Abstract

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

Details

Title
Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia
Author
Gialluisi Alessandro 1   VIAFID ORCID Logo  ; Andlauer Till F M 2   VIAFID ORCID Logo  ; Mirza-Schreiber Nazanin 3 ; Moll, Kristina 4 ; Becker, Jessica 5 ; Hoffmann, Per 5   VIAFID ORCID Logo  ; Ludwig, Kerstin U 5   VIAFID ORCID Logo  ; Czamara Darina 3   VIAFID ORCID Logo  ; St Pourcain Beate 6   VIAFID ORCID Logo  ; Brandler, William 7 ; Honbolygó Ferenc 8 ; Tóth Dénes 8 ; Csépe Valéria 8 ; Huguet Guillaume 9 ; Morris, Andrew P 10 ; Hulslander Jacqueline 11 ; Willcutt, Erik G 11 ; DeFries, John C 11 ; Olson, Richard K 11 ; Smith, Shelley D 12 ; Pennington, Bruce F 13 ; Vaessen Anniek 14 ; Maurer Urs 15 ; Lyytinen Heikki 16 ; Peyrard-Janvid Myriam 17 ; Leppänen Paavo H T 16 ; Brandeis, Daniel 18 ; Bonte Milene 14 ; Stein, John F 19   VIAFID ORCID Logo  ; Talcott, Joel B 20   VIAFID ORCID Logo  ; Fauchereau Fabien 9 ; Wilcke Arndt 21 ; Francks Clyde 22 ; Bourgeron, Thomas 9 ; Monaco, Anthony P 23 ; Ramus Franck 24   VIAFID ORCID Logo  ; Landerl Karin 25 ; Kere Juha 26   VIAFID ORCID Logo  ; Scerri, Thomas S 27 ; Paracchini Silvia 28   VIAFID ORCID Logo  ; Fisher, Simon E 22   VIAFID ORCID Logo  ; Schumacher, Johannes 5 ; Nöthen, Markus M 5 ; Müller-Myhsok Bertram 29 ; Schulte-Körne Gerd 4 

1  Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany (GRID:grid.419548.5) (ISNI:0000 0000 9497 5095); Munich Cluster for Systems Neurology (Sypartially), Munich, Germany (GRID:grid.452617.3); IRCCS Istituto Neurologico Mediterraneo Neuromed, Department of Epidemiology and Prevention, Pozzilli, Italy (GRID:grid.419543.e) (ISNI:0000 0004 1760 3561) 
2  Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany (GRID:grid.419548.5) (ISNI:0000 0000 9497 5095); Munich Cluster for Systems Neurology (Sypartially), Munich, Germany (GRID:grid.452617.3) 
3  Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany (GRID:grid.419548.5) (ISNI:0000 0000 9497 5095) 
4  Ludwig-Maximilians University, Department of Child and Adolescent Psychiatry, Psychosomatic, and Psychotherapy, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
5  University of Bonn, Institute of Human Genetics, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300); University of Bonn, Department of Genomics, Life & Brain Center, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
6  Max Planck Institute for Psycholinguistics, Language and Genetics Department, Nijmegen, Netherlands (GRID:grid.419550.c) (ISNI:0000 0004 0501 3839); Radboud University, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605); University of Bristol, MRC Integrative Epidemiology Unit, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
7  University of California San Diego, Department of Psychiatry, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
8  Research Centre of Natural Sciences of the Hungarian Academy of Sciences, Brain Imaging Centre, Budapest, Hungary (GRID:grid.5018.c) (ISNI:0000 0001 2149 4407) 
9  Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535); University Paris Diderot, Sorbonne Paris Cité, Paris, France (GRID:grid.7452.4) (ISNI:0000 0001 2217 0017) 
10  Universiy of Liverpool, Department of Biostatistics, Liverpool, UK (GRID:grid.10025.36) (ISNI:0000 0004 1936 8470); University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
11  University of Colorado Boulder, Institute for Behavioral Genetics and Department of Psychology and Neuroscience, Boulder, USA (GRID:grid.266190.a) (ISNI:0000000096214564) 
12  University of Nebraska Medical Center, Developmental Neuroscience Munroe-Meyer Institute, Omaha, USA (GRID:grid.266813.8) (ISNI:0000 0001 0666 4105) 
13  University of Denver, Developmental Neuropsychology Lab & Clinic, Department of Psychology, Denver, USA (GRID:grid.266239.a) (ISNI:0000 0001 2165 7675) 
14  Maastricht University, Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience & Maastricht Brain Imaging Center (M-BIC), Maastricht, Netherlands (GRID:grid.5012.6) (ISNI:0000 0001 0481 6099) 
15  The Chinese University of Hong Kong, Department of Psychology, Shatin, Hong Kong (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482) 
16  University of Jyväskylä, Centre for Research on Learning and Teaching, Department of Psychology, Jyväskylä, Finland (GRID:grid.9681.6) (ISNI:0000 0001 1013 7965) 
17  Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
18  University of Zurich, Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650); Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650); Medical Faculty Mannheim/Heidelberg University, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373); University of Zurich and ETH Zurich, Neuroscience Center Zurich, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650) 
19  University of Oxford, Department of Physiology, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
20  Aston University, School of Life and Health Sciences, Birmingham, UK (GRID:grid.7273.1) (ISNI:0000 0004 0376 4727) 
21  Cognitive Genetics Unit, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany (GRID:grid.418008.5) (ISNI:0000 0004 0494 3022) 
22  Max Planck Institute for Psycholinguistics, Language and Genetics Department, Nijmegen, Netherlands (GRID:grid.419550.c) (ISNI:0000 0004 0501 3839); Radboud University, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605) 
23  University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); Tufts University, Medford, USA (GRID:grid.429997.8) (ISNI:0000 0004 1936 7531) 
24  PSL Research University, Laboratoire de Sciences Cognitives et Psycholinguistique, Ecole Normale Supérieure, CNRS, EHESS, Paris, France (GRID:grid.440907.e) 
25  University of Graz, Graz, Austria and BioTechMed, Institute of Psychology, Graz, Austria (GRID:grid.5110.5) (ISNI:0000000121539003) 
26  Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); University of Helsinki, and Folkhälsan Institute of Genetics, Molecular Medicine Program, Biomedicum, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); School of Basic and Medical Biosciences, King’s College London, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
27  University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); The Walter and Eliza Hall Institute of Medical Research & Melbourne University, Melbourne, Australia (GRID:grid.1042.7) 
28  University of St Andrews, School of Medicine, St Andrews, UK (GRID:grid.11914.3c) (ISNI:0000 0001 0721 1626) 
29  Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany (GRID:grid.419548.5) (ISNI:0000 0000 9497 5095); Munich Cluster for Systems Neurology (Sypartially), Munich, Germany (GRID:grid.452617.3); Institute of Translational Medicine, University of Liverpool, Liverpool, UK (GRID:grid.10025.36) (ISNI:0000 0004 1936 8470) 
Publication year
2019
Publication date
Dec 2019
Publisher
Nature Publishing Group
e-ISSN
21583188
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41398-019-0402-0
ProQuest document ID
2178602592
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.