Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

Else Eising¹, Nazanin Mirza-Schreiber², Eveline L de Zeeuw³, Carol A Wang^{4

5}, Dongnhu T Truong⁶, Andrea G Allegrini⁷, Chin Yang Shapland^{8

9}, Gu Zhu¹⁰, Karen G Wigg¹¹, Margot L Gerritse¹, Barbara Molz¹, Gökberk Alagöz¹, Alessandro Gialluisi^{12

13

14}, Filippo Abbondanza¹⁵, Kaili Rimfeld^{7

16}, Marjolein van Donkelaar¹, Zhijie Liao¹⁷, Philip R Jansen^{18

19

20}, Till F M Andlauer^{12

21}, Timothy C Bates²², Manon Bernard²³, Kirsten Blokland²⁴, Milene Bonte²⁵, Anders D Børglum^{26

27

28}, Thomas Bourgeron²⁹, Daniel Brandeis^{30

31

32

33}, Fabiola Ceroni^{34

35}, Valéria Csépe^{36

37}, Philip S Dale³⁸, Peter F de Jong³⁹, John C DeFries^{40

41}, Jean-François Démonet⁴², Ditte Demontis^{26

27}, Yu Feng¹¹, Scott D Gordon¹⁰, Sharon L Guger⁴³, Marianna E Hayiou-Thomas⁴⁴, Juan A Hernández-Cabrera⁴⁵, Jouke-Jan Hottenga³, Charles Hulme⁴⁶, Juha Kere^{47

48}, Elizabeth N Kerr^{43

49

50}, Tanner Koomar⁵¹, Karin Landerl^{52

53}, Gabriel T Leonard⁵⁴, Maureen W Lovett^{24

50}, Heikki Lyytinen⁵⁵, Nicholas G Martin¹⁰, Angela Martinelli¹⁵, Urs Maurer⁵⁶, Jacob J Michaelson⁵¹, Kristina Moll⁵⁷, Anthony P Monaco⁵⁸, Angela T Morgan^{59

60

61}, Markus M Nöthen⁶², Zdenka Pausova^{23

63}, Craig E Pennell^{4

5

64}, Bruce F Pennington⁶⁵, Kaitlyn M Price^{11

24

66}, Veera M Rajagopal^{26

27}, Franck Ramus⁶⁷, Louis Richer⁶⁸, Nuala H Simpson⁶⁹, Shelley D Smith⁷⁰, Margaret J Snowling^{69

71}, John Stein⁷², Lisa J Strug^{73

74}, Joel B Talcott⁷⁵, Henning Tiemeier^{18

76}, Marc P van der Schroeff^{77

78}, Ellen Verhoef¹, Kate E Watkins⁶⁹, Margaret Wilkinson²⁴, Margaret J Wright⁷⁹, Cathy L Barr^{11

24

66}, Dorret I Boomsma^{3

80

81}, Manuel Carreiras^{82

83

84}, Marie-Christine J Franken⁷⁷, Jeffrey R Gruen⁶, Michelle Luciano²², Bertram Müller-Myhsok^{12

85}, Dianne F Newbury³⁵, Richard K Olson⁴⁰, Silvia Paracchini¹⁵, Tomáš Paus⁸⁶, Robert Plomin⁷, Sheena Reilly^{59

