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

Else Eising; Nazanin Mirza-Schreiber; Eveline L. de Zeeuw; Carol A. Wang; Dongnhu T. Truong; Andrea G. Allegrini; Chin Yang Shapland; Gu Zhu; Karen G. Wigg; Margot L. Gerritse; Barbara Molz; Gokberk Alagoz; Alessandro Gialluisi; Filippo Abbondanza; Kaili Rimfeld; Marjolein van Donkelaar; Zhijie Liao; Philip R. Jansen; Till F.M. Andlauer; Timothy C. Bates; Manon Bernard; Kirsten Blokland; Milene Bonte; Anders D. Børglum; Thomas Bourgeron; Daniel Brandeis; Fabiola Ceroni; Valeria Csepe; Philip S. Dale; Peter F. de Jong; John C. DeFries; Jean François Demonet; Ditte Demontis; Yu Feng; Scott D. Gordon; Sharon L. Guger; Marianna E. Hayiou-Thomas; Juan A. Hernandez-Cabrera; Jouke Jan Hottenga; Charles Hulme; Juha Kere; Elizabeth N. Kerr; Tanner Koomar; Karin Landerl; Gabriel T. Leonard; Maureen W. Lovett; Heikki Lyytinen; Nicholas G. Martin; Angela Martinelli; Urs Maurer; Jacob J. Michaelson; Kristina Moll; Anthony P. Monaco; Angela T. Morgan; Markus M. Nothen; Zdenka Pausova; Craig E. Pennell; Bruce F. Pennington; Kaitlyn M. Price; Veera M. Rajagopal; Franck Ramus; Louis Richer; Nuala H. Simpson; Shelley D. Smith; Margaret J. Snowling; John Stein; Lisa J. Strug; Joel B. Talcott; Henning Tiemeier; Marc P. van der Schroeff; Ellen Verhoef; Kate E. Watkins; Margaret Wilkinson; Margaret J. Wright; Cathy L. Barr; Dorret I. Boomsma; Manuel Carreiras; Marie Christine J. Franken; Jeffrey R. Gruen; Michelle Luciano; Bertram Muller-Myhsok; Dianne F. Newbury; Richard K. Olson; Silvia Paracchini; Tomas Paus; Robert Plomin; Sheena Reilly; Gerd Schulte-Korne; J. Bruce Tomblin; Elsje van Bergen; Andrew J.O. Whitehouse; Erik G. Willcutt; Beate St Pourcain; Clyde Francks; Simon E. Fisher

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, Nazanin Mirza-Schreiber, Eveline L. de Zeeuw, Carol A. Wang, Dongnhu T. Truong, Andrea G. Allegrini, Chin Yang Shapland, Gu Zhu, Karen G. Wigg, Margot L. Gerritse, Barbara Molz, Gokberk Alagoz, Alessandro Gialluisi, Filippo Abbondanza, Kaili Rimfeld, Marjolein van Donkelaar, Zhijie Liao, Philip R. Jansen, Till F.M. Andlauer, Timothy C. BatesManon Bernard, Kirsten Blokland, Milene Bonte, Anders D. Børglum, Thomas Bourgeron, Daniel Brandeis, Fabiola Ceroni, Valeria Csepe, Philip S. Dale, Peter F. de Jong, John C. DeFries, Jean François Demonet, Ditte Demontis, Yu Feng, Scott D. Gordon, Sharon L. Guger, Marianna E. Hayiou-Thomas, Juan A. Hernandez-Cabrera, Jouke Jan Hottenga, Charles Hulme, Juha Kere, Elizabeth N. Kerr, Tanner Koomar, Karin Landerl, Gabriel T. Leonard, Maureen W. Lovett, Heikki Lyytinen, Nicholas G. Martin, Angela Martinelli, Urs Maurer, Jacob J. Michaelson, Kristina Moll, Anthony P. Monaco, Angela T. Morgan, Markus M. Nothen, Zdenka Pausova, Craig E. Pennell, Bruce F. Pennington, Kaitlyn M. Price, Veera M. Rajagopal, Franck Ramus, Louis Richer, Nuala H. Simpson, Shelley D. Smith, Margaret J. Snowling, John Stein, Lisa J. Strug, Joel B. Talcott, Henning Tiemeier, Marc P. van der Schroeff, Ellen Verhoef, Kate E. Watkins, Margaret Wilkinson, Margaret J. Wright, Cathy L. Barr, Dorret I. Boomsma, Manuel Carreiras, Marie Christine J. Franken, Jeffrey R. Gruen, Michelle Luciano, Bertram Muller-Myhsok, Dianne F. Newbury, Richard K. Olson, Silvia Paracchini, Tomas Paus, Robert Plomin, Sheena Reilly, Gerd Schulte-Korne, J. Bruce Tomblin, Elsje van Bergen, Andrew J.O. Whitehouse, Erik G. Willcutt, Beate St Pourcain, Clyde Francks, Simon E. Fisher^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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 × 10²⁸) 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.

