Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia

Alessandro Gialluisi; Till F M Andlauer; Nazanin Mirza-Schreiber; Kristina Moll; Jessica Becker; Per Hoffmann; Kerstin U Ludwig; Darina Czamara; Beate St Pourcain; William Brandler; Ferenc Honbolygó; Dénes Tóth; Valéria Csépe; Guillaume Huguet; 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; 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/s41398-019-0402-0

Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia

Alessandro Gialluisi, Till F M Andlauer, Nazanin Mirza-Schreiber, Kristina Moll, Jessica Becker, Per Hoffmann, Kerstin U Ludwig, Darina Czamara, Beate St Pourcain, William Brandler, Ferenc Honbolygó, Dénes Tóth, Valéria Csépe, Guillaume Huguet, Andrew P Morris, Jacqueline Hulslander, Erik G Willcutt, John C DeFries, Richard K Olson, Shelley D SmithBruce 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, 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

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

Abstract

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10-8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10-9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10-8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10-8) and with all the cognitive traits tested (p = 3.07 × 10-8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10-5-10-7]) and negatively associated with ADHD PRS (p ~ [10-8-10-17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

Original language	English
Article number	77
Number of pages	15
Journal	Translational Psychiatry
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41398-019-0402-0
Publication status	Published - 11 Feb 2019

Keywords

AUTOMATIZED NAMING RAN
CANDIDATE GENES
DEVELOPMENTAL DYSLEXIA
ENVIRONMENTAL-INFLUENCES
IMAGING-GENETICS
LANGUAGE
MOLECULAR-GENETICS
READING-DISABILITY
SHORT-TERM-MEMORY
SUSCEPTIBILITY LOCUS

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Gialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Brandler, W., Honbolygó, F., Tóth, D., Csépe, V., Huguet, G., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C., Olson, R. K., ... Schulte-Körne, G. (2019). Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia. Translational Psychiatry, 9(1), Article 77. https://doi.org/10.1038/s41398-019-0402-0

@article{6883deb333db4ff59c9b20b8e9c7b487,

title = "Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia",

abstract = "Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10-8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10-9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10-8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10-8) and with all the cognitive traits tested (p = 3.07 × 10-8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10-5-10-7]) and negatively associated with ADHD PRS (p ~ [10-8-10-17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.",

keywords = "AUTOMATIZED NAMING RAN, CANDIDATE GENES, DEVELOPMENTAL DYSLEXIA, ENVIRONMENTAL-INFLUENCES, IMAGING-GENETICS, LANGUAGE, MOLECULAR-GENETICS, READING-DISABILITY, SHORT-TERM-MEMORY, SUSCEPTIBILITY LOCUS",

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 {St Pourcain}, Beate and William Brandler and Ferenc Honbolyg{\'o} and D{\'e}nes T{\'o}th and Val{\'e}ria Cs{\'e}pe and Guillaume Huguet 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 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 Information: A.G. and T.F.M.A. were supported by the Munich Cluster for Systems Neurology (SyNergy). S.P. is a Royal Society University research Fellow. B.M.M., C.F., B.S.P., and S.E.F. are supported by the Max Planck Society. A.P.M. is a Wellcome Senior Fellow in Basic Biomedical Science (WT098017). F.R. is supported by Agence Nationale de la Recherche (ANR-06-NEURO-019-01, ANR-10-LABX-0087 IEC, ANR-10-IDEX-0001-02 PSL, ANR-11-BSV4-014-01), European Commission (LSHM-CT-2005-018696), Ville de Paris. We would also like to acknowledge our project partners Catherine Billard, Caroline Bogliotti, Vanessa Bongiovanni, Laure Bricout, Camille Chabernaud, Yves Chaix, Isabelle Comte-Gervais, Florence Delteil-Pinton, Jean-Fran{\c c}ois D{\'e}monet, Florence George, Christophe-Lo{\"i}c G{\'e}rard, St{\'e}phanie Iannuzzi, Marie Lageat, Marie-France Leheuzey, Marie-Th{\'e}r{\`e}se Lenormand, Marion Li{\'e}bert, Emilie Longeras, Emilie Racaud, Isabelle Soares-Boucaud, Sylviane Valdois, Nad{\`e}ge Villiermet, Johannes Ziegler, Dr Else Eising, Dr Holger Kirsten, and Dr Bent M{\"u}ller. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = feb,