87}, Gerd Schulte-Körne⁵⁷, J Bruce Tomblin⁸⁸, Elsje van Bergen^{3

80

89}, Andrew J O Whitehouse⁹⁰, Erik G Willcutt⁴¹, Beate St Pourcain^{1

8

91}, Clyde Francks^{1

91

92}, Simon E Fisher^{1

91}

Affiliations

¹ Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, the Netherlands.
² Institute of Neurogenomics, Helmholtz Zentrum Munich, 85764 Munich, Germany.
³ Department of Biological Psychology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, the Netherlands.
⁴ School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW 2308, Australia.
⁵ Mothers and Babies Research Program, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
⁶ Department of Pediatrics and Genetics, Yale Medical School, New Haven, CT 06510.
⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
⁸ MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, United Kingdom.
⁹ Population Health Sciences, University of Bristol, Bristol BS8 2PS, United Kingdom.
¹⁰ Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
¹¹ Division of Experimental and Translational Neuroscience, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada.
¹² Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
¹³ Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.
¹⁴ Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy.
¹⁵ School of Medicine, University of St Andrews, KY16 9TF, St. Andrews, Scotland.
¹⁶ Department of Psychology, Royal Holloway, University of London, Egham TW20 0EY, United Kingdom.
¹⁷ Department of Psychology, University of Toronto, Toronto, ON M5S 3G3,Canada.
¹⁸ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, 3000 CB Rotterdam, the Netherlands.
¹⁹ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, 1081 HV the Netherlands.
²⁰ Department of Human Genetics, VU Medical Center, Amsterdam University Medical Center, 1081 BT Amsterdam, the Netherlands.
²¹ Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
²² Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
²³ Department of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada.
²⁴ Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, M5G 1X8 ON, Canada.
²⁵ Department of Cognitive Neuroscience and Maastricht Brain Imaging Center, Faculty of Psychology and Neuroscience, Maastricht University, 6229 ER Maastricht, the Netherlands.
²⁶ Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
²⁷ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus, Denmark.
²⁸ Center for Genomics and Personalized Medicine (CGPM), 8000 Aarhus, Denmark.
²⁹ Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 Centre national de la recherche scientifique (CNRS), Université Paris Cité, Paris, 75015, France.
³⁰ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, 8032 Zurich, Switzerland.
³¹ Zurich Center for Integrative Human Physiology, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
³² Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
³³ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
³⁴ Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
³⁵ Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, United Kingdom.
³⁶ Brain Imaging Centre, Research Centre for Natural Sciences, Budapest, 1117 Hungary.
³⁷ Multilingualism Doctoral School, Faculty of Modern Philology and Social Sciences, University of Pannonia, Veszprém, 8200 Hungary.
³⁸ Department of Speech & Hearing Sciences, University of New Mexico, Albuquerque, NM 87131.
³⁹ Department of Child Development and Education, University of Amsterdam, 1012 WX Amsterdam, the Netherlands.
⁴⁰ Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309-0447.
⁴¹ Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309-0447.
⁴² Leenaards Memory Centre, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), University of Lausanne, CH-1011 Lausanne, Switzerland.
⁴³ Department of Psychology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁴⁴ Department of Psychology, University of York, York YO10 5DD, United Kingdom.
⁴⁵ Departamento de Psicología, Clínica Psicobiología y Metodología, 38200, La Laguna, Santa Cruz de Tenerife, Spain.
⁴⁶ Department of Education, University of Oxford, Oxford, Oxfordshire OX2 6PY, United Kingdom.
⁴⁷ Department of Biosciences and Nutrition, Karolinska Institutet, 171 77 Stockholm, Sweden.
⁴⁸ Stem Cells and Metabolism Research Program, University of Helsinki and Folkhälsan Research Center, 00014 Helsinki, Finland.
⁴⁹ Department of Neurology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁵⁰ Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
⁵¹ Department of Psychiatry, University of Iowa, Iowa City, IA 52242.
⁵² Institute of Psychology, University of Graz, 8010 Graz, Austria.
⁵³ BioTechMed-Graz, 8010 Graz, Austria.
⁵⁴ Cognitive Neuroscience Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1G1, Canada.
⁵⁵ Department of Psychology, University of Jyväskylä, 40014 Jyväskylä, Finland.
⁵⁶ Department of Psychology, The Chinese University of Hong Kong, Hong Kong, China.
⁵⁷ Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwig-Maximilians-University Hospital Munich, Munich, 80336 Germany.
⁵⁸ Office of the President, Tufts University, Medford, MA 02155.
⁵⁹ Speech and Language, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
⁶⁰ Department of Audiology and Speech Pathology, University of Melbourne, Melbourne, VIC 3052, Australia.
⁶¹ Speech Pathology Department, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
⁶² Institute of Human Genetics, University Hospital of Bonn, 53127 Bonn, Germany.
⁶³ Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁴ Maternity and Gynaecology, John Hunter Hospital, Newcastle, NSW 2305, Australia.
⁶⁵ Department of Psychology, University of Denver, Denver, CO 80210.
⁶⁶ Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁶⁷ Laboratoire de Sciences Cognitives et Psycholinguistique, Ecole Normale Supérieure, Paris Sciences & Lettres University, École des Hautes Études en Sciences Sociales (EHESS), Centre National de la Recherche Scientifique (CNRS), Paris, 75005 France.
⁶⁸ Department of Health Sciences, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada.
⁶⁹ Department of Experimental Psychology, University of Oxford, Oxford OX2 6GG, United Kingdom.
⁷⁰ Department of Neurological Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198.
⁷¹ St. John's College, University of Oxford, Oxford OX1 3JP, United Kingdom.
⁷² Department of Physiology, Anatomy and Genetics, Oxford University, Oxford OX1 3PT, United Kingdom.
⁷³ Department of Statistical Sciences and Computer Science and Division of Biostatistics, University of Toronto, Toronto, ON M5S 3G3, Canada.
⁷⁴ Program in Genetics and Genome Biology and the Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁷⁵ Institute for Health and Neurodevelopment, Aston University, Birmingham B4 7ET, United Kingdom.
⁷⁶ T. H. Chan School of Public Health, Harvard, Boston, MA 02115.
⁷⁷ Department of Otolaryngology, Head and Neck Surgery, Erasmus University Medical Center, 3015 GD Rotterdam, the Netherlands.
⁷⁸ Generation R Study Group, Erasmus University Medical Center, 3015 GD Rotterdam, the Netherlands.
⁷⁹ Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.
⁸⁰ Netherlands Twin Register, 1081 BT Amsterdam, the Netherlands.
⁸¹ Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁸² Basque Center on Cognition, Brain and Language, Donostia-San Sebastian, 20009 Gipuzkoa, Spain.
⁸³ Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Vizcaya, Spain.
⁸⁴ Lengua Vasca y Comunicación, University of the Basque Country, 48940 Bilbao, Vizcaya, Spain.
⁸⁵ Department of Health Science, University of Liverpool, Liverpool L69 7ZX, United Kingdom.
⁸⁶ Department of Psychiatry and Neuroscience and Centre Hospitalier Universitaire Sainte Justine, University of Montreal, Montreal, QC H3T 1J4, Canada.
⁸⁷ Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia.
⁸⁸ Communication Sciences and Disorders, University of Iowa, Iowa City, IA 52242.
⁸⁹ Research Institute LEARN!, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, the Netherlands.
⁹⁰ Telethon Kids Institute, The University of Western Australia, Perth, WA 6009, Australia.
⁹¹ Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, the Netherlands.
⁹² Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.