Original language	English
Article number	e2202764119
Pages (from-to)	1-12
Number of pages	12
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	35
Early online date	23 Aug 2022
DOIs	https://doi.org/10.1073/pnas.2202764119
Publication status	Published - 30 Aug 2022

Bibliographical note

Funding Information:
Adele and Daniel Kubert and thanks the NIH data repository. The Raine study was supported by long-term funding from NHMRC Grants 572613, 403981, and 1059711 and Canadian Institutes of Health Research (CIHR) Grant MOP-82893. Funding was also provided by the University of Western Australia, Curtin University, the Women and Infants Research Foundation, the Telethon Kids Institute, Edith Cowan University, Murdoch University, the University of Notre Dame Australia, and the Raine Medical Research Foundation. The Raine study analyses were supported by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The Saguenay Youth Study is supported by the CIHR, the Heart and Stroke Foundation of Quebec, and the Canadian Foundation for Innovation. The SLI Consortium was funded by Wellcome Trust Grant 076566 and UK Medical Research Council Grant G1000569. The Twins Early Development Study is supported by UK Medical Research Council Grants MR/V012878/1 and MR/M021475/1, NIH Grant AG046938, and the EU FP7 grant FP7/2007-2013/: 602768. Toronto was supported by CIHR Grant MOP-133440. UK Dyslexia was supported by Wellcome Trust Grants 076566/Z/05/Z and 075491/Z/04, Waterloo Foundation Grant 797–1720, EU Grant 018696, and Royal Society Grant UF100463. The York cohort was funded by Wellcome Trust Grant 082036/B/07/Z. We acknowledge iPSYCH for sharing their summary statistics. The iPSYCH team was supported by Lundbeck Foundation Grants R102-A9118, R155-2014-1724, and R248-2017-2003; NIMH Grant 1U01MH109514-01; and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, Aarhus University, Denmark.

Funding Information:
ACKNOWLEDGMENTS. We thank all the children, twins, families, and participants who took part and are taking part in the 22 cohorts whose data contributed to these GWAS meta-analyses; the staff working on the different cohorts, including volunteers, study coordinators, interviewers, teachers, nurses, research scientists, general practitioners, midwives, psychologists, psychometrists, computer and laboratory technicians, and colleagues who assisted in the quality control and preparation of the imputed GWAS data; and the pharmacies and hospitals that were involved. B.M., B.M.-M., B.S.P., C.F., E.E., E.V., G.A., M.v.D., and S.E.F. are supported by the Max Planck Society. A.G. and T.F.M.A. were supported by the Munich Cluster for Systems Neurology (SyNergy), and A.G. was supported by Fondazione Umberto Veronesi. A.T.M. is supported by National Health and Medical Research Council of Australia (NHMRC) Grants 1105008 and 1195955 and Centre of Research Excellence Grant 1116976. A.J.O.W. is supported by NHMRC Grant 1173896. B.S.P. is supported by Simons Foundation Autism Research Initiative Grant 514787. C.Y.S. works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/3). D.I.B. acknowledges Royal Netherlands Academy of Science Professor Award PAH/6635. E.E. is supported by NIH Grant R01DC016977. E.G.W. and J.R.G. are supported by National Institute of Child Health and Human Development (NICHD) Grant P50 HD 27802. F.R. is supported by Agence Nationale de la Recherche Grants ANR-06-NEURO-019-01, ANR-17-EURE-0017 IEC, ANR-10-IDEX-0001-02 PSL, and ANR-11-BSV4-014-01 and European Commission Grant LSHM-CT-2005-018696. H.T. is supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) Grant VICI 016.VICI.170.200. J.C.D. was supported by NICHD Grant P50 HD 27802. J.J.M., J.B.To., and T.K. were supported by NIH Grant R01 DC014489. K.M.P. was supported by the Hospital for Sick Children Research Training Program (Restracomp). K.R. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (213514/Z/18/Z). M.J.S. is supported by Wellcome Trust Grant WT082032MA. S.P. and F.A. are supported by Royal Society Grants UF150663 and RGF\EA\180141. T.B. is supported by Institut Pasteur, the Bettencourt-Schueller Foundation, and Universitéde Paris. The Adolescent Brain Cognitive Development Study is supported by the NIH and additional federal partners (NIH Grants U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147). The Aston Cohort was supported by funding from European Union (EU) Horizon 2020 Programme 641652 and Waterloo Foundation Grant 797/17290. The St. Andrews Bioinformatics Unit is funded by Wellcome Trust Grants 105621/Z/14/Z and 204821/Z/16/Z. ALSPAC is supported by UK Medical Research Council and Wellcome Grant 217065/Z/19/Z and the University of Bristol. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Basque Center on Cognition, Brain and Language (BCBL) cohort was supported by the Basque Government through the Basic Excellence Research Centre program and the Agencia Estatal de Investigación through BCBL Severo Ochoa excellence accreditation. The Brisbane Adolescent Twin Sample was supported by Australian Research Council Grants A7960034, A79906588, A79801419, DP0212016, and DP0343921, with genotyping funded by the NHMRC Grant 389891. The Colorado Learning Disabilities Research Center cohort was supported by NICHD Grant P50 HD 27802. The Early Language in Victoria Study was supported by NHMRC Grant 436958. The Familial Influences on Literacy Abilities cohort is supported by the University of Amsterdam, the Max Planck Institue Nijmegen, and NWO Grants Rubicon 446-12-005 and VENI 451-15-017. The GRaD study was funded by the Manton Foundation, NIH Grants P50-HD027802 and K99-HD094902, and the Lambert Family. NeuroDys was funded by an EU Sixth Framework Program grant to the NeuroDys Consortium, Swiss National Science Foundation Grant 32-108130, and Austrian Science Fund Grant 18351-B02. The Netherlands Twin Register is funded by NWO Grants 480-04-004, 481-08-011, 056-32-010, 024.001.003, 480-15-001/674, 184.021.007, 184.033.111, and 56-464-14192; ZonMW Grants 911-09-032 and 912-10-020; the Amsterdam Public Health and Amsterdam Reproduction and Development Research Institutes; European Science Council Grant ERC Advanced 230374; EU Seventh Framework Program (FP7) Grant FP7/2007-2013: 602768; National Institute of Mental Health (NIMH) Grants U24 MH068457-06, R01 MH58799-03, and 1RC2 MH089995; and the Avera Institute for Human Genetics. The Pediatric Imaging, Neurocogni-tion, and Genetics cohort is funded by NIH Grant RC2DA029475, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver NICHD. The Philadelphia Neurodevelopmental Cohort is funded by NIH Grants RC2MH089983 and RC2MH089924, an institutional development award to the Center for Applied Genomics from The Children’s Hospital of Philadelphia, and a donation from

Publisher Copyright:
Copyright © 2022 the Author(s).

