Accepted Article Preview: Published ahead of advance online publication Case-Control Genome-Wide Association Study of Persistent Attention-Deficit Hyperactivity Disorder Identifies FBXO33 as a Novel Susceptibility Gene for the Disorder Cristina Sa´nchez-Mora, Josep A Ramos-Quiroga, Rosa Bosch, Montse Corrales, Iris Garcia-Martinez, Mariana Nogueira, Mireia Pagerols, Gloria Palomar, Vanesa Richarte, Raquel Vidal, Alejandro Arias-Vasquez, Mariona Bustamante, Joan Forns, Silke Gross-Lesch, Monica Guxens, Anke Hinney, Martine Hoogman, Christian Jacob, Kaya K Jacobsen, Cornelis Kan, Lambertus Kiemeney, Sarah KittelSchneider, Marieke Klein, Marten Onnink, Olga Rivero, Tetyana Zayats, Jan Buitelaar, Steve V Faraone, Barbara Franke, Jan Haavik, Stefan Johansson, Klaus-Peter Lesch, Andreas Reif, Jordi Sunyer, Mo`nica Baye´s, Miguel Casas, Bru Cormand, Marta Ribase´s
Cite this article as: Cristina Sa´nchez-Mora, Josep A Ramos-Quiroga, Rosa Bosch, Montse Corrales, Iris Garcia-Martinez, Mariana Nogueira, Mireia Pagerols, Gloria Palomar, Vanesa Richarte, Raquel Vidal, Alejandro Arias-Vasquez, Mariona Bustamante, Joan Forns, Silke Gross-Lesch, Monica Guxens, Anke Hinney, Martine Hoogman, Christian Jacob, Kaya K Jacobsen, Cornelis Kan, Lambertus Kiemeney, Sarah Kittel-Schneider, Marieke Klein, Marten Onnink, Olga Rivero, Tetyana Zayats, Jan Buitelaar, Steve V Faraone, Barbara Franke, Jan Haavik, Stefan Johansson, Klaus-Peter Lesch, Andreas Reif, Jordi Sunyer, Mo`nica Baye´s, Miguel Casas, Bru Cormand, Marta Ribase´s, Case-Control Genome-Wide Association Study of Persistent Attention-Deficit Hyperactivity Disorder Identifies FBXO33 as a Novel Susceptibility Gene for the Disorder, Neuropsychopharmacology accepted article preview 6 October 2014; doi: 10.1038/ npp.2014.267. This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply. Received 17 June 2014; revised 22 August 2014; accepted 5 September 2014; Accepted article preview online 6 October 2014
©
2014 Macmillan Publishers Limited. All rights reserved.
Sánchez-Mora et al.
Case-control genome-wide association study of persistent Attention-Deficit Hyperactivity Disorder identifies FBXO33 as a novel susceptibility gene for the disorder Cristina Sánchez-Mora1,2,3, Josep A Ramos-Quiroga2,3,4, Rosa Bosch2,3, Montse Corrales2, Iris Garcia-Martinez1,2, Mariana Nogueira2, Mireia Pagerols1,2, Gloria Palomar2, Vanesa Richarte2, Raquel Vidal2, Alejandro Arias-Vasquez5,6,7, Mariona Bustamante8,9,10,11, Joan Forns8,9,10, Silke Gross-Lesch12, Monica Guxens8,9,10, Anke Hinney13, Martine Hoogman5, Christian Jacob12, Kaya K Jacobsen14, Cornelis Kan6, Lambertus Kiemeney15, Sarah Kittel-Schneider12, Marieke Klein5, Marten Onnink5,6, Olga Rivero16, Tetyana Zayats14, Jan Buitelaar7,17, Steve V Faraone18, Barbara Franke5,6, Jan Haavik14, Stefan Johansson14, Klaus-Peter Lesch16, Andreas Reif12, Jordi Sunyer8,9,10, Mònica Bayés19, Miguel Casas2,3,4, Bru Cormand20, 21, 22*, Marta Ribasés1,2,3*
1
Psychiatric Genetics Unit, Vall d‟Hebron Research Institute (VHIR), Universitat Autònoma de
Barcelona, Barcelona, Spain;
2
Department of Psychiatry, Hospital Universitari Vall d‟Hebron,
Barcelona, Spain;
3
Biomedical Network Research Centre on Mental Health (CIBERSAM),
Barcelona, Spain;
4
Department of Psychiatry and Legal Medicine, Universitat Autònoma de
Barcelona, Spain;
5
Radboud University Medical Center, Donders Institute for Brain, Cognition
and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands;
6
Radboud
university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Nijmegen, The Netherlands; 7 Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands; 8 Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; 9 IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; 10 CIBER Epidemiología y Salud Pública (CIBERESP), Spain; 12
11
Centre for Genomic Regulation (CRG), Barcelona, Spain;
Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg,
Würzburg, Germany;
