Genome-wide association 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 Gerritse; Barbara Molz; Gökberk Alagöz; 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; Anders D. Børglum; Thomas Bourgeron; Daniel Brandeis; Fabiola Ceroni; Philip S. Dale; Karin Landerl; Heikki Lyytinen; Peter F. de Jong; John C. DeFries; Ditte Demontis; Yu Feng; Scott D. Gordon; Sharon L. Guger; Marianna E. Hayiou-Thomas; Juan A. Hernández-Cabrera; Jouke-Jan Hottenga; Charles Hulme; Elizabeth N. Kerr; Tanner Koomar; Maureen W. Lovett; Nicholas G. Martin; Angela Martinelli; Urs Maurer; Jacob J. Michaelson; Kristina Moll; Anthony P. Monaco; Angela T. Morgan; Markus M. Nöthen; Zdenka Pausova; Craig E. Pennell; Bruce F Pennington; Kaitlyn M. Price; Veera M. Rajagopal; Frank Ramus; Louis Richer; Nuala H. Simpson; Shelley Smith; Margaret J. Snowling; John Stein; Lisa J. Strug; Joel B. Talcott; Henning Tiemeier; Marc M.P. van de 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 Müller-Myhsok; Dianne F. Newbury; Richard K. Olson; Silvia Paracchini; Tomas Paus; Robert Plomin; Gerd Schulte-Körne; Sheena Reilly; J. Bruce Tomblin; Elsje van Bergen; Andrew J.O. Whitehouse; Erik G. Willcutt; Beate St Pourcain; Clyde Francks; Simon E. Fisher

doi:10.1101/2021.11.04.466897

Genome-wide association 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 Gerritse, Barbara Molz, Gökberk Alagöz, Alessandro Gialluisi, Filippo Abbondanza, Kaili Rimfeld, Marjolein van Donkelaar, Zhijie Liao, Philip R. Jansen, Till F. M. Andlauer, Timothy C. BatesManon Bernard, Kirsten Blokland, Anders D. Børglum, Thomas Bourgeron, Daniel Brandeis, Fabiola Ceroni, Philip S. Dale, Karin Landerl, Heikki Lyytinen, Peter F. de Jong, John C. DeFries, Ditte Demontis, Yu Feng, Scott D. Gordon, Sharon L. Guger, Marianna E. Hayiou-Thomas, Juan A. Hernández-Cabrera, Jouke-Jan Hottenga, Charles Hulme, Elizabeth N. Kerr, Tanner Koomar, Maureen W. Lovett, Nicholas G. Martin, Angela Martinelli, Urs Maurer, Jacob J. Michaelson, Kristina Moll, Anthony P. Monaco, Angela T. Morgan, Markus M. Nöthen, Zdenka Pausova, Craig E. Pennell, Bruce F Pennington, Kaitlyn M. Price, Veera M. Rajagopal, Frank Ramus, Louis Richer, Nuala H. Simpson, Shelley Smith, Margaret J. Snowling, John Stein, Lisa J. Strug, Joel B. Talcott, Henning Tiemeier, Marc M.P. van de 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 Müller-Myhsok, Dianne F. Newbury, Richard K. Olson, Silvia Paracchini, Tomas Paus, Robert Plomin, Gerd Schulte-Körne, Sheena Reilly, J. Bruce Tomblin, Elsje van Bergen, Andrew J.O. Whitehouse, Erik G. Willcutt, Beate St Pourcain, Clyde Francks, Simon E. Fisher

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Abstract

The use of spoken and written language is a capacity that is unique to humans. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80 depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be investigated with well-powered studies. Here, 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, with total sample sizes ranging from 13,633 to 33,959 participants aged 5-26 years (12,411 to 27,180 for those with European ancestry, defined by principal component analyses). We identified a genome-wide significant association with word reading (rs11208009, p=1.098 texttimes 10-8) independent of known loci associated with intelligence or educational attainment. All five reading-/language-related traits had robust SNP-heritability estimates (0.13textendash0.26), and genetic correlations between them were modest to high. Using genomic structural equation modelling, we found evidence for a shared genetic factor explaining the majority of variation in word and nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS was performed to jointly analyse word and nonword reading, spelling, and phoneme awareness, maximizing power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with cortical surface area of the banks of the left superior temporal sulcus, a brain region with known links to processing of spoken and written language. Analysis of evolutionary annotations on the lineage that led to modern humans showed enriched heritability in regions depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of these uniquely human traits.Competing Interest StatementThe authors have declared no competing interest.

