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Mol Psychiatry. 2018 Aug 16. doi: 10.1038/s41380-018-0210-6. [Epub ahead of print]

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing.

Author information

1
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
2
K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
3
Division of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition, Center of Mental Health, University of Würzburg, Würzburg, Germany.
4
Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
6
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
7
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
8
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
9
Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
10
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
11
Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
12
Biomedical Network Research Center on Mental Health (CIBERSAM), Institute of Salud Carlos III, Madrid, Spain.
13
Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
14
Department of Psychiatry, University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
15
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
16
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Catalonia, Spain.
17
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain.
18
Instituto de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Salud Carlos III, Madrid, Spain.
19
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain.
20
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
21
HUNT Research Centre, Department of Public Health, Norwegian University of Science and Technology, Levanger, Norway.
22
Institute of Human Genetics, University of Bonn, Bonn, Germany.
23
Department of Genomics, Life&Brain Center, University of Bonn, Bonn, Germany.
24
Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
25
Department of Biomedicine, University of Basel, Basel, Switzerland.
26
Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
27
Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
28
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
29
K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Clinical Science, University of Bergen, Bergen, Norway.
30
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. barbara.franke@radboudumc.nl.
31
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. barbara.franke@radboudumc.nl.
32
Division of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition, Center of Mental Health, University of Würzburg, Würzburg, Germany. kplesch@mail.uni-wuerzburg.de.
33
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia. kplesch@mail.uni-wuerzburg.de.
34
Department of Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. kplesch@mail.uni-wuerzburg.de.

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 (Ntotal = 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.

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

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