PMID: 35998220
PMCID: PMC9436320
DOI: 10.1073/pnas.2202764119

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

Else Eising et al. Proc Natl Acad Sci U S A. 2022.

. 2022 Aug 30;119(35):e2202764119.

doi: 10.1073/pnas.2202764119. Epub 2022 Aug 23.

Authors

Affiliations

¹ Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, the Netherlands.
² Institute of Neurogenomics, Helmholtz Zentrum Munich, 85764 Munich, Germany.
³ Department of Biological Psychology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, the Netherlands.
⁴ School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW 2308, Australia.
⁵ Mothers and Babies Research Program, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
⁶ Department of Pediatrics and Genetics, Yale Medical School, New Haven, CT 06510.
⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
⁸ MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, United Kingdom.
⁹ Population Health Sciences, University of Bristol, Bristol BS8 2PS, United Kingdom.
¹⁰ Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
¹¹ Division of Experimental and Translational Neuroscience, Krembil Research Institute, University Health Network, Toronto, ON M5T 0S8, Canada.
¹² Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
¹³ Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.
¹⁴ Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy.
¹⁵ School of Medicine, University of St Andrews, KY16 9TF, St. Andrews, Scotland.
¹⁶ Department of Psychology, Royal Holloway, University of London, Egham TW20 0EY, United Kingdom.
¹⁷ Department of Psychology, University of Toronto, Toronto, ON M5S 3G3,Canada.
¹⁸ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, 3000 CB Rotterdam, the Netherlands.
¹⁹ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, 1081 HV the Netherlands.
²⁰ Department of Human Genetics, VU Medical Center, Amsterdam University Medical Center, 1081 BT Amsterdam, the Netherlands.
²¹ Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
²² Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.
²³ Department of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada.
²⁴ Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, M5G 1X8 ON, Canada.
²⁵ Department of Cognitive Neuroscience and Maastricht Brain Imaging Center, Faculty of Psychology and Neuroscience, Maastricht University, 6229 ER Maastricht, the Netherlands.
²⁶ Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
²⁷ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus, Denmark.
²⁸ Center for Genomics and Personalized Medicine (CGPM), 8000 Aarhus, Denmark.
²⁹ Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 Centre national de la recherche scientifique (CNRS), Université Paris Cité, Paris, 75015, France.
³⁰ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, 8032 Zurich, Switzerland.
³¹ Zurich Center for Integrative Human Physiology, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
³² Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057 Zurich, Switzerland.
³³ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
³⁴ Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
³⁵ Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, United Kingdom.
³⁶ Brain Imaging Centre, Research Centre for Natural Sciences, Budapest, 1117 Hungary.
³⁷ Multilingualism Doctoral School, Faculty of Modern Philology and Social Sciences, University of Pannonia, Veszprém, 8200 Hungary.
³⁸ Department of Speech & Hearing Sciences, University of New Mexico, Albuquerque, NM 87131.
³⁹ Department of Child Development and Education, University of Amsterdam, 1012 WX Amsterdam, the Netherlands.
⁴⁰ Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309-0447.
⁴¹ Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309-0447.
⁴² Leenaards Memory Centre, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), University of Lausanne, CH-1011 Lausanne, Switzerland.
⁴³ Department of Psychology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁴⁴ Department of Psychology, University of York, York YO10 5DD, United Kingdom.
⁴⁵ Departamento de Psicología, Clínica Psicobiología y Metodología, 38200, La Laguna, Santa Cruz de Tenerife, Spain.
