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Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing
Corominas, Jordi (Radboud University Medical Center)
Klein, Marieke (Radboud University Medical Center)
Zayats, Tetyana (University of Bergen)
Rivero, Olga (University of Würzburg)
Ziegler, Georg C. (University of Würzburg)
Pauper, Marc (Radboud University Medical Center)
Neveling, Kornelia (Radboud University Medical Center)
Poelmans, Geert (Radboud University Medical Center)
Jansch, Charline (University of Würzburg)
Svirin, Evgeniy (I.M. Sechenov First Moscow State Medical University)
Geissler, Julia (University Hospital of Würzburg)
Weber, Heike (University Hospital Frankfurt)
Reif, Andreas (University Hospital Frankfurt)
Arias Vasquez, Alejandro (Radboud University Medical Center)
Galesloot, Tessel E. (Radboud University Medical Center)
Kiemeney, Lambertus A. L. M. (Radboud University Medical Center)
Buitelaar, Jan K. (Radboud University Medical Center)
Ramos Quiroga, Josep Antoni (Universitat Autònoma de Barcelona. Departament de Psiquiatria i de Medicina Legal)
Cormand, Bru (Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat)
Ribasés, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Hveem, Kristian (Norwegian University of Science and Technology)
Gabrielsen, Maiken Elvestad (Norwegian University of Science and Technology)
Hoffmann, Per (University of Basel)
Cichon, Sven (University Hospital Basel)
Haavik, Jan (Haukeland University Hospital)
Johansson, Stefan (University of Bergen)
Jacob, Christian P. (University of Würzburg)
Romanos, Marcel (University Hospital of Würzburg)
Franke, Barbara (Radboud University Medical Center)
Lesch, Klaus-Peter (Maastricht University)

Date: 2018
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1. 1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.
Note: Altres ajuts: This work was partly carried out on the Dutch national e-infrastructure with the support of the SURF Foundation. Barbara Franke and her team are supported by funding from a personal Vici grant of the Netherlands Organisation for Scientific Research (NWO; grant 016-130-669, to BF), [...]. In addition, this work was supported by the European College of Neuropsychopharmacology (ECNP Network "ADHD across the Lifespan"). Klaus-Peter Lesch and his team are supported by the Deutsche Forschungsgemeinschaft (DFG: CRU 125, CRC TRR 58 A1/A5), [...], Fritz Thyssen Foundation (No. 10.13.1185), ERA-Net NEURON/RESPOND, No. 01EW1602B, and 5-100 Russian Academic Excellence Project. [...]. The NBS exome chip data were generated in a research project that was financially supported by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007). The Heinz Nixdorf Recall (HNR) study is supported by the Heinz Nixdorf Foundation (Germany). Additionally, the study is funded by the German Ministry of Education and Science and the German Research Council (DFG; Project SI 236/8-1, SI236/9-1, ER 155/6-1). [...]. MR is a recipient of [...] and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. Jan Haavik and his team are supported by the K.G. Jebsen Foundation for Medical Research, University of Bergen, the Western Norwegian Health Authorities (Helse Vest). [...]. SC is supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Program (grant 01ZX1314A). He also receives support by the Swiss National Science Foundation (project no. 310030_156791). This publication was funded by the German Research Foundation (DFG) and the University of Wuerzburg in the funding programme Open Access Publishing.
Note: Número d'acord de subvenció EC/FP7/602805
Note: Número d'acord de subvenció EC/FP7/602450
Note: Número d'acord de subvenció EC/FP7/278948
Note: Número d'acord de subvenció EC/H2020/643051
Note: Número d'acord de subvenció EC/H2020/667302
Note: Número d'acord de subvenció MINECO/SAF2015-68341-R
Note: Número d'acord de subvenció AGAUR/2014SGR932
Note: Número d'acord de subvenció MINECO/ISCIII/CP09-00119
Note: Número d'acord de subvenció MINECO/ISCIII/CPII15-00023
Note: Número d'acord de subvenció ISCIII/PI12-01139
Note: Número d'acord de subvenció ISCIII/PI14-01700
Note: Número d'acord de subvenció ISCIII/PI15-01789
Note: Número d'acord de subvenció ISCIII/PI16-01505
Note: Número d'acord de subvenció AGAUR/2014SGR1357
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. Creative Commons
Language: Anglès
Document: article ; recerca ; publishedVersion
Subject: Genetics ; ADHD
Published in: Molecular Psychiatry, Vol. 25 (august 2018) , p. 2047-2057, ISSN 1476-5578

DOI: 10.1038/s41380-018-0210-6
PMID: 30116028

11 p, 912.1 KB

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 Record created 2020-09-21, last modified 2021-02-20

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