Original language	English
DOIs	https://doi.org/10.1101/2021.11.04.466897
Publication status	Published - 4 Nov 2021

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Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people
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., Molz, B., Alagöz, G., Gialluisi, A., Abbondanza, F., Rimfeld, K., van Donkelaar, M., Liao, Z., Jansen, P. R., Andlauer, T. F. M. & Bates, T. C. & 75 others, Bernard, M., Blokland, K., Bonte, M., Børglum, A. D., Bourgeron, T., Brandeis, D., Ceroni, F., Csépe, V., Dale, P. S., de Jong, P. F., DeFries, J. C., Démonet, J.-F., Demontis, D., Feng, Y., Gordon, S. D., Guger, S. L., Hayiou-Thomas, M. E., Hernández-Cabrera, J. A., Hottenga, J.-J., Hulme, C., Kere, J., Kerr, E. N., Koomar, T., Landerl, K., Leonard, G., Lovett, M. W., Lyytinen, H., Martin, N. G., Martinelli, A., Maurer, U., Michaelson, J., Moll, K., Monaco, A. P., Morgan, A. T., Nőthen, M. M., Pausova, Z., Pennell, C. E., Pennington, B. F., Price, K. M., Rajagopal, V. M., Ramus, F., Richer, L., Simpson, N. H., Smith, S., Snowling, M. J., Stein, J., Strug, L. J., Talcott, J. B., Tiemeier, H., van der Schroeff, M. M. P., Verhoef, E., Watkins, K. E., Wilkinson, M., Wright, M. J., Barr, C. L., Boomsma, D. I., Carreiras, M., Franken, M.-C. J., Gruen, J. R., Luciano, M., Müller-Myhsok, B., Newbury, D. F., Olson, R. .., Paracchini, S., Paus, T., Plomin, R., Reilly, S., Schulte-Körne, G., Tomblin, B., van Bergen, E., Whitehouse, A. J. O., Willcutt, E. G., St Pourcain, B., Francks, C. & Fisher, S. E., 30 Aug 2022, In: Proceedings of the National Academy of Sciences of the United States of America. 119, 35, 12 p., e2202764119.
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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., Molz, B., Alagöz, G., Gialluisi, A., Abbondanza, F., Rimfeld, K., van Donkelaar, M., Liao, Z., Jansen, P. R., Andlauer, T. F. M., ... Fisher, S. E. (2021). Genome-wide association analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people. https://doi.org/10.1101/2021.11.04.466897

@techreport{da870aa9ecfb47d8abf4372d2d8eb0ab,

title = "Genome-wide association 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 capacity that is unique to humans. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80 depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be investigated with well-powered studies. Here, 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, with total sample sizes ranging from 13,633 to 33,959 participants aged 5-26 years (12,411 to 27,180 for those with European ancestry, defined by principal component analyses). We identified a genome-wide significant association with word reading (rs11208009, p=1.098 texttimes 10-8) independent of known loci associated with intelligence or educational attainment. All five reading-/language-related traits had robust SNP-heritability estimates (0.13textendash0.26), and genetic correlations between them were modest to high. Using genomic structural equation modelling, we found evidence for a shared genetic factor explaining the majority of variation in word and nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS was performed to jointly analyse word and nonword reading, spelling, and phoneme awareness, maximizing power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with cortical surface area of the banks of the left superior temporal sulcus, a brain region with known links to processing of spoken and written language. Analysis of evolutionary annotations on the lineage that led to modern humans showed enriched heritability in regions depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of these uniquely human traits.Competing Interest StatementThe authors have declared no competing interest.",