⁴⁶ Department of Education, University of Oxford, Oxford, Oxfordshire OX2 6PY, United Kingdom.
⁴⁷ Department of Biosciences and Nutrition, Karolinska Institutet, 171 77 Stockholm, Sweden.
⁴⁸ Stem Cells and Metabolism Research Program, University of Helsinki and Folkhälsan Research Center, 00014 Helsinki, Finland.
⁴⁹ Department of Neurology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁵⁰ Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
⁵¹ Department of Psychiatry, University of Iowa, Iowa City, IA 52242.
⁵² Institute of Psychology, University of Graz, 8010 Graz, Austria.
⁵³ BioTechMed-Graz, 8010 Graz, Austria.
⁵⁴ Cognitive Neuroscience Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1G1, Canada.
⁵⁵ Department of Psychology, University of Jyväskylä, 40014 Jyväskylä, Finland.
⁵⁶ Department of Psychology, The Chinese University of Hong Kong, Hong Kong, China.
⁵⁷ Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwig-Maximilians-University Hospital Munich, Munich, 80336 Germany.
⁵⁸ Office of the President, Tufts University, Medford, MA 02155.
⁵⁹ Speech and Language, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
⁶⁰ Department of Audiology and Speech Pathology, University of Melbourne, Melbourne, VIC 3052, Australia.
⁶¹ Speech Pathology Department, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
⁶² Institute of Human Genetics, University Hospital of Bonn, 53127 Bonn, Germany.
⁶³ Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁶⁴ Maternity and Gynaecology, John Hunter Hospital, Newcastle, NSW 2305, Australia.
⁶⁵ Department of Psychology, University of Denver, Denver, CO 80210.
⁶⁶ Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁶⁷ Laboratoire de Sciences Cognitives et Psycholinguistique, Ecole Normale Supérieure, Paris Sciences & Lettres University, École des Hautes Études en Sciences Sociales (EHESS), Centre National de la Recherche Scientifique (CNRS), Paris, 75005 France.
⁶⁸ Department of Health Sciences, Université du Québec à Chicoutimi, Chicoutimi, QC G7H 2B1, Canada.
⁶⁹ Department of Experimental Psychology, University of Oxford, Oxford OX2 6GG, United Kingdom.
⁷⁰ Department of Neurological Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198.
⁷¹ St. John's College, University of Oxford, Oxford OX1 3JP, United Kingdom.
⁷² Department of Physiology, Anatomy and Genetics, Oxford University, Oxford OX1 3PT, United Kingdom.
⁷³ Department of Statistical Sciences and Computer Science and Division of Biostatistics, University of Toronto, Toronto, ON M5S 3G3, Canada.
⁷⁴ Program in Genetics and Genome Biology and the Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁷⁵ Institute for Health and Neurodevelopment, Aston University, Birmingham B4 7ET, United Kingdom.
⁷⁶ T. H. Chan School of Public Health, Harvard, Boston, MA 02115.
⁷⁷ Department of Otolaryngology, Head and Neck Surgery, Erasmus University Medical Center, 3015 GD Rotterdam, the Netherlands.
⁷⁸ Generation R Study Group, Erasmus University Medical Center, 3015 GD Rotterdam, the Netherlands.
⁷⁹ Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.
⁸⁰ Netherlands Twin Register, 1081 BT Amsterdam, the Netherlands.
⁸¹ Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁸² Basque Center on Cognition, Brain and Language, Donostia-San Sebastian, 20009 Gipuzkoa, Spain.
⁸³ Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Vizcaya, Spain.
⁸⁴ Lengua Vasca y Comunicación, University of the Basque Country, 48940 Bilbao, Vizcaya, Spain.
⁸⁵ Department of Health Science, University of Liverpool, Liverpool L69 7ZX, United Kingdom.
⁸⁶ Department of Psychiatry and Neuroscience and Centre Hospitalier Universitaire Sainte Justine, University of Montreal, Montreal, QC H3T 1J4, Canada.
⁸⁷ Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia.
⁸⁸ Communication Sciences and Disorders, University of Iowa, Iowa City, IA 52242.
⁸⁹ Research Institute LEARN!, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, the Netherlands.
⁹⁰ Telethon Kids Institute, The University of Western Australia, Perth, WA 6009, Australia.
⁹¹ Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, the Netherlands.
⁹² Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.

