Genome-wide analyses of vocabulary size in infancy and toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits

Ellen Verhoef; Andrea G Allegrini; Philip R Jansen; Meike Bartels; Dorret Boomsma; Christel Middeldorp; Josine L Min; Camiel van der Laan; Eero Vuoksimaa; Alyce Whipp; Eivind Ystrom; EAGLE working group

doi:10.1016/j.biopsych.2023.11.025

Genome-wide analyses of vocabulary size in infancy and toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits

Ellen Verhoef
, Andrea G Allegrini
, Philip R Jansen
, Meike Bartels
, Dorret Boomsma
, Christel Middeldorp
, Josine L Min
, Camiel van der Laan
, Eero Vuoksimaa
, Alyce Whipp
, Eivind Ystrom
, EAGLE working group

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

Abstract

BACKGROUND: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes and neurodevelopmental conditions, including Attention-Deficit/Hyperactivity Disorder (ADHD).

METHODS: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 European descent children. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h 2) and genetic correlations (r g), and modelled underlying factor structures with multivariate models.

RESULTS: Early-life vocabulary size was modestly heritable (SNP-h 2: 0.08(SE=0.01) to 0.24(SE=0.03)). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (r g=0.07(SE=0.10)), although each measure was moderately related to toddler expressive vocabulary (r g=0.69(SE=0.14) and r g=0.67(SE=0.16), respectively), suggesting a multi-factorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g. spelling: r g=0.58(SE=0.20) and r g=0.79(SE=0.25), respectively), underlining genetic similarity. However, genetic association of early-life vocabulary with educational attainment and intelligence emerged in toddlerhood only (e.g. receptive vocabulary and intelligence: r g=0.36(SE=0.12)). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (r g=0.23(SE=0.08)). Multivariate genetic models in the ALSPAC cohort confirmed this finding for ADHD symptoms (r g=0.54(SE=0.26)), but showed that the association effect reversed for toddler receptive vocabulary (r g=-0.74(SE=0.23)), highlighting developmental heterogeneity.

CONCLUSIONS: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy and cognition-related traits.

Original language	English
Pages (from-to)	859-869
Number of pages	11
Journal	Biological psychiatry
Volume	95
Issue number	9
Early online date	7 Dec 2023
DOIs	https://doi.org/10.1016/j.biopsych.2023.11.025
Publication status	Published - 1 May 2024

Bibliographical note

Funding

EVe, EEi, FS, SEF and BSTP were funded by the Max Planck Society. TSA was supported by the Novo Nordisk Foundation Grant NNF18OC0052457. ATM is supported by the National Health and Medical Research Council. CS was supported by an Australian Government NHMRC Postgraduate Research Scholarship. EH receives funding from the National Health and Medical Research Council Australia, Australian Research Council, Medical Research Future Fund, and Tour de Cure. MG is funded by a Miguel Servet II fellowship (CPII18/00018) awarded by the Spanish Institute of Health Carlos III. We acknowledge support from the Spanish Ministry of Science and Innovation and the State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. SH receives support from the UK National Institute for Health Research through the academic clinical fellowship scheme. KR is supported by a Sir Henry Wellcome Postdoctoral Fellowship. CYS and JLM are supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00032/02). OAA is supported by KG Jebsen Stiftelsen, Research Council of Norway (#223273, 273291, 324252). EY receives support from the Research Council of Norway (grant numbers 262177; 288083). PRN was supported by grants from the European Research Council (AdG SELECTionPREDISPOSED #293574), the Bergen Research Foundation (“Utilizing the Mother and Child Cohort and the Medical Birth Registry for Better Health”), Stiftelsen Kristian Gerhard Jebsen (Translational Medical Center), the University of Bergen, the Research Council of Norway (FRIPRO grant #240413), the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”), the Novo Nordisk Foundation (grant #54741), and the Norwegian Diabetes Association. CAMC receives support from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No 848158 (EarlyCause Project). EV, EE, FS, SEF, and BSP were funded by the Max Planck Society. TSA was supported by the Novo Nordisk Foundation (Grant No. NNF18OC0052457). ATM is supported by the National Health and Medical Research Council. CS was supported by an Australian Government National Health and Medical Research Council Postgraduate Research Scholarship. EH receives funding from the National Health and Medical Research Council Australia, Australian Research Council, Medical Research Future Fund, and Tour de Cure. MB is funded by an NWO VICI grant (Grant No. VI.C.211.054) and an ERC consolidation grant (WELL-BEING 771057). MG is funded by a Miguel Servet II fellowship (CPII18/00018) awarded by the Spanish Institute of Health Carlos III. We acknowledge support from the grant CEX2018-000806-S funded by MCIN/AEI/10.13039/501100011033 and support from the Generalitat de Catalunya through the CERCA (Centres de Recerca de Catalunya) Program. SH receives support from the UK National Institute for Health Research through the academic clinical fellowship scheme. KR is supported by a Sir Henry Wellcome Postdoctoral Fellowship. CYS and JLM are supported by the UK Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00032/02). OAA is supported by KG Jebsen Stiftelsen, Research Council of Norway (Grant No. 223273, 273291, 324252). EY receives support from Research Council of Norway (Grant Nos. 262177 and 288083). PRN was supported by grants from the European Research Council (AdG SELECTionPREDISPOSED #293574), the Bergen Research Foundation (“Utilizing the Mother and Child Cohort and the Medical Birth Registry for Better Health”), Stiftelsen Kristian Gerhard Jebsen (Translational Medical Center), the University of Bergen, the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”), Novo Nordisk Foundation Grant No. 54741, and the Norwegian Diabetes Association. CAMC receives support from the European Union's Horizon 2020 Research and Innovation Programme (Grant agreement No. 848158) (EarlyCause Project). BSP, EV, and the EAGLE Working Group report that the EAGLE Working Group is one of the named authors and that all members qualify for authorship. We thank all children, parents, and caregivers for making this study possible. The project was embedded within the EAGLE Consortium. Cohort-specific acknowledgments and funding information can be found in the Supplemental Note. In addition, we thank all cohorts and researchers that made their summary statistics available to us. This includes the GenLang Consortium, Social Science Genetic Association Consortium, Early Growth Genetics Consortium, EAGLE Consortium, Psychiatric Genomics Consortium, and the Danish Lundbeck Foundation Initiative for Integrative Psychiatric Research. A previous version of this article was published as a preprint on bioRxiv: https://www.biorxiv.org/content/10.1101/2022.06.01.494306. Derived single-trait (stage I) and multitrait (stage II) vocabulary summary statistics will be made available upon publication of the article via a data repository. EV and BSP had full access to all summary statistic-level data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest.

