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

Research output: Contribution to journal › Article › 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
Journal	Translational psychiatry
Volume	9
Issue number	1
Early online date	11 Feb 2019
DOIs	https://doi.org/10.1038/s41398-019-0402-0
Publication status	Published - 11 Feb 2019

Bibliographical note

© The Author(s) 2019. Open Access 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/.

Keywords

Adolescent
Adult
Child
Cognition
Cohort Studies
Dyslexia/genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Male
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Young Adult

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10.1038/s41398-019-0402-0Licence: CC BY 3.0

Genome-wide association scan identifies
© The Author(s) 2019.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/.
Final published version, 1.49 MBLicence: CC BY 3.0

Cite this

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

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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.",

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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 = "{\textcopyright} The Author(s) 2019. Open Access 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/.",

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

language = "English",

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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 - © The Author(s) 2019. Open Access 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 - 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 - Adolescent

KW - Adult

KW - Child

KW - Cognition

KW - Cohort Studies

KW - Dyslexia/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Male

KW - Multifactorial Inheritance

KW - Polymorphism, Single Nucleotide

KW - Young Adult

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UR - http://www.nature.com/articles/s41398-019-0402-0

U2 - 10.1038/s41398-019-0402-0

DO - 10.1038/s41398-019-0402-0

M3 - Article

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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