13
Department of Child and Adolescent Psychiatry, University Duisburg-
1 ©
2014 Macmillan Publishers Limited. All rights reserved.
Sánchez-Mora et al.
Essen, Essen, Germany; 14 K. G. Jebsen Center for Research on Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; 15 Radboud university medical center, Radboud Institute for Health Sciences, Department for Health Evidence, Nijmegen, The Netherlands; 16 Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany;
17
Adolescent Psychiatry University Centre, Nijmegen, The Netherlands;
Karakter Child and 18
Department of
Psychiatry and of Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, NY; 19
Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), Spain;
Department of Genetics, University of Barcelona, Catalonia, Spain; Research Centre on Rare Diseases (CIBERER), Spain;
22
21
20
Biomedical Network
Institute of Biomedicine of the
University of Barcelona (IBUB), Catalonia, Spain * These authors contributed equally to this work. Number of figures: 1 Number of Tables: 4 Supplementary material: 14 Corresponding author: Marta Ribasés, Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d‟Hebron Research Institute, Passeig Vall d‟Hebron 119-129, 08035 Barcelona, Spain. Tel. (+34) 93 274 67 34. Fax (+34) 93 489 45 87. email: [email protected]. Key words: Attention-deficit hyperactivity disorder, ADHD, Genome-Wide Association Studies, GWAS, Single Nucleotide Polymorphism, SNP, FBXO33, ubiquitination Running title: Association between FBXO33 and persistent ADHD
2 ©
2014 Macmillan Publishers Limited. All rights reserved.
Sánchez-Mora et al.
ABSTRACT Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, Genome-Wide Association Studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2,104 ADHD patients and 1,901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC
Cite this article as: Cristina Sa´nchez-Mora, Josep A Ramos-Quiroga, Rosa Bosch, Montse Corrales, Iris Garcia-Martinez, Mariana Nogueira, Mireia Pagerols, Gloria Palomar, Vanesa Richarte, Raquel Vidal, Alejandro Arias-Vasquez, Mariona Bustamante, Joan Forns, Silke Gross-Lesch, Monica Guxens, Anke Hinney, Martine Hoogman, Christian Jacob, Kaya K Jacobsen, Cornelis Kan, Lambertus Kiemeney, Sarah Kittel-Schneider, Marieke Klein, Marten Onnink, Olga Rivero, Tetyana Zayats, Jan Buitelaar, Steve V Faraone, Barbara Franke, Jan Haavik, Stefan Johansson, Klaus-Peter Lesch, Andreas Reif, Jordi Sunyer, Mo`nica Baye´s, Miguel Casas, Bru Cormand, Marta Ribase´s, Case-Control Genome-Wide Association Study of Persistent Attention-Deficit Hyperactivity Disorder Identifies FBXO33 as a Novel Susceptibility Gene for the Disorder, Neuropsychopharmacology accepted article preview 6 October 2014; doi: 10.1038/ npp.2014.267. This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply. Received 17 June 2014; revised 22 August 2014; accepted 5 September 2014; Accepted article preview online 6 October 2014
©
2014 Macmillan Publishers Limited. All rights reserved.
Sánchez-Mora et al.
