Abstract

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10–2, threshold = 2.5 × 10–2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

Details

Title
Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities
Author
Price, Kaitlyn M. 1 ; Wigg, Karen G. 2 ; Eising, Else 3   VIAFID ORCID Logo  ; Feng, Yu 2 ; Blokland, Kirsten 4 ; Wilkinson, Margaret 4 ; Kerr, Elizabeth N. 5 ; Guger, Sharon L. 6 ; Abbondanza, Filippo 7 ; Allegrini, Andrea G. 8 ; Andlauer, Till F. M. 9 ; Bates, Timothy C. 10 ; Bernard, Manon 11 ; Bonte, Milene 12 ; Boomsma, Dorret I. 13 ; Bourgeron, Thomas 14 ; Brandeis, Daniel 15 ; Carreiras, Manuel 16 ; Ceroni, Fabiola 17 ; Csépe, Valéria 18 ; Dale, Philip S. 19 ; DeFries, John C. 20 ; de Jong, Peter F. 21 ; Démonet, Jean Francois 22 ; de Zeeuw, Eveline L. 23 ; Franken, Marie-Christine J. 24 ; Francks, Clyde 25 ; Gerritse, Margot 3 ; Gialluisi, Alessandro 26 ; Gordon, Scott D. 27 ; Gruen, Jeffrey R. 28 ; Hayiou-Thomas, Marianna E. 29 ; Hernández-Cabrera, Juan 30 ; Hottenga, Jouke-Jan 23 ; Hulme, Charles 31 ; Jansen, Philip R. 32 ; Kere, Juha 33 ; Koomar, Tanner 34 ; Landerl, Karin 35 ; Leonard, Gabriel T. 36 ; Liao, Zhijie 37 ; Luciano, Michelle 10 ; Lyytinen, Heikki 38 ; Martin, Nicholas G. 27 ; Martinelli, Angela 7 ; Maurer, Urs 39 ; Michaelson, Jacob J. 34 ; Mirza-Schreiber, Nazanin 40 ; Moll, Kristina 41 ; Monaco, Anthony P. 42 ; Morgan, Angela T. 43 ; Müller-Myhsok, Bertram 44 ; Newbury, Dianne F. 45 ; Nöthen, Markus M. 46 ; Olson, Richard K. 20 ; Paracchini, Silvia 7 ; Paus, Tomas 47 ; Pausova, Zdenka 48 ; Pennell, Craig E. 49 ; Pennington, Bruce F. 50 ; Plomin, Robert J. 8 ; Ramus, Franck 51 ; Reilly, Sheena 52 ; Richer, Louis 53 ; Rimfeld, Kaili 54 ; Schulte-Körne, Gerd 41 ; Shapland, Chin Yang 55 ; Simpson, Nuala H. 56 ; Smith, Shelley D. 57 ; Snowling, Margaret J. 58 ; St Pourcain, Beate 59 ; Stein, John F. 60 ; Talcott, Joel B. 61 ; Tiemeier, Henning 62 ; Tomblin, J. Bruce 63 ; Truong, Dongnhu T. 28 ; van Bergen, Elsje 64 ; van der Schroeff, Marc P. 65 ; Van Donkelaar, Marjolein 3 ; Verhoef, Ellen 3 ; Wang, Carol A. 66 ; Watkins, Kate E. 56 ; Whitehouse, Andrew J. O. 67 ; Willcutt, Erik G. 20 ; Wright, Margaret J. 68 ; Zhu, Gu 27 ; Fisher, Simon E. 69   VIAFID ORCID Logo  ; Lovett, Maureen W. 70 ; Strug, Lisa J. 71 ; Barr, Cathy L. 1   VIAFID ORCID Logo 

1  University Health Network, Division of Experimental and Translational Neuroscience, Krembil Research Institute, Toronto, Canada (GRID:grid.231844.8) (ISNI:0000 0004 0474 0428); Hospital for Sick Children, Program in Neuroscience and Mental Health, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Department of Physiology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
2  University Health Network, Division of Experimental and Translational Neuroscience, Krembil Research Institute, Toronto, Canada (GRID:grid.231844.8) (ISNI:0000 0004 0474 0428) 
3  Max Planck Institute for Psycholinguistics, Language and Genetics Department, Nijmegen, The Netherlands (GRID:grid.419550.c) (ISNI:0000 0004 0501 3839) 
4  Hospital for Sick Children, Program in Neuroscience and Mental Health, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
5  Hospital for Sick Children, Department of Psychology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Department of Pediatrics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
6  Hospital for Sick Children, Department of Psychology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
7  University of St Andrews, School of Medicine, St. Andrews, Scotland (GRID:grid.11914.3c) (ISNI:0000 0001 0721 1626) 
8  King’s College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
9  Max Planck Institute of Psychiatry, Translational Research in Psychiatry, Munich, Germany (GRID:grid.419548.5) (ISNI:0000 0000 9497 5095); Technical University of Munich, Department of Neurology, Klinikum rechts der Isar, School of Medicine, Munich, Germany (GRID:grid.6936.a) (ISNI:0000000123222966) 
10  University of Edinburgh, Department of Psychology, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
11  University of Toronto, Department of Physiology and Nutritional Sciences, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