Funding

Adele and Daniel Kubert and thanks the NIH data repository. The Raine study was supported by long-term funding from NHMRC Grants 572613, 403981, and 1059711 and Canadian Institutes of Health Research (CIHR) Grant MOP-82893. Funding was also provided by the University of Western Australia, Curtin University, the Women and Infants Research Foundation, the Telethon Kids Institute, Edith Cowan University, Murdoch University, the University of Notre Dame Australia, and the Raine Medical Research Foundation. The Raine study analyses were supported by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The Saguenay Youth Study is supported by the CIHR, the Heart and Stroke Foundation of Quebec, and the Canadian Foundation for Innovation. The SLI Consortium was funded by Wellcome Trust Grant 076566 and UK Medical Research Council Grant G1000569. The Twins Early Development Study is supported by UK Medical Research Council Grants MR/V012878/1 and MR/M021475/1, NIH Grant AG046938, and the EU FP7 grant FP7/2007-2013/: 602768. Toronto was supported by CIHR Grant MOP-133440. UK Dyslexia was supported by Wellcome Trust Grants 076566/Z/05/Z and 075491/Z/04, Waterloo Foundation Grant 797–1720, EU Grant 018696, and Royal Society Grant UF100463. The York cohort was funded by Wellcome Trust Grant 082036/B/07/Z. We acknowledge iPSYCH for sharing their summary statistics. The iPSYCH team was supported by Lundbeck Foundation Grants R102-A9118, R155-2014-1724, and R248-2017-2003; NIMH Grant 1U01MH109514-01; and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, Aarhus University, Denmark. ACKNOWLEDGMENTS. We thank all the children, twins, families, and participants who took part and are taking part in the 22 cohorts whose data contributed to these GWAS meta-analyses; the staff working on the different cohorts, including volunteers, study coordinators, interviewers, teachers, nurses, research scientists, general practitioners, midwives, psychologists, psychometrists, computer and laboratory technicians, and colleagues who assisted in the quality control and preparation of the imputed GWAS data; and the pharmacies and hospitals that were involved. B.M., B.M.-M., B.S.P., C.F., E.E., E.V., G.A., M.v.D., and S.E.F. are supported by the Max Planck Society. A.G. and T.F.M.A. were supported by the Munich Cluster for Systems Neurology (SyNergy), and A.G. was supported by Fondazione Umberto Veronesi. A.T.M. is supported by National Health and Medical Research Council of Australia (NHMRC) Grants 1105008 and 1195955 and Centre of Research Excellence Grant 1116976. A.J.O.W. is supported by NHMRC Grant 1173896. B.S.P. is supported by Simons Foundation Autism Research Initiative Grant 514787. C.Y.S. works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/3). D.I.B. acknowledges Royal Netherlands Academy of Science Professor Award PAH/6635. E.E. is supported by NIH Grant R01DC016977. E.G.W. and J.R.G. are supported by National Institute of Child Health and Human Development (NICHD) Grant P50 HD 27802. F.R. is supported by Agence Nationale de la Recherche Grants ANR-06-NEURO-019-01, ANR-17-EURE-0017 IEC, ANR-10-IDEX-0001-02 PSL, and ANR-11-BSV4-014-01 and European Commission Grant LSHM-CT-2005-018696. H.T. is supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) Grant VICI 016.VICI.170.200. J.C.D. was supported by NICHD Grant P50 HD 27802. J.J.M., J.B.To., and T.K. were supported by NIH Grant R01 DC014489. K.M.P. was supported by the Hospital for Sick Children Research Training Program (Restracomp). K.R. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (213514/Z/18/Z). M.J.S. is supported by Wellcome Trust Grant WT082032MA. S.P. and F.A. are supported by Royal Society Grants UF150663 and RGF\EA\180141. T.B. is supported by Institut Pasteur, the Bettencourt-Schueller Foundation, and Universitéde Paris. The Adolescent Brain Cognitive Development Study is supported by the NIH and additional federal partners (NIH Grants U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147). The Aston Cohort was supported by funding from European Union (EU) Horizon 2020 Programme 641652 and Waterloo Foundation Grant 797/17290. The St. Andrews Bioinformatics Unit is funded by Wellcome Trust Grants 105621/Z/14/Z and 204821/Z/16/Z. ALSPAC is supported by UK Medical Research Council and Wellcome Grant 217065/Z/19/Z and the University of Bristol. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Basque Center on Cognition, Brain and Language (BCBL) cohort was supported by the Basque Government through the Basic Excellence Research Centre program and the Agencia Estatal de Investigación through BCBL Severo Ochoa excellence accreditation. The Brisbane Adolescent Twin Sample was supported by Australian Research Council Grants A7960034, A79906588, A79801419, DP0212016, and DP0343921, with genotyping funded by the NHMRC Grant 389891. The Colorado Learning Disabilities Research Center cohort was supported by NICHD Grant P50 HD 27802. The Early Language in Victoria Study was supported by NHMRC Grant 436958. The Familial Influences on Literacy Abilities cohort is supported by the University of Amsterdam, the Max Planck Institue Nijmegen, and NWO Grants Rubicon 446-12-005 and VENI 451-15-017. The GRaD study was funded by the Manton Foundation, NIH Grants P50-HD027802 and K99-HD094902, and the Lambert Family. NeuroDys was funded by an EU Sixth Framework Program grant to the NeuroDys Consortium, Swiss National Science Foundation Grant 32-108130, and Austrian Science Fund Grant 18351-B02. The Netherlands Twin Register is funded by NWO Grants 480-04-004, 481-08-011, 056-32-010, 024.001.003, 480-15-001/674, 184.021.007, 184.033.111, and 56-464-14192; ZonMW Grants 911-09-032 and 912-10-020; the Amsterdam Public Health and Amsterdam Reproduction and Development Research Institutes; European Science Council Grant ERC Advanced 230374; EU Seventh Framework Program (FP7) Grant FP7/2007-2013: 602768; National Institute of Mental Health (NIMH) Grants U24 MH068457-06, R01 MH58799-03, and 1RC2 MH089995; and the Avera Institute for Human Genetics. The Pediatric Imaging, Neurocogni-tion, and Genetics cohort is funded by NIH Grant RC2DA029475, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver NICHD. The Philadelphia Neurodevelopmental Cohort is funded by NIH Grants RC2MH089983 and RC2MH089924, an institutional development award to the Center for Applied Genomics from The Children’s Hospital of Philadelphia, and a donation from