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 Margot Gerritse and Barbara Molz and G{\"o}kberk Alag{\"o}z 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 B{\o}rglum, {Anders D.} and Thomas Bourgeron and Daniel Brandeis and Fabiola Ceroni and Dale, {Philip S.} and Karin Landerl and Heikki Lyytinen and {de Jong}, {Peter F.} and DeFries, {John C.} and Ditte Demontis and Yu Feng and Gordon, {Scott D.} and Guger, {Sharon L.} and Hayiou-Thomas, {Marianna E.} and Hern{\'a}ndez-Cabrera, {Juan A.} and Jouke-Jan Hottenga and Charles Hulme and Kerr, {Elizabeth N.} and Tanner Koomar and Lovett, {Maureen W.} 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 N{\"o}then, {Markus M.} and Zdenka Pausova and Pennell, {Craig E.} and Pennington, {Bruce F} and Price, {Kaitlyn M.} and Rajagopal, {Veera M.} and Frank Ramus and Louis Richer and Simpson, {Nuala H.} and Shelley Smith and Snowling, {Margaret J.} and John Stein and Strug, {Lisa J.} and Talcott, {Joel B.} and Henning Tiemeier and {van de Schroeff}, {Marc M.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 M{\"u}ller-Myhsok and Newbury, {Dianne F.} and Olson, {Richard K.} and Silvia Paracchini and Tomas Paus and Robert Plomin and Gerd Schulte-K{\"o}rne and Sheena Reilly and Tomblin, {J. Bruce} and {van Bergen}, Elsje and Whitehouse, {Andrew J.O.} and Willcutt, {Erik G.} and Pourcain, {Beate St} and Clyde Francks and Fisher, {Simon E.}",

year = "2021",

month = nov,

day = "4",

doi = "10.1101/2021.11.04.466897",

language = "English",

type = "WorkingPaper",

}

Eising, E, Mirza-Schreiber, N, de Zeeuw, EL, Wang, CA, Truong, DT, Allegrini, AG, Shapland, CY, Zhu, G, Wigg, KG, Gerritse, M, Molz, B, Alagöz, G, Gialluisi, A, Abbondanza, F, Rimfeld, K, van Donkelaar, M, Liao, Z, Jansen, PR, Andlauer, TFM, Bates, TC, Bernard, M, Blokland, K, Børglum, AD, Bourgeron, T, Brandeis, D, Ceroni, F, Dale, PS, Landerl, K, Lyytinen, H, de Jong, PF, DeFries, JC, Demontis, D, Feng, Y, Gordon, SD, Guger, SL, Hayiou-Thomas, ME, Hernández-Cabrera, JA, Hottenga, J-J, Hulme, C, Kerr, EN, Koomar, T, Lovett, MW, Martin, NG, Martinelli, A, Maurer, U, Michaelson, JJ, Moll, K, Monaco, AP, Morgan, AT, Nöthen, MM, Pausova, Z, Pennell, CE, Pennington, BF, Price, KM, Rajagopal, VM, Ramus, F, Richer, L, Simpson, NH, Smith, S, Snowling, MJ, Stein, J, Strug, LJ, Talcott, JB, Tiemeier, H, van de Schroeff, MMP, Verhoef, E, Watkins, KE, Wilkinson, M, Wright, MJ, Barr, CL, Boomsma, DI, Carreiras, M, Franken, M-CJ, Gruen, JR, Luciano, M, Müller-Myhsok, B, Newbury, DF, Olson, RK, Paracchini, S, Paus, T, Plomin, R, Schulte-Körne, G, Reilly, S, Tomblin, JB, van Bergen, E, Whitehouse, AJO, Willcutt, EG, Pourcain, BS, Francks, C & Fisher, SE 2021 'Genome-wide association analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people'. https://doi.org/10.1101/2021.11.04.466897

TY - UNPB

T1 - Genome-wide association 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

AU - Molz, Barbara

AU - Alagöz, Gökberk

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 - Børglum, Anders D.