12  Maastricht University, Department of Cognitive Neuroscience and Maastricht Brain Imaging Center, Faculty of Psychology and Neuroscience, Maastricht, The Netherlands (GRID:grid.5012.6) (ISNI:0000 0001 0481 6099) 
13  Netherlands Twin Register, Amsterdam, The Netherlands (GRID:grid.5012.6); Vrije Universiteit Amsterdam, Department of Biological Psychology, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227); Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam, The Netherlands (GRID:grid.12380.38) 
14  Human Genetics and Cognitive Function Unit, Institut Pasteur, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535); Université de Paris, Centre National Recherche Scientifique (CNRS) UMR 3571, Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602) 
15  Psychiatric University Hospital Zurich, University of Zurich, Department of Child and Adolescent Psychiatry and Psychotherapy, Zurich, Switzerland (GRID:grid.412004.3) (ISNI:0000 0004 0478 9977); University of Zurich and ETH Zurich, Zurich Center for Integrative Human Physiology, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650); University of Zurich and ETH Zurich, Neuroscience Center Zurich, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650); Heidelberg University, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Mannheim, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
16  Brain and Language (BCBL), Basque Center on Cognition, Donostia-San Sebastian, Spain (GRID:grid.423986.2) (ISNI:0000 0004 0536 1366); Ikerbasque, Basque Foundation for Science, Bilbao, Spain (GRID:grid.424810.b) (ISNI:0000 0004 0467 2314); University of the Basque Country (UPV/EHU), Lengua Vasca y Comunicación, Bilbao, Spain (GRID:grid.11480.3c) (ISNI:0000000121671098) 
17  University of Bologna, Department of Pharmacy and Biotechnology, Bologna, Italy (GRID:grid.6292.f) (ISNI:0000 0004 1757 1758); Oxford Brookes University, Faculty of Health and Life Sciences, Oxford, UK (GRID:grid.7628.b) (ISNI:0000 0001 0726 8331) 
18  Research Centre for Natural Sciences, Brain Imaging Centre, Budapest, Hungary (GRID:grid.425578.9) (ISNI:0000 0004 0512 3755); University of Pannonia, Multilingualism Doctoral School, Faculty of Modern Philology and Social Sciences, Veszprém, Hungary (GRID:grid.7336.1) (ISNI:0000 0001 0203 5854) 
19  University of New Mexico, Department of Speech & Hearing Sciences, Albuquerque, USA (GRID:grid.266832.b) (ISNI:0000 0001 2188 8502) 
20  University of Colorado, Institute for Behavioral Genetics, Boulder, USA (GRID:grid.266190.a) (ISNI:0000000096214564); University of Colorado, Department of Psychology and Neuroscience, Boulder, USA (GRID:grid.266190.a) (ISNI:0000000096214564) 
21  University of Amsterdam, Department of Child Development and Education, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262) 
22  Lausanne University Hospital (CHUV), University of Lausanne, Leenaards Memory Centre, Department of Clinical Neurosciences, Lausanne, Switzerland (GRID:grid.9851.5) (ISNI:0000 0001 2165 4204) 
23  Vrije Universiteit Amsterdam, Department of Biological Psychology, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227) 
24  Erasmus University Medical Center, Department of Otolaryngology, Head and Neck Surgery, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
25  Max Planck Institute for Psycholinguistics, Language and Genetics Department, Nijmegen, The Netherlands (GRID:grid.419550.c) (ISNI:0000 0004 0501 3839); Radboud University, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605); Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
26  Max Planck Institute of Psychiatry, Translational Research in Psychiatry, Munich, Germany (GRID:grid.419548.5) (ISNI:0000 0000 9497 5095); IRCCS Istituto Neurologico Mediterraneo Neuromed, Department of Epidemiology and Prevention, Pozzilli, Italy (GRID:grid.419543.e) (ISNI:0000 0004 1760 3561); University of Insubria, EPIMED Research Center, Department of Medicine and Surgery, Varese, Italy (GRID:grid.18147.3b) (ISNI:0000000121724807) 
27  QIMR Berghofer Medical Research Institute, Genetic Epidemiology Laboratory, Brisbane, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395) 
28  Yale Medical School, Departments of Pediatrics and Genetics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
29  University of York, Department of Psychology, York, UK (GRID:grid.5685.e) (ISNI:0000 0004 1936 9668) 