Funders	Funder number
ANR-17-EURE-0017 IEC	ANR-11-BSV4-014-01, ANR-10-IDEX-0001-02 PSL
Amsterdam Public Health and Amsterdam Reproduction and Development Research Institutes
BCBL
Basque Center on Cognition, Brain and Language
Eunice Kennedy Shriver NICHD
European Science Council
Hospital for Sick Children Research Training Program	213514/Z/18/Z
Max Planck Institue Nijmegen	446-12-005, VENI 451-15-017
Munich Cluster for Systems Neurology
NeuroDys Consortium
Telethon Kids Institute
University Hospitals of Aarhus and Copenhagen
Universitéde Paris
National Institutes of Health	MOP-133440, R01DC016977, AG046938, FP7/2007-2013/: 602768, 075491/Z/04, 076566/Z/05/Z
National Institute of Mental Health	1RC2 MH089995, RC2MH089983, 1U01MH109514-01, R01 MH58799-03, U24 MH068457-06, RC2MH089924
National Institute on Drug Abuse	U01DA051039, U01DA051016, U01DA051038, U01DA051018, U01DA051037, U01DA041106, U01DA041117, U01DA041028, U01DA041148, U24DA041147, U01DA041048, U01DA041025, U24DA041123, U01DA041134, U01DA041156, U01DA041089, RC2DA029475, U01DA041022, U01DA041120, U01DA041174, U01DA050987, U01DA050988, U01DA050989, U01DA041093
National Institute of Neurological Disorders and Stroke	R01NS043530
National Institute of Child Health and Human Development	P50 HD 27802
Simons Foundation	514787
Children's Hospital of Philadelphia
Wellcome Trust	217065/Z/19/Z, WT082032MA, 076566
Waterloo Foundation	797–1720, 105621/Z/14/Z, 797/17290, 204821/Z/16
Australian Government
Heart And Stroke Foundation Of Quebec
Manton Foundation	K99-HD094902, P50-HD027802
Canadian Institutes of Health Research	MOP-82893
Canada Foundation for Innovation
Medical Research Council	MR/V012878/1, G1000569, MR/M021475/1
Royal Society	082036/B/07/Z., UF100463, RGF\EA\180141, UF150663
European Commission	LSHM-CT-2005-018696, 018696, 641652
European Research Council	230374
University of Bristol
Australian Research Council	436958, A7960034, DP0212016, A79801419, DP0343921, 389891, A79906588
National Health and Medical Research Council	403981, 1173896, 1195955, 1116976, 1059711, 1105008
Raine Medical Research Foundation
Women and Infants Research Foundation
Agence Nationale de la Recherche	ANR-06-NEURO-019-01
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	32-108130
Curtin University of Technology
University of Notre Dame Australia
University of Western Australia
ZonMw	R01 DC014489, VICI 016
Universiteit van Amsterdam
Austrian Science Fund	480-04-004, 481-08-011, 024.001.003, 056-32-010, 184.033.111, 911-09-032, 56-464-14192, 18351-B02, 184.021.007, 480-15-001/674, 912-10-020
Eusko Jaurlaritza
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Lundbeckfonden	R155-2014-1724, R248-2017-2003, R102-A9118
Institut Pasteur
Max-Planck-Gesellschaft
Fondazione Umberto Veronesi
Seventh Framework Programme	602768, FP7/2007-2013
Sixth Framework Programme
Fondation Bettencourt Schueller
Novo Nordisk Fonden
Government of Western Australia
Agencia Estatal de Investigación
Avera Institute for Human Genetics

Keywords

genome-wide association study
language
meta-analysis
reading

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.2202764119

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Eising, E., Mirza-Schreiber, N., de Zeeuw, E. L., Wang, C. A., Truong, D. T., Allegrini, A. G., Shapland, C. Y., Zhu, G., Wigg, K. G., Gerritse, M. L., Molz, B., Alagoz, G., Gialluisi, A., Abbondanza, F., Rimfeld, K., van Donkelaar, M., Liao, Z., Jansen, P. R., Andlauer, T. F. M., ... Fisher, S. E. (2022). Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people. Proceedings of the National Academy of Sciences of the United States of America, 119(35), 1-12. Article e2202764119. https://doi.org/10.1073/pnas.2202764119

