Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

Alessandro Gialluisi; Till F.M. Andlauer; Nazanin Mirza-Schreiber; Kristina Moll; Jessica Becker; Per Hoffmann; Kerstin U. Ludwig; Darina Czamara; Beate St Pourcain; Ferenc Honbolygó; Dénes Tóth; Valéria Csépe; Guillaume Huguet; Yves Chaix; Stephanie Iannuzzi; Jean Francois Demonet; Andrew P. Morris; Jacqueline Hulslander; Erik G. Willcutt; John C. DeFries; Richard K. Olson; Shelley D. Smith; Bruce F. Pennington; Anniek Vaessen; Urs Maurer; Heikki Lyytinen; Myriam Peyrard-Janvid; Paavo H.T. Leppänen; Daniel Brandeis; Milene Bonte; John F. Stein; Joel B. Talcott; Fabien Fauchereau; Arndt Wilcke; Holger Kirsten; Bent Müller; Clyde Francks; Thomas Bourgeron; Anthony P. Monaco; Franck Ramus; Karin Landerl; Juha Kere; Thomas S. Scerri; Silvia Paracchini; Simon E. Fisher; Johannes Schumacher; Markus M. Nöthen; Bertram Müller-Myhsok; Gerd Schulte-Körne

doi:10.1038/s41380-020-00898-x

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

Alessandro Gialluisi, Till F.M. Andlauer, Nazanin Mirza-Schreiber, Kristina Moll, Jessica Becker, Per Hoffmann, Kerstin U. Ludwig, Darina Czamara, Beate St Pourcain, Ferenc Honbolygó, Dénes Tóth, Valéria Csépe, Guillaume Huguet, Yves Chaix, Stephanie Iannuzzi, Jean Francois Demonet, Andrew P. Morris, Jacqueline Hulslander, Erik G. Willcutt, John C. DeFriesRichard K. Olson, Shelley D. Smith, Bruce F. Pennington, Anniek Vaessen, Urs Maurer, Heikki Lyytinen, Myriam Peyrard-Janvid, Paavo H.T. Leppänen, Daniel Brandeis, Milene Bonte, John F. Stein, Joel B. Talcott, Fabien Fauchereau, Arndt Wilcke, Holger Kirsten, Bent Müller, Clyde Francks, Thomas Bourgeron, Anthony P. Monaco, Franck Ramus, Karin Landerl, Juha Kere, Thomas S. Scerri, Silvia Paracchini, Simon E. Fisher, Johannes Schumacher, Markus M. Nöthen, Bertram Müller-Myhsok^*, Gerd Schulte-Körne^*

^*Corresponding author for this work

School of Psychology

Research output: Contribution to journal › Article › peer-review

Abstract

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10⁻⁶) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at p_T = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10⁻¹³), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10⁻⁴³), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10⁻²²), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10⁻¹²), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10⁻⁴), educational attainment (0.86[0.82; 0.91]; p = 2 × 10⁻⁷), and intelligence (0.72[0.68; 0.76]; p = 9 × 10⁻²⁹). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Original language	English
Pages (from-to)	3004–3017
Number of pages	14
Journal	Molecular Psychiatry
Volume	26
Issue number	7
Early online date	14 Oct 2020
DOIs	https://doi.org/10.1038/s41380-020-00898-x
Publication status	Published - Jul 2021

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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Genome-wide association study reveals new insights
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Gialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., Pourcain, B. S., Honbolygó, F., Tóth, D., Csépe, V., Huguet, G., Chaix, Y., Iannuzzi, S., Demonet, J. F., Morris, A. P., Hulslander, J., Willcutt, E. G., ... Schulte-Körne, G. (2021). Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia. Molecular Psychiatry, 26(7), 3004–3017. https://doi.org/10.1038/s41380-020-00898-x

@article{d34410e24e104877b50d3079055c4abc,

title = "Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia",

abstract = "Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.",

author = "Alessandro Gialluisi and Andlauer, {Till F.M.} and Nazanin Mirza-Schreiber and Kristina Moll and Jessica Becker and Per Hoffmann and Ludwig, {Kerstin U.} and Darina Czamara and Pourcain, {Beate St} and Ferenc Honbolyg{\'o} and D{\'e}nes T{\'o}th and Val{\'e}ria Cs{\'e}pe and Guillaume Huguet and Yves Chaix and Stephanie Iannuzzi and Demonet, {Jean Francois} and Morris, {Andrew P.} and Jacqueline Hulslander and Willcutt, {Erik G.} and DeFries, {John C.} and Olson, {Richard K.} and Smith, {Shelley D.} and Pennington, {Bruce F.} and Anniek Vaessen and Urs Maurer and Heikki Lyytinen and Myriam Peyrard-Janvid and Lepp{\"a}nen, {Paavo H.T.} and Daniel Brandeis and Milene Bonte and Stein, {John F.} and Talcott, {Joel B.} and Fabien Fauchereau and Arndt Wilcke and Holger Kirsten and Bent M{\"u}ller and Clyde Francks and Thomas Bourgeron and Monaco, {Anthony P.} and Franck Ramus and Karin Landerl and Juha Kere and Scerri, {Thomas S.} and Silvia Paracchini and Fisher, {Simon E.} and Johannes Schumacher and N{\"o}then, {Markus M.} and Bertram M{\"u}ller-Myhsok and Gerd Schulte-K{\"o}rne",

note = "This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.",

year = "2021",

month = jul,

doi = "10.1038/s41380-020-00898-x",

language = "English",

volume = "26",

pages = "3004–3017",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "7",

}

Gialluisi, A, Andlauer, TFM, Mirza-Schreiber, N, Moll, K, Becker, J, Hoffmann, P, Ludwig, KU, Czamara, D, Pourcain, BS, Honbolygó, F, Tóth, D, Csépe, V, Huguet, G, Chaix, Y, Iannuzzi, S, Demonet, JF, Morris, AP, Hulslander, J, Willcutt, EG, DeFries, JC, Olson, RK, Smith, SD, Pennington, BF, Vaessen, A, Maurer, U, Lyytinen, H, Peyrard-Janvid, M, Leppänen, PHT, Brandeis, D, Bonte, M, Stein, JF, Talcott, JB, Fauchereau, F, Wilcke, A, Kirsten, H, Müller, B, Francks, C, Bourgeron, T, Monaco, AP, Ramus, F, Landerl, K, Kere, J, Scerri, TS, Paracchini, S, Fisher, SE, Schumacher, J, Nöthen, MM, Müller-Myhsok, B & Schulte-Körne, G 2021, 'Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia', Molecular Psychiatry, vol. 26, no. 7, pp. 3004–3017. https://doi.org/10.1038/s41380-020-00898-x

TY - JOUR

T1 - Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

AU - Gialluisi, Alessandro

AU - Andlauer, Till F.M.

AU - Mirza-Schreiber, Nazanin

AU - Moll, Kristina

AU - Becker, Jessica

AU - Hoffmann, Per

AU - Ludwig, Kerstin U.

AU - Czamara, Darina

AU - Pourcain, Beate St

AU - Honbolygó, Ferenc

AU - Tóth, Dénes

AU - Csépe, Valéria

AU - Huguet, Guillaume

AU - Chaix, Yves

AU - Iannuzzi, Stephanie

AU - Demonet, Jean Francois

AU - Morris, Andrew P.

AU - Hulslander, Jacqueline

AU - Willcutt, Erik G.

AU - DeFries, John C.

AU - Olson, Richard K.

AU - Smith, Shelley D.

AU - Pennington, Bruce F.

AU - Vaessen, Anniek

AU - Maurer, Urs

AU - Lyytinen, Heikki

AU - Peyrard-Janvid, Myriam

AU - Leppänen, Paavo H.T.

AU - Brandeis, Daniel

AU - Bonte, Milene

AU - Stein, John F.

AU - Talcott, Joel B.

AU - Fauchereau, Fabien

AU - Wilcke, Arndt

AU - Kirsten, Holger

AU - Müller, Bent

AU - Francks, Clyde

AU - Bourgeron, Thomas

AU - Monaco, Anthony P.

AU - Ramus, Franck

AU - Landerl, Karin

AU - Kere, Juha

AU - Scerri, Thomas S.

AU - Paracchini, Silvia

AU - Fisher, Simon E.

AU - Schumacher, Johannes

AU - Nöthen, Markus M.

AU - Müller-Myhsok, Bertram

AU - Schulte-Körne, Gerd

N1 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PY - 2021/7

Y1 - 2021/7

N2 - Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

AB - Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

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U2 - 10.1038/s41380-020-00898-x

DO - 10.1038/s41380-020-00898-x

M3 - Article

C2 - 33057169

AN - SCOPUS:85092500860

SN - 1359-4184

VL - 26

SP - 3004

EP - 3017

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 7

ER -

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

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