Exploring the contribution to ADHD of genes involved in Mendelian disorders presenting with hyperactivity and/or inattention

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  • dc.contributor.author Fernàndez-Castillo, Noèlia
  • dc.contributor.author Cabana-Domínguez, Judit
  • dc.contributor.author Kappel, Djenifer B.
  • dc.contributor.author Torrico, Bàrbara
  • dc.contributor.author Weber, Keike
  • dc.contributor.author Lesch, Klaus-Peter
  • dc.contributor.author Lao Grueso, Oscar, 1976-
  • dc.contributor.author Reif, Andreas
  • dc.contributor.author Cormand, Bru
  • dc.date.accessioned 2022-04-04T06:31:12Z
  • dc.date.available 2022-04-04T06:31:12Z
  • dc.date.issued 2021
  • dc.description.abstract Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.
  • dc.description.sponsorship This work was supported mainly by funding from the European Union H2020 Program [H2020/2014–2020, grant agreements n° 667302, 643051 and 728018, corresponding to projects CoCA, coca-project.eu/; Eat2BeNice: newbrainnutrition.com/ (accessed on 16 December 2021); and MiND; www.mind-project.eu (accessed on 16 December 2021), respectively], and from the ‘ECNP network on ADHD across the lifespan’. NC-F received funding from ‘Plan Nacional Sobre Drogas of the Spanish Ministry of Health‘ [PNSD-2020I042] and was supported by a contract of the ‘Centro de Investigación Biomédica en Red de Enfermedades Raras' (CIBERER). BC received funding from the Spanish ‘Ministerio de Economía y Competitividad’ [SAF2015-68341-R, RTI2018-100968-B-100 and PID2021-1277760B-I100], ‘Plan Nacional sobre Drogas of the Spanish Ministry of Health’ [PNSD-2017I050] and AGAUR, ‘Generalitat de Catalunya’ [2017-SGR-738]. JC-D and BT were supported by the H2020 CoCA (n° 667302) and Eat2beNICE (n° 728018) projects. DBK was supported by the European Union H2020 Program [H2020/2014-2020] under grant agreements n° 643051 (MiND) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-148273/2016-5). OL acknowledges the support from Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa, CERCA Program/Generalitat de Catalunya, Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement, Co-financing with funds from the European Regional Development Fund by the Spanish Ministry of Science and Innovation corresponding to the Programa Operativo FEDER Plurirregional de España (POPE) 2014–2020 and by the Secretaria d’Universitats i Recerca, Departament d’Empresa i Coneixement of the Generalitat de Catalunya corresponding to the Programa Operatiu FEDER de Catalunya 2014–2020, Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness)—RYC-2013-14797, BFU2015-68759-P and PGC2018-098574-B-I00 and Generalitat de Catalunya (Government of Catalonia)—GRC 2017 SGR 937.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Fernàndez-Castillo N, Cabana-Domínguez J, Kappel DB, Torrico B, Weber H, Lesch KP, Lao O, Reif A, Cormand B. Exploring the contribution to ADHD of genes involved in Mendelian disorders presenting with hyperactivity and/or inattention. Genes (Basel). 2021 Dec 30;13(1):93. DOI: 10.3390/genes13010093
  • dc.identifier.doi http://dx.doi.org/10.3390/genes13010093
  • dc.identifier.issn 2073-4425
  • dc.identifier.uri http://hdl.handle.net/10230/52820
  • dc.language.iso eng
  • dc.publisher MDPI
  • dc.relation.ispartof Genes (Basel). 2021 Dec 30;13(1):93
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/667302
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/643051
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/728018
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-68341-R
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-100968-B-100
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2021-1277760B-I100
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-68759-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-098574-B-I00
  • dc.rights © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword ADHD
  • dc.subject.keyword Genetic variants
  • dc.subject.keyword Rare mendelian disorders
  • dc.title Exploring the contribution to ADHD of genes involved in Mendelian disorders presenting with hyperactivity and/or inattention
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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