Exploring the Contribution to ADHD of Genes Involved in Mendelian Disorders Presenting with Hyperactivity and/or Inattention
Fernàndez-Castillo, Noèlia (Institut de Recerca Sant Joan de Déu)
Cabana-Domínguez, Judit (Hospital Universitari Vall d'Hebron)
Kappel, Djenifer B. (Cardiff University)
Torrico, Bàrbara (Institut de Recerca Sant Joan de Déu)
Weber, Heike (University Hospital Würzburg)
Lesch, Klaus-Peter (I.M Sechenov First Moscow State Medical University)
Lao, Oscar (Universitat Pompeu Fabra)
Reif, Andreas (University Hospital of Frankfurt (Alemanya))
Cormand, Bru (Institut de Recerca Sant Joan de Déu)
Universitat Autònoma de Barcelona

Date:	2021
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.
Grants:	European Commission 667302 European Commission 643051 European Commission 728018 Ministerio de Economía y Competitividad RYC-2013-14797 Ministerio de Economía y Competitividad BFU2015-68759-P Agencia Estatal de Investigación PGC2018-098574-B-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-937 Ministerio de Economía y Competitividad SAF2015-68341-R Ministerio de Economía y Competitividad RTI2018-100968-B-100 Ministerio de Economía y Competitividad PID2021-1277760B-I100 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-738
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	ADHD ; Rare mendelian disorders ; Genetic variants
Published in:	Genes, Vol. 13 (december 2021) , ISSN 2073-4425

DOI: 10.3390/genes13010093
PMID: 35052433

12 p, 620.2 KB

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