@article{ff2630af59b0454184b832ebbf3d9853,

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

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 × 1028) 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",

author = "Else Eising and Nazanin Mirza-Schreiber and {de Zeeuw}, {Eveline L.} and Wang, {Carol A.} and Truong, {Dongnhu T.} and Allegrini, {Andrea G.} and Shapland, {Chin Yang} and Gu Zhu and Wigg, {Karen G.} and Gerritse, {Margot L.} and Barbara Molz and Gokberk Alagoz and Alessandro Gialluisi and Filippo Abbondanza and Kaili Rimfeld and {van Donkelaar}, Marjolein and Zhijie Liao and Jansen, {Philip R.} and Andlauer, {Till F.M.} and Bates, {Timothy C.} and Manon Bernard and Kirsten Blokland and Milene Bonte and B{\o}rglum, {Anders D.} and Thomas Bourgeron and Daniel Brandeis and Fabiola Ceroni and Valeria Csepe and Dale, {Philip S.} and {de Jong}, {Peter F.} and DeFries, {John C.} and Demonet, {Jean Fran{\c c}ois} and Ditte Demontis and Yu Feng and Gordon, {Scott D.} and Guger, {Sharon L.} and Hayiou-Thomas, {Marianna E.} and Hernandez-Cabrera, {Juan A.} and Hottenga, {Jouke Jan} and Charles Hulme and Juha Kere and Kerr, {Elizabeth N.} and Tanner Koomar and Karin Landerl and Leonard, {Gabriel T.} and Lovett, {Maureen W.} and Heikki Lyytinen and Martin, {Nicholas G.} and Angela Martinelli and Urs Maurer and Michaelson, {Jacob J.} and Kristina Moll and Monaco, {Anthony P.} and Morgan, {Angela T.} and Nothen, {Markus M.} and Zdenka Pausova and Pennell, {Craig E.} and Pennington, {Bruce F.} and Price, {Kaitlyn M.} and Rajagopal, {Veera M.} and Franck Ramus and Louis Richer and Simpson, {Nuala H.} and Smith, {Shelley D.} and Snowling, {Margaret J.} and John Stein and Strug, {Lisa J.} and Talcott, {Joel B.} and Henning Tiemeier and {van der Schroeff}, {Marc P.} and Ellen Verhoef and Watkins, {Kate E.} and Margaret Wilkinson and Wright, {Margaret J.} and Barr, {Cathy L.} and Boomsma, {Dorret I.} and Manuel Carreiras and Franken, {Marie Christine J.} and Gruen, {Jeffrey R.} and Michelle Luciano and Bertram Muller-Myhsok and Newbury, {Dianne F.} and Olson, {Richard K.} and Silvia Paracchini and Tomas Paus and Robert Plomin and Sheena Reilly and Gerd Schulte-Korne and {Bruce Tomblin}, J. and {van Bergen}, Elsje and Whitehouse, {Andrew J.O.} and Willcutt, {Erik G.} and Pourcain, {Beate St} and Clyde Francks and Fisher, {Simon E.}",