30  Clínica Psicobiología y Metodología, Departamento de Psicología, Santa Cruz de Tenerife, Spain (GRID:grid.5685.e) 
31  University of Oxford, Department of Education, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
32  Erasmus University Medical Center, Department of Child and Adolescent Psychiatry/Psychology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X); VU University, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227); VU Medical Center, Amsterdam University Medical Center, Department of Human Genetics, Amsterdam, The Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X) 
33  Karolinska Institutet, Department of Biosciences and Nutrition, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); University of Helsinki and Folkhälsan Research Center, Stem Cells and Metabolism Research Program, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
34  University of Iowa, Department of Psychiatry, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
35  Karl-Franzens-Universität Graz, Institute of Psychology, Graz, Austria (GRID:grid.5110.5) (ISNI:0000000121539003); BioTechMed-Graz, Graz, Austria (GRID:grid.452216.6) 
36  McGill University, Cognitive Neuroscience Neurology and Neurosurgery, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649) 
37  University of Toronto, Department of Psychology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
38  University of Jyväskylä, Department of Psychology, Jyväskylä, Finland (GRID:grid.9681.6) (ISNI:0000 0001 1013 7965) 
39  The Chinese University of Hong Kong, Department of Psychology, Hong Kong, China (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482) 
40  Helmholtz Zentrum München, Institute of Neurogenomics, Munich, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525) 
41  Ludwig-Maximilians-University Hospital Munich, Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Munich, Germany (GRID:grid.411095.8) (ISNI:0000 0004 0477 2585) 
42  Tufts University, Office of the President, Medford, USA (GRID:grid.429997.8) (ISNI:0000 0004 1936 7531) 
43  Murdoch Children’s Research Institute, Speech and Language, Melbourne, Australia (GRID:grid.1058.c) (ISNI:0000 0000 9442 535X); University of Melbourne, Department of Audiology and Speech Pathology, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Royal Children’s Hospital, Speech Pathology Department, Melbourne, Australia (GRID:grid.416107.5) (ISNI:0000 0004 0614 0346) 
44  Max Planck Institute of Psychiatry, Translational Research in Psychiatry, Munich, Germany (GRID:grid.419548.5) (ISNI:0000 0000 9497 5095); University of Liverpool, Department of Health Science, Liverpool, UK (GRID:grid.10025.36) (ISNI:0000 0004 1936 8470) 
45  Oxford Brookes University, Faculty of Health and Life Sciences, Oxford, UK (GRID:grid.7628.b) (ISNI:0000 0001 0726 8331) 
46  University Hospital of Bonn, Institute of Human Genetics, Bonn, Germany (GRID:grid.15090.3d) (ISNI:0000 0000 8786 803X) 
47  University of Montreal, Department of Psychiatry and Neuroscience and Centre Hospitalier Universitaire Sainte Justine, Montreal, Canada (GRID:grid.14848.31) (ISNI:0000 0001 2292 3357); University of Toronto, Department of Psychiatry, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, Department of Psychology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
48  University of Toronto, Department of Physiology and Nutritional Sciences, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); Hospital for Sick Children, Translational Medicine, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
49  University of Newcastle, School of Medicine and Public Health, College of Health, Medicine and Wellbeing, Newcastle, Australia (GRID:grid.266842.c) (ISNI:0000 0000 8831 109X); Hunter Medical Research Institute, Mothers and Babies Research Program, Newcastle, Australia (GRID:grid.413648.c); John Hunter Hospital, Maternity and Gynaecology, Newcastle, Australia (GRID:grid.414724.0) (ISNI:0000 0004 0577 6676) 
50  University of Denver, Department of Psychology, Denver, USA (GRID:grid.266239.a) (ISNI:0000 0001 2165 7675) 
51  Centre National de la Recherche Scientifique (CNRS), Laboratoire de Sciences Cognitives et Psycholinguistique, Ecole Normale Supérieure, Paris Sciences & Lettres University, École des Hautes Études en Sciences Sociales (EHESS), Paris, France (GRID:grid.4444.0) (ISNI:0000 0001 2112 9282) 
