 083948/Z/07/Z Max Planck Society Eli Lilly and Company ; info:eu-repo/grantAgreement/EC/FP7/218251