day = "11",

doi = "10.1038/s41398-019-0402-0",

language = "English",

volume = "9",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

Gialluisi, A, Andlauer, TFM, Mirza-Schreiber, N, Moll, K, Becker, J, Hoffmann, P, Ludwig, KU, Czamara, D, St Pourcain, B, Brandler, W, Honbolygó, F, Tóth, D, Csépe, V, Huguet, G, 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, 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 2019, 'Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia', Translational Psychiatry, vol. 9, no. 1, 77. https://doi.org/10.1038/s41398-019-0402-0

TY - JOUR

T1 - Genome-wide association scan identifies new variants associated with a cognitive predictor of 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 - St Pourcain, Beate

AU - Brandler, William

AU - Honbolygó, Ferenc

AU - Tóth, Dénes

AU - Csépe, Valéria

AU - Huguet, Guillaume

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 - 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 Information: A.G. and T.F.M.A. were supported by the Munich Cluster for Systems Neurology (SyNergy). S.P. is a Royal Society University research Fellow. B.M.M., C.F., B.S.P., and S.E.F. are supported by the Max Planck Society. A.P.M. is a Wellcome Senior Fellow in Basic Biomedical Science (WT098017). F.R. is supported by Agence Nationale de la Recherche (ANR-06-NEURO-019-01, ANR-10-LABX-0087 IEC, ANR-10-IDEX-0001-02 PSL, ANR-11-BSV4-014-01), European Commission (LSHM-CT-2005-018696), Ville de Paris. We would also like to acknowledge our project partners Catherine Billard, Caroline Bogliotti, Vanessa Bongiovanni, Laure Bricout, Camille Chabernaud, Yves Chaix, Isabelle Comte-Gervais, Florence Delteil-Pinton, Jean-François Démonet, Florence George, Christophe-Loïc Gérard, Stéphanie Iannuzzi, Marie Lageat, Marie-France Leheuzey, Marie-Thérèse Lenormand, Marion Liébert, Emilie Longeras, Emilie Racaud, Isabelle Soares-Boucaud, Sylviane Valdois, Nadège Villiermet, Johannes Ziegler, Dr Else Eising, Dr Holger Kirsten, and Dr Bent Müller. Publisher Copyright: © 2019, The Author(s).

PY - 2019/2/11

Y1 - 2019/2/11

N2 - Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10-8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10-9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10-8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10-8) and with all the cognitive traits tested (p = 3.07 × 10-8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10-5-10-7]) and negatively associated with ADHD PRS (p ~ [10-8-10-17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

AB - Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10-8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10-9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10-8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10-8) and with all the cognitive traits tested (p = 3.07 × 10-8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10-5-10-7]) and negatively associated with ADHD PRS (p ~ [10-8-10-17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

KW - AUTOMATIZED NAMING RAN

KW - CANDIDATE GENES

KW - DEVELOPMENTAL DYSLEXIA

KW - ENVIRONMENTAL-INFLUENCES

KW - IMAGING-GENETICS

KW - LANGUAGE

KW - MOLECULAR-GENETICS

KW - READING-DISABILITY

KW - SHORT-TERM-MEMORY

KW - SUSCEPTIBILITY LOCUS

U2 - 10.1038/s41398-019-0402-0

DO - 10.1038/s41398-019-0402-0

M3 - Article

C2 - 30741946

SN - 2158-3188

VL - 9

JO - Translational Psychiatry

JF - Translational Psychiatry

IS - 1

M1 - 77

ER -

Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia

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