52  Murdoch Children’s Research Institute, Speech and Language, Melbourne, Australia (GRID:grid.1058.c) (ISNI:0000 0000 9442 535X); Griffith University, The Health Group, Gold Coast, Australia (GRID:grid.1022.1) (ISNI:0000 0004 0437 5432) 
53  Université du Québec à Chicoutimi, Department of Health Sciences, Chicoutimi, Canada (GRID:grid.265696.8) (ISNI:0000 0001 2162 9981) 
54  King’s College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); University of London, Department of Psychology, Royal Holloway, Egham, UK (GRID:grid.4464.2) (ISNI:0000 0001 2161 2573) 
55  University of Bristol, MRC Integrative Epidemiology Unit, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603); University of Bristol, Population Health Sciences, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
56  University of Oxford, Department of Experimental Psychology, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
57  University of Nebraska Medical Center, Department of Neurological Sciences, College of Medicine, Omaha, USA (GRID:grid.266813.8) (ISNI:0000 0001 0666 4105) 
58  University of Oxford, Department of Experimental Psychology, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University of Oxford, St John’s College, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
59  Max Planck Institute for Psycholinguistics, Language and Genetics Department, Nijmegen, The Netherlands (GRID:grid.419550.c) (ISNI:0000 0004 0501 3839); Radboud University, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The 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) 
60  Oxford University, Department of Physiology, Anatomy and Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
61  Aston University, Institute of Health and Neurodevelopment, Birmingham, UK (GRID:grid.7273.1) (ISNI:0000 0004 0376 4727) 
62  Erasmus University Medical Center, Department of Child and Adolescent Psychiatry/Psychology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X); T.H. Chan School of Public Health, Harvard, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
63  University of Iowa, Communication Sciences and Disorders, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
64  Netherlands Twin Register, Amsterdam, The Netherlands (GRID:grid.47100.32); Vrije Universiteit Amsterdam, Department of Biological Psychology, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227); Vrije Universiteit Amsterdam, Research Institute LEARN!, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227) 
65  Erasmus University Medical Center, Department of Otolaryngology, Head and Neck Surgery, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X); Generation R Study Group, Erasmus MC, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
66  University of Newcastle, School of Medicine and Public Health, College of Health, Medicine and Wellbeing, Newcastle, Australia (GRID:grid.266842.c) (ISNI:0000 0000 8831 109X); Hunter Medical Research Institute, Mothers and Babies Research Program, Newcastle, Australia (GRID:grid.413648.c) 
67  The University of Western Australia, Telethon Kids Institute, Perth, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910) 
68  University of Queensland, Queensland Brain Institute, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537) 
69  Max Planck Institute for Psycholinguistics, Language and Genetics Department, Nijmegen, The Netherlands (GRID:grid.419550.c) (ISNI:0000 0004 0501 3839); Radboud University, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605) 
70  Hospital for Sick Children, Program in Neuroscience and Mental Health, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Department of Pediatrics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
71  Hospital for Sick Children, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Departments of Statistical Sciences and Computer Science, Faculty of Arts and Science and Division of Biostatistics, Dalla Lana School of Public Health, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
21583188
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41398-022-02250-z
ProQuest document ID
2741145207
Copyright
© The Author(s) 2022. 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.