note = "Funding Information: Adele and Daniel Kubert and thanks the NIH data repository. The Raine study was supported by long-term funding from NHMRC Grants 572613, 403981, and 1059711 and Canadian Institutes of Health Research (CIHR) Grant MOP-82893. Funding was also provided by the University of Western Australia, Curtin University, the Women and Infants Research Foundation, the Telethon Kids Institute, Edith Cowan University, Murdoch University, the University of Notre Dame Australia, and the Raine Medical Research Foundation. The Raine study analyses were supported by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The Saguenay Youth Study is supported by the CIHR, the Heart and Stroke Foundation of Quebec, and the Canadian Foundation for Innovation. The SLI Consortium was funded by Wellcome Trust Grant 076566 and UK Medical Research Council Grant G1000569. The Twins Early Development Study is supported by UK Medical Research Council Grants MR/V012878/1 and MR/M021475/1, NIH Grant AG046938, and the EU FP7 grant FP7/2007-2013/: 602768. Toronto was supported by CIHR Grant MOP-133440. UK Dyslexia was supported by Wellcome Trust Grants 076566/Z/05/Z and 075491/Z/04, Waterloo Foundation Grant 797–1720, EU Grant 018696, and Royal Society Grant UF100463. The York cohort was funded by Wellcome Trust Grant 082036/B/07/Z. We acknowledge iPSYCH for sharing their summary statistics. The iPSYCH team was supported by Lundbeck Foundation Grants R102-A9118, R155-2014-1724, and R248-2017-2003; NIMH Grant 1U01MH109514-01; and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, Aarhus University, Denmark. Funding Information: ACKNOWLEDGMENTS. We thank all the children, twins, families, and participants who took part and are taking part in the 22 cohorts whose data contributed to these GWAS meta-analyses; the staff working on the different cohorts, including volunteers, study coordinators, interviewers, teachers, nurses, research scientists, general practitioners, midwives, psychologists, psychometrists, computer and laboratory technicians, and colleagues who assisted in the quality control and preparation of the imputed GWAS data; and the pharmacies and hospitals that were involved. B.M., B.M.-M., B.S.P., C.F., E.E., E.V., G.A., M.v.D., and S.E.F. are supported by the Max Planck Society. A.G. and T.F.M.A. were supported by the Munich Cluster for Systems Neurology (SyNergy), and A.G. was supported by Fondazione Umberto Veronesi. A.T.M. is supported by National Health and Medical Research Council of Australia (NHMRC) Grants 1105008 and 1195955 and Centre of Research Excellence Grant 1116976. A.J.O.W. is supported by NHMRC Grant 1173896. B.S.P. is supported by Simons Foundation Autism Research Initiative Grant 514787. C.Y.S. works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/3). D.I.B. acknowledges Royal Netherlands Academy of Science Professor Award PAH/6635. E.E. is supported by NIH Grant R01DC016977. E.G.W. and J.R.G. are supported by National Institute of Child Health and Human Development (NICHD) Grant P50 HD 27802. F.R. is supported by Agence Nationale de la Recherche Grants ANR-06-NEURO-019-01, ANR-17-EURE-0017 IEC, ANR-10-IDEX-0001-02 PSL, and ANR-11-BSV4-014-01 and European Commission Grant LSHM-CT-2005-018696. H.T. is supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) Grant VICI 016.VICI.170.200. J.C.D. was supported by NICHD Grant P50 HD 27802. J.J.M., J.B.To., and T.K. were supported by NIH Grant R01 DC014489. K.M.P. was supported by the Hospital for Sick Children Research Training Program (Restracomp). K.R. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (213514/Z/18/Z). M.J.S. is supported by Wellcome Trust Grant WT082032MA. S.P. and F.A. are supported by Royal Society Grants UF150663 and RGF\EA\180141. T.B. is supported by Institut Pasteur, the Bettencourt-Schueller Foundation, and Universit{\'e}de Paris. The Adolescent Brain Cognitive Development Study is supported by the NIH and additional federal partners (NIH Grants U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147). The Aston Cohort was supported by funding from European Union (EU) Horizon 2020 Programme 641652 and Waterloo Foundation Grant 797/17290. The St. Andrews Bioinformatics Unit is funded by Wellcome Trust Grants 105621/Z/14/Z and 204821/Z/16/Z. ALSPAC is supported by UK Medical Research Council and Wellcome Grant 217065/Z/19/Z and the University of Bristol. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Basque Center on Cognition, Brain and Language (BCBL) cohort was supported by the Basque Government through the Basic Excellence Research Centre program and the Agencia Estatal de Investigaci{\'o}n through BCBL Severo Ochoa excellence accreditation. The Brisbane Adolescent Twin Sample was supported by Australian Research Council Grants A7960034, A79906588, A79801419, DP0212016, and DP0343921, with genotyping funded by the NHMRC Grant 389891. The Colorado Learning Disabilities Research Center cohort was supported by NICHD Grant P50 HD 27802. The Early Language in Victoria Study was supported by NHMRC Grant 436958. The Familial Influences on Literacy Abilities cohort is supported by the University of Amsterdam, the Max Planck Institue Nijmegen, and NWO Grants Rubicon 446-12-005 and VENI 451-15-017. The GRaD study was funded by the Manton Foundation, NIH Grants P50-HD027802 and K99-HD094902, and the Lambert Family. NeuroDys was funded by an EU Sixth Framework Program grant to the NeuroDys Consortium, Swiss National Science Foundation Grant 32-108130, and Austrian Science Fund Grant 18351-B02. The Netherlands Twin Register is funded by NWO Grants 480-04-004, 481-08-011, 056-32-010, 024.001.003, 480-15-001/674, 184.021.007, 184.033.111, and 56-464-14192; ZonMW Grants 911-09-032 and 912-10-020; the Amsterdam Public Health and Amsterdam Reproduction and Development Research Institutes; European Science Council Grant ERC Advanced 230374; EU Seventh Framework Program (FP7) Grant FP7/2007-2013: 602768; National Institute of Mental Health (NIMH) Grants U24 MH068457-06, R01 MH58799-03, and 1RC2 MH089995; and the Avera Institute for Human Genetics. The Pediatric Imaging, Neurocogni-tion, and Genetics cohort is funded by NIH Grant RC2DA029475, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver NICHD. The Philadelphia Neurodevelopmental Cohort is funded by NIH Grants RC2MH089983 and RC2MH089924, an institutional development award to the Center for Applied Genomics from The Children{\textquoteright}s Hospital of Philadelphia, and a donation from Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s).",

year = "2022",

month = aug,

day = "30",

doi = "10.1073/pnas.2202764119",

language = "English",

volume = "119",

pages = "1--12",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Acad Sciences",

number = "35",

}

Eising, E, Mirza-Schreiber, N, de Zeeuw, EL, Wang, CA, Truong, DT, Allegrini, AG, Shapland, CY, Zhu, G, Wigg, KG, Gerritse, ML, Molz, B, Alagoz, G, Gialluisi, A, Abbondanza, F, Rimfeld, K, van Donkelaar, M, Liao, Z, Jansen, PR, Andlauer, TFM, Bates, TC, Bernard, M, Blokland, K, Bonte, M, Børglum, AD, Bourgeron, T, Brandeis, D, Ceroni, F, Csepe, V, Dale, PS, de Jong, PF, DeFries, JC, Demonet, JF, Demontis, D, Feng, Y, Gordon, SD, Guger, SL, Hayiou-Thomas, ME, Hernandez-Cabrera, JA, Hottenga, JJ, Hulme, C, Kere, J, Kerr, EN, Koomar, T, Landerl, K, Leonard, GT, Lovett, MW, Lyytinen, H, Martin, NG, Martinelli, A, Maurer, U, Michaelson, JJ, Moll, K, Monaco, AP, Morgan, AT, Nothen, MM, Pausova, Z, Pennell, CE, Pennington, BF, Price, KM, Rajagopal, VM, Ramus, F, Richer, L, Simpson, NH, Smith, SD, Snowling, MJ, Stein, J, Strug, LJ, Talcott, JB, Tiemeier, H, van der Schroeff, MP, Verhoef, E, Watkins, KE, Wilkinson, M, Wright, MJ, Barr, CL, Boomsma, DI, Carreiras, M, Franken, MCJ, Gruen, JR, Luciano, M, Muller-Myhsok, B, Newbury, DF, Olson, RK, Paracchini, S, Paus, T, Plomin, R, Reilly, S, Schulte-Korne, G, Bruce Tomblin, J, van Bergen, E, Whitehouse, AJO, Willcutt, EG, Pourcain, BS, Francks, C & Fisher, SE 2022, 'Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 35, e2202764119, pp. 1-12. https://doi.org/10.1073/pnas.2202764119

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people. / Eising, Else; Mirza-Schreiber, Nazanin; de Zeeuw, Eveline L. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 35, e2202764119, 30.08.2022, p. 1-12.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

AU - Eising, Else

AU - Mirza-Schreiber, Nazanin

AU - de Zeeuw, Eveline L.