Case-control genome-wide association study of persistent Attention-Deficit Hyperactivity Disorder identifies FBXO33 as a novel susceptibility gene for the disorder Cristina Sánchez-Mora1,2,3, Josep A Ramos-Quiroga2,3,4, Rosa Bosch2,3, Montse Corrales2, Iris Garcia-Martinez1,2, Mariana Nogueira2, Mireia Pagerols1,2, Gloria Palomar2, Vanesa Richarte2, Raquel Vidal2, Alejandro Arias-Vasquez5,6,7, Mariona Bustamante8,9,10,11, Joan Forns8,9,10, Silke Gross-Lesch12, Monica Guxens8,9,10, Anke Hinney13, Martine Hoogman5, Christian Jacob12, Kaya K Jacobsen14, Cornelis Kan6, Lambertus Kiemeney15, Sarah Kittel-Schneider12, Marieke Klein5, Marten Onnink5,6, Olga Rivero16, Tetyana Zayats14, Jan Buitelaar7,17, Steve V Faraone18, Barbara Franke5,6, Jan Haavik14, Stefan Johansson14, Klaus-Peter Lesch16, Andreas Reif12, Jordi Sunyer8,9,10, Mònica Bayés19, Miguel Casas2,3,4, Bru Cormand20, 21, 22*, Marta Ribasés1,2,3*
1
Psychiatric Genetics Unit, Vall d‟Hebron Research Institute (VHIR), Universitat Autònoma de
Barcelona, Barcelona, Spain;
2
Department of Psychiatry, Hospital Universitari Vall d‟Hebron,
Barcelona, Spain;
3
Biomedical Network Research Centre on Mental Health (CIBERSAM),
Barcelona, Spain;
4
Department of Psychiatry and Legal Medicine, Universitat Autònoma de
Barcelona, Spain;
5
Radboud University Medical Center, Donders Institute for Brain, Cognition
and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands;
6
Radboud
university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Nijmegen, The Netherlands; 7 Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands; 8 Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; 9 IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; 10 CIBER Epidemiología y Salud Pública (CIBERESP), Spain; 12
11
Centre for Genomic Regulation (CRG), Barcelona, Spain;
Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg,
Würzburg, Germany;
13
Department of Child and Adolescent Psychiatry, University Duisburg-
1 ©
2014 Macmillan Publishers Limited. All rights reserved.
Sánchez-Mora et al.
Essen, Essen, Germany; 14 K. G. Jebsen Center for Research on Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; 15 Radboud university medical center, Radboud Institute for Health Sciences, Department for Health Evidence, Nijmegen, The Netherlands; 16 Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany;
17
Adolescent Psychiatry University Centre, Nijmegen, The Netherlands;
Karakter Child and 18
Department of
Psychiatry and of Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, NY; 19
Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), Spain;
Department of Genetics, University of Barcelona, Catalonia, Spain; Research Centre on Rare Diseases (CIBERER), Spain;
22
21
20
Biomedical Network
Institute of Biomedicine of the
University of Barcelona (IBUB), Catalonia, Spain * These authors contributed equally to this work. Number of figures: 1 Number of Tables: 4 Supplementary material: 14 Corresponding author: Marta Ribasés, Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addictions, Vall d‟Hebron Research Institute, Passeig Vall d‟Hebron 119-129, 08035 Barcelona, Spain. Tel. (+34) 93 274 67 34. Fax (+34) 93 489 45 87. email: [email protected]. Key words: Attention-deficit hyperactivity disorder, ADHD, Genome-Wide Association Studies, GWAS, Single Nucleotide Polymorphism, SNP, FBXO33, ubiquitination Running title: Association between FBXO33 and persistent ADHD
2 ©
2014 Macmillan Publishers Limited. All rights reserved.
Sánchez-Mora et al.
ABSTRACT Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, Genome-Wide Association Studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2,104 ADHD patients and 1,901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC
