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 Hoffman; Krestin 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 Hoffman
, Krestin 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

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
Number of pages	14
Journal	Molecular Psychiatry
Early online date	14 Oct 2020
DOIs	https://doi.org/10.1038/s41380-020-00898-x
Publication status	Published - Jul 2021

Keywords

Developmental dyslexia
GWAS
Reading
Genetics
Heritability
Polygenic risk
Schizophrenia
ADHD
Bipolar disorder
Educational attaintment
Intelligence
Brain cortical thickness
Transverse temporal gyrus

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Dr Silvia Paracchini - Public Enhancemen: Is there a link between asymmetries and congnition
Paracchini, S. (PI)
The Royal Society
27/05/18 → 26/05/22
Project: Standard

Silvia Paracchini
- sp58st-andrews.acuk
- School of Medicine - Professor of Neurogenetics and Genomics
- Global Research Centre for Diverse Intelligences
- Centre for Biophotonics
- Biomedical Sciences Research Complex
- Institute of Behavioural and Neural Sciences
- St Andrews Bioinformatics Unit
- Cellular Medicine Division
Person: Academic

Cite this

Gialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffman, P., Ludwig, K. U., Czamara, D., St Pourcain, B., 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. https://doi.org/10.1038/s41380-020-00898-x

@article{be047dd14235448fba0f9041d4ebdf5e,

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.",

keywords = "Developmental dyslexia, GWAS, Reading, Genetics, Heritability, Polygenic risk, Schizophrenia, ADHD, Bipolar disorder, Educational attaintment, Intelligence, Brain cortical thickness, Transverse temporal gyrus",

author = "Alessandro Gialluisi and Andlauer, \{Till F M\} and Nazanin Mirza-Schreiber and Kristina Moll and Jessica Becker and Per Hoffman and Ludwig, \{Krestin U\} and Darina Czamara and \{St Pourcain\}, Beate 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 Jean-Francois Demonet 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 = "Funding: AG and TFMA were supported by the Munich Cluster for Systems Neurology (SyNergy). AG 535 was supported by Fondazione Umberto Veronesi. SP is a Royal Society University Research fellow. BMM, CF, BSP and SEF are supported by the Max Planck Society. AW, BM and HK were funded by the Fraunhofer Society and the Max Planck Society within the {\textquoteleft}Pakt f{\"u}r Forschung und Innovation{\textquoteright}. HK was also supported by LIFE – Leipzig Research Center for Civilization Diseases funded by means of the European Union; the European Regional Development Fund (ERDF); and the Free State of Saxony within the excellence initiative. FR is supported by Agence Nationale de la Recherche (ANR-06-NEURO-019-01, ANR-17-EURE-542 0017 IEC, ANR-10-IDEX-0001-02 PSL, ANR-11-BSV4-014-01), European Commission (LSHM-CT-2005-018696). TFMA was supported by the BMBF through the DIFUTURE consortium of the Medical Informatics Initiative Germany (grant 01ZZ1804A) and by the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (grant MultipleMS, EU RIA 733161).",

year = "2021",

month = jul,

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

language = "English",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

}

Gialluisi, A, Andlauer, TFM, Mirza-Schreiber, N, Moll, K, Becker, J, Hoffman, P, Ludwig, KU, Czamara, D, St Pourcain, B, Honbolygó, F, Tóth, D, Csépe, V, Huguet, G, Chaix, Y, Iannuzzi, S, Demonet, J-F, 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. 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 - Hoffman, Per

AU - Ludwig, Krestin U

AU - Czamara, Darina

AU - St Pourcain, Beate

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 - Funding: AG and TFMA were supported by the Munich Cluster for Systems Neurology (SyNergy). AG 535 was supported by Fondazione Umberto Veronesi. SP is a Royal Society University Research fellow. BMM, CF, BSP and SEF are supported by the Max Planck Society. AW, BM and HK were funded by the Fraunhofer Society and the Max Planck Society within the ‘Pakt für Forschung und Innovation’. HK was also supported by LIFE – Leipzig Research Center for Civilization Diseases funded by means of the European Union; the European Regional Development Fund (ERDF); and the Free State of Saxony within the excellence initiative. FR is supported by Agence Nationale de la Recherche (ANR-06-NEURO-019-01, ANR-17-EURE-542 0017 IEC, ANR-10-IDEX-0001-02 PSL, ANR-11-BSV4-014-01), European Commission (LSHM-CT-2005-018696). TFMA was supported by the BMBF through the DIFUTURE consortium of the Medical Informatics Initiative Germany (grant 01ZZ1804A) and by the European Union’s Horizon 2020 Research and Innovation Programme (grant MultipleMS, EU RIA 733161).

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.

KW - Developmental dyslexia

KW - GWAS

KW - Reading

KW - Genetics

KW - Heritability

KW - Polygenic risk

KW - Schizophrenia

KW - ADHD

KW - Bipolar disorder

KW - Educational attaintment

KW - Intelligence

KW - Brain cortical thickness

KW - Transverse temporal gyrus

U2 - 10.1038/s41380-020-00898-x

DO - 10.1038/s41380-020-00898-x

M3 - Article

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

Genome Wide Association Study reveals new insights into the heritability and genetic correlates of developmental dyslexia

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