AU - Wang, Carol A.

AU - Truong, Dongnhu T.

AU - Allegrini, Andrea G.

AU - Shapland, Chin Yang

AU - Zhu, Gu

AU - Wigg, Karen G.

AU - Gerritse, Margot L.

AU - Molz, Barbara

AU - Alagoz, Gokberk

AU - Gialluisi, Alessandro

AU - Abbondanza, Filippo

AU - Rimfeld, Kaili

AU - van Donkelaar, Marjolein

AU - Liao, Zhijie

AU - Jansen, Philip R.

AU - Andlauer, Till F.M.

AU - Bates, Timothy C.

AU - Bernard, Manon

AU - Blokland, Kirsten

AU - Bonte, Milene

AU - Børglum, Anders D.

AU - Bourgeron, Thomas

AU - Brandeis, Daniel

AU - Ceroni, Fabiola

AU - Csepe, Valeria

AU - Dale, Philip S.

AU - de Jong, Peter F.

AU - DeFries, John C.

AU - Demonet, Jean François

AU - Demontis, Ditte

AU - Feng, Yu

AU - Gordon, Scott D.

AU - Guger, Sharon L.

AU - Hayiou-Thomas, Marianna E.

AU - Hernandez-Cabrera, Juan A.

AU - Hottenga, Jouke Jan

AU - Hulme, Charles

AU - Kere, Juha

AU - Kerr, Elizabeth N.

AU - Koomar, Tanner

AU - Landerl, Karin

AU - Leonard, Gabriel T.

AU - Lovett, Maureen W.

AU - Lyytinen, Heikki

AU - Martin, Nicholas G.

AU - Martinelli, Angela

AU - Maurer, Urs

AU - Michaelson, Jacob J.

AU - Moll, Kristina

AU - Monaco, Anthony P.

AU - Morgan, Angela T.

AU - Nothen, Markus M.

AU - Pausova, Zdenka

AU - Pennell, Craig E.

AU - Pennington, Bruce F.

AU - Price, Kaitlyn M.

AU - Rajagopal, Veera M.

AU - Ramus, Franck

AU - Richer, Louis

AU - Simpson, Nuala H.

AU - Smith, Shelley D.

AU - Snowling, Margaret J.

AU - Stein, John

AU - Strug, Lisa J.

AU - Talcott, Joel B.

AU - Tiemeier, Henning

AU - van der Schroeff, Marc P.

AU - Verhoef, Ellen

AU - Watkins, Kate E.

AU - Wilkinson, Margaret

AU - Wright, Margaret J.

AU - Barr, Cathy L.

AU - Boomsma, Dorret I.

AU - Carreiras, Manuel

AU - Franken, Marie Christine J.

AU - Gruen, Jeffrey R.

AU - Luciano, Michelle

AU - Muller-Myhsok, Bertram

AU - Newbury, Dianne F.

AU - Olson, Richard K.

AU - Paracchini, Silvia

AU - Paus, Tomas

AU - Plomin, Robert

AU - Reilly, Sheena

AU - Schulte-Korne, Gerd

AU - Bruce Tomblin, J.

AU - van Bergen, Elsje

AU - Whitehouse, Andrew J.O.

AU - Willcutt, Erik G.

AU - Pourcain, Beate St

AU - Francks, Clyde

AU - Fisher, Simon E.