AU - Bourgeron, Thomas

AU - Brandeis, Daniel

AU - Ceroni, Fabiola

AU - Dale, Philip S.

AU - Landerl, Karin

AU - Lyytinen, Heikki

AU - de Jong, Peter F.

AU - DeFries, John C.

AU - Demontis, Ditte

AU - Feng, Yu

AU - Gordon, Scott D.

AU - Guger, Sharon L.

AU - Hayiou-Thomas, Marianna E.

AU - Hernández-Cabrera, Juan A.

AU - Hottenga, Jouke-Jan

AU - Hulme, Charles

AU - Kerr, Elizabeth N.

AU - Koomar, Tanner

AU - Lovett, Maureen W.

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 - Nöthen, Markus M.

AU - Pausova, Zdenka

AU - Pennell, Craig E.

AU - Pennington, Bruce F

AU - Price, Kaitlyn M.

AU - Rajagopal, Veera M.

AU - Ramus, Frank

AU - Richer, Louis

AU - Simpson, Nuala H.

AU - Smith, Shelley

AU - Snowling, Margaret J.

AU - Stein, John

AU - Strug, Lisa J.

AU - Talcott, Joel B.

AU - Tiemeier, Henning

AU - van de Schroeff, Marc M.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 - Müller-Myhsok, Bertram

AU - Newbury, Dianne F.

AU - Olson, Richard K.

AU - Paracchini, Silvia

AU - Paus, Tomas

AU - Plomin, Robert

AU - Schulte-Körne, Gerd

AU - Reilly, Sheena

AU - Tomblin, J. Bruce

AU - van Bergen, Elsje

AU - Whitehouse, Andrew J.O.

AU - Willcutt, Erik G.

AU - Pourcain, Beate St

AU - Francks, Clyde

AU - Fisher, Simon E.

PY - 2021/11/4

Y1 - 2021/11/4

N2 - The use of spoken and written language is a capacity that is unique to humans. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80 depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be investigated with well-powered studies. Here, 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, with total sample sizes ranging from 13,633 to 33,959 participants aged 5-26 years (12,411 to 27,180 for those with European ancestry, defined by principal component analyses). We identified a genome-wide significant association with word reading (rs11208009, p=1.098 texttimes 10-8) independent of known loci associated with intelligence or educational attainment. All five reading-/language-related traits had robust SNP-heritability estimates (0.13textendash0.26), and genetic correlations between them were modest to high. Using genomic structural equation modelling, we found evidence for a shared genetic factor explaining the majority of variation in word and nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS was performed to jointly analyse word and nonword reading, spelling, and phoneme awareness, maximizing power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with cortical surface area of the banks of the left superior temporal sulcus, a brain region with known links to processing of spoken and written language. Analysis of evolutionary annotations on the lineage that led to modern humans showed enriched heritability in regions depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of these uniquely human traits.Competing Interest StatementThe authors have declared no competing interest.

AB - The use of spoken and written language is a capacity that is unique to humans. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80 depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be investigated with well-powered studies. Here, 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, with total sample sizes ranging from 13,633 to 33,959 participants aged 5-26 years (12,411 to 27,180 for those with European ancestry, defined by principal component analyses). We identified a genome-wide significant association with word reading (rs11208009, p=1.098 texttimes 10-8) independent of known loci associated with intelligence or educational attainment. All five reading-/language-related traits had robust SNP-heritability estimates (0.13textendash0.26), and genetic correlations between them were modest to high. Using genomic structural equation modelling, we found evidence for a shared genetic factor explaining the majority of variation in word and nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS was performed to jointly analyse word and nonword reading, spelling, and phoneme awareness, maximizing power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with cortical surface area of the banks of the left superior temporal sulcus, a brain region with known links to processing of spoken and written language. Analysis of evolutionary annotations on the lineage that led to modern humans showed enriched heritability in regions depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of these uniquely human traits.Competing Interest StatementThe authors have declared no competing interest.

U2 - 10.1101/2021.11.04.466897

DO - 10.1101/2021.11.04.466897

M3 - Preprint

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

ER -

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

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

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