PMID: 35998220
PMCID: PMC9436320
DOI: 10.1073/pnas.2202764119

Abstract

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10^-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Keywords: genome-wide association study; language; meta-analysis; reading.

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Conflict of interest statement

The authors declare no competing interest.

Figures

**Fig. 1.**
Reading- and language-related traits have a shared genetic architecture that is largely independent of performance IQ. (A) Genetic correlations (rg) among the reading- and language-related traits estimated with LDSC. Estimates are capped at one. Full LDSC results are reported in Dataset S4. In addition, genetic correlations are given between the GenLang traits and 1) performance IQ (using GenLang cohorts only); 2) educational attainment (EA; n = 766,345) and full-scale IQ (n = 257,828) (18); 3) noncognitive abilities involved in EA, resulting from a recent GWAS by subtraction study (n = 510,795) (19); and 4) components associated with distinct performance domains identified used a decomposition analysis of Danish school grades (n = 30,982) (20). Full results can be found in Dataset S8. *Significant genetic correlation after correction for 18.28 independent comparisons (P < 2.74 × 10⁻³); **P < 2.74 × 10⁻⁴; ***P < 2.74 × 10⁻⁵. (B) Three-factor model fitted to the GenLang summary statistics for word reading, nonword reading, spelling, phoneme awareness, nonword repetition, and performance IQ and to published GWAS summary statistics for full-scale IQ and EA (18) using GenomicSEM (21). Black and gray paths represent factor loadings with P < 0.05 and P > 0.05, respectively. Standardized factor loadings are shown, with SE in parentheses. The subscript g represents the genetic variables; the u variables represent the residual genetic variance not explained by the models. Unstandardized results and model fit indices are reported in Dataset S9.

**Fig. 2.**
The multivariate GenLang GWAS results show significant genetic correlation with the cortical surface area around the left STS. Genetic correlations (rg) were estimated with LDSC. Included traits are 58 structural brain imaging traits from the UK Biobank selected based on known links of regions and circuits with language processing. The results of the 22 cortical surface areas are shown; gray areas were not included in the analysis. Full results can be found in Dataset S12 and *SI Appendix*, Figs. S6 and S7. *Significant genetic correlation after correcting for 24.85 independent brain imaging traits (P < 2.01 × 10⁻³).

**Fig. 3.**
Genetic correlation results of the multivariate GenLang GWAS analysis with comparisons with those for the largest published GWAS of full-scale IQ in LD Hub. Summary statistics for full-scale IQ (n = 257,828) were obtained from the Social Science Genetic Association Consortium (18). Genetic correlations between the multivariate GenLang results (blue–green), full-scale IQ (purple), and traits in LD Hub reveal an overlap with cognitive traits, education, eyesight, chronotype, lifestyle, well-being, psychiatric disorders, pain, physical health and exercise, and socioeconomic status. A subset of representative traits is shown; 143 traits showed significant associations with the multivariate GenLang results, and 245 traits showed significant correlations with full-scale IQ, of which 135 traits overlap after correction for multiple testing for 535 × 2 traits (P < 4.67 × 10⁻⁵). Significant correlations are shown in dark colors; nonsignificant correlations are in light colors. Full results can be found in Dataset S13. UKBB: UK Biobank, GCSE: General Certificate of Secondary Education, NVQ: National Vocational Qualification, HND: Higher National Diploma, HNC: Higher National Certificate, CSE: Certificate of Secondary Education, PGC: Psychiatric Genomics Consortium, BMI: body mass index, SES: socioeconomic status. Genetic correlation (rg) is presented as a dot, and error bars indicate the SE.

See this image and copyright information in PMC

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Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

Affiliations

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

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