N1 - Funding Information: Adele and Daniel Kubert and thanks the NIH data repository. The Raine study was supported by long-term funding from NHMRC Grants 572613, 403981, and 1059711 and Canadian Institutes of Health Research (CIHR) Grant MOP-82893. Funding was also provided by the University of Western Australia, Curtin University, the Women and Infants Research Foundation, the Telethon Kids Institute, Edith Cowan University, Murdoch University, the University of Notre Dame Australia, and the Raine Medical Research Foundation. The Raine study analyses were supported by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The Saguenay Youth Study is supported by the CIHR, the Heart and Stroke Foundation of Quebec, and the Canadian Foundation for Innovation. The SLI Consortium was funded by Wellcome Trust Grant 076566 and UK Medical Research Council Grant G1000569. The Twins Early Development Study is supported by UK Medical Research Council Grants MR/V012878/1 and MR/M021475/1, NIH Grant AG046938, and the EU FP7 grant FP7/2007-2013/: 602768. Toronto was supported by CIHR Grant MOP-133440. UK Dyslexia was supported by Wellcome Trust Grants 076566/Z/05/Z and 075491/Z/04, Waterloo Foundation Grant 797–1720, EU Grant 018696, and Royal Society Grant UF100463. The York cohort was funded by Wellcome Trust Grant 082036/B/07/Z. We acknowledge iPSYCH for sharing their summary statistics. The iPSYCH team was supported by Lundbeck Foundation Grants R102-A9118, R155-2014-1724, and R248-2017-2003; NIMH Grant 1U01MH109514-01; and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, Aarhus University, Denmark. Funding Information: ACKNOWLEDGMENTS. We thank all the children, twins, families, and participants who took part and are taking part in the 22 cohorts whose data contributed to these GWAS meta-analyses; the staff working on the different cohorts, including volunteers, study coordinators, interviewers, teachers, nurses, research scientists, general practitioners, midwives, psychologists, psychometrists, computer and laboratory technicians, and colleagues who assisted in the quality control and preparation of the imputed GWAS data; and the pharmacies and hospitals that were involved. B.M., B.M.-M., B.S.P., C.F., E.E., E.V., G.A., M.v.D., and S.E.F. are supported by the Max Planck Society. A.G. and T.F.M.A. were supported by the Munich Cluster for Systems Neurology (SyNergy), and A.G. was supported by Fondazione Umberto Veronesi. A.T.M. is supported by National Health and Medical Research Council of Australia (NHMRC) Grants 1105008 and 1195955 and Centre of Research Excellence Grant 1116976. A.J.O.W. is supported by NHMRC Grant 1173896. B.S.P. is supported by Simons Foundation Autism Research Initiative Grant 514787. C.Y.S. works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/3). D.I.B. acknowledges Royal Netherlands Academy of Science Professor Award PAH/6635. E.E. is supported by NIH Grant R01DC016977. E.G.W. and J.R.G. are supported by National Institute of Child Health and Human Development (NICHD) Grant P50 HD 27802. F.R. is supported by Agence Nationale de la Recherche Grants ANR-06-NEURO-019-01, ANR-17-EURE-0017 IEC, ANR-10-IDEX-0001-02 PSL, and ANR-11-BSV4-014-01 and European Commission Grant LSHM-CT-2005-018696. H.T. is supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) Grant VICI 016.VICI.170.200. J.C.D. was supported by NICHD Grant P50 HD 27802. J.J.M., J.B.To., and T.K. were supported by NIH Grant R01 DC014489. K.M.P. was supported by the Hospital for Sick Children Research Training Program (Restracomp). K.R. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (213514/Z/18/Z). M.J.S. is supported by Wellcome Trust Grant WT082032MA. S.P. and F.A. are supported by Royal Society Grants UF150663 and RGF\EA\180141. T.B. is supported by Institut Pasteur, the Bettencourt-Schueller Foundation, and Universitéde Paris. The Adolescent Brain Cognitive Development Study is supported by the NIH and additional federal partners (NIH Grants U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147). The Aston Cohort was supported by funding from European Union (EU) Horizon 2020 Programme 641652 and Waterloo Foundation Grant 797/17290. The St. Andrews Bioinformatics Unit is funded by Wellcome Trust Grants 105621/Z/14/Z and 204821/Z/16/Z. ALSPAC is supported by UK Medical Research Council and Wellcome Grant 217065/Z/19/Z and the University of Bristol. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Basque Center on Cognition, Brain and Language (BCBL) cohort was supported by the Basque Government through the Basic Excellence Research Centre program and the Agencia Estatal de Investigación through BCBL Severo Ochoa excellence accreditation. The Brisbane Adolescent Twin Sample was supported by Australian Research Council Grants A7960034, A79906588, A79801419, DP0212016, and DP0343921, with genotyping funded by the NHMRC Grant 389891. The Colorado Learning Disabilities Research Center cohort was supported by NICHD Grant P50 HD 27802. The Early Language in Victoria Study was supported by NHMRC Grant 436958. The Familial Influences on Literacy Abilities cohort is supported by the University of Amsterdam, the Max Planck Institue Nijmegen, and NWO Grants Rubicon 446-12-005 and VENI 451-15-017. The GRaD study was funded by the Manton Foundation, NIH Grants P50-HD027802 and K99-HD094902, and the Lambert Family. NeuroDys was funded by an EU Sixth Framework Program grant to the NeuroDys Consortium, Swiss National Science Foundation Grant 32-108130, and Austrian Science Fund Grant 18351-B02. The Netherlands Twin Register is funded by NWO Grants 480-04-004, 481-08-011, 056-32-010, 024.001.003, 480-15-001/674, 184.021.007, 184.033.111, and 56-464-14192; ZonMW Grants 911-09-032 and 912-10-020; the Amsterdam Public Health and Amsterdam Reproduction and Development Research Institutes; European Science Council Grant ERC Advanced 230374; EU Seventh Framework Program (FP7) Grant FP7/2007-2013: 602768; National Institute of Mental Health (NIMH) Grants U24 MH068457-06, R01 MH58799-03, and 1RC2 MH089995; and the Avera Institute for Human Genetics. The Pediatric Imaging, Neurocogni-tion, and Genetics cohort is funded by NIH Grant RC2DA029475, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver NICHD. The Philadelphia Neurodevelopmental Cohort is funded by NIH Grants RC2MH089983 and RC2MH089924, an institutional development award to the Center for Applied Genomics from The Children’s Hospital of Philadelphia, and a donation from Publisher Copyright: Copyright © 2022 the Author(s).

PY - 2022/8/30

Y1 - 2022/8/30

N2 - 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 × 1028) 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.

AB - 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 × 1028) 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.

KW - genome-wide association study

KW - language

KW - meta-analysis

KW - reading

UR - http://www.scopus.com/inward/record.url?scp=85136345356&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85136345356&partnerID=8YFLogxK

U2 - 10.1073/pnas.2202764119

DO - 10.1073/pnas.2202764119

M3 - Article

C2 - 35998220

AN - SCOPUS:85136345356

SN - 0027-8424

VL - 119

SP - 1

EP - 12

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 35

M1 - e2202764119

ER -

Eising E, Mirza-Schreiber N, de Zeeuw EL, Wang CA, Truong DT, Allegrini AG et al. Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people. Proceedings of the National Academy of Sciences of the United States of America. 2022 Aug 30;119(35):1-12. e2202764119. Epub 2022 Aug 23. 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

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