Funders	Funder number
Australian Research Council
Sir Henry Wellcome Postdoctoral Fellowship
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Ministerio de Ciencia e Innovación
Generalitat de Catalunya
Diabetesforbundet
Miguel Servet II fellowship
Stiftelsen Kristian Gerhard Jebsen
National Institute for Health and Care Research
State Research Agency
Max-Planck-Gesellschaft
European Commission
Medical Research Future Fund
Australian Government National Health and Medical Research Council
National Health and Medical Research Council
Universitetet i Bergen
Helse Vest Regionalt Helseføretak
Bergens Forskningsstiftelse
Horizon 2020
Centro de Excelencia Severo Ochoa 2019-2023	CEX2018-000806-S
Medical Research Council	MR/M021475/1
Norges Forskningsråd	262177, 288083
Tour de Cure	CPII18/00018
Horizon 2020 Framework Programme	771057, 848158
KG Jebsen Stiftelsen, Research Council of Norway	223273, 324252, 273291
FRIPRO	240413
Personalized Medicine for Children and Adults	54741
European Research Council	293574, CPII18/00018
Novo Nordisk Fonden	NNF18OC0052457
University of Bristol	MC_UU_00032/02
Spanish Institute of Health Carlos III	MCIN/AEI/10.13039/501100011033

Cohort Studies

Netherlands Twin Register (NTR)

Access to Document

10.1016/j.biopsych.2023.11.025

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Cite this

Verhoef, E., Allegrini, A. G., Jansen, P. R., Bartels, M., Boomsma, D., Middeldorp, C., Min, J. L., van der Laan, C., Vuoksimaa, E., Whipp, A., Ystrom, E., & EAGLE working group (2024). Genome-wide analyses of vocabulary size in infancy and toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits. Biological psychiatry, 95(9), 859-869. https://doi.org/10.1016/j.biopsych.2023.11.025

@article{30fc6b6a22e140fd81247d5d53a125fb,

title = "Genome-wide analyses of vocabulary size in infancy and toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits",

abstract = "BACKGROUND: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes and neurodevelopmental conditions, including Attention-Deficit/Hyperactivity Disorder (ADHD).METHODS: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 European descent children. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h 2) and genetic correlations (r g), and modelled underlying factor structures with multivariate models. RESULTS: Early-life vocabulary size was modestly heritable (SNP-h 2: 0.08(SE=0.01) to 0.24(SE=0.03)). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (r g=0.07(SE=0.10)), although each measure was moderately related to toddler expressive vocabulary (r g=0.69(SE=0.14) and r g=0.67(SE=0.16), respectively), suggesting a multi-factorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g. spelling: r g=0.58(SE=0.20) and r g=0.79(SE=0.25), respectively), underlining genetic similarity. However, genetic association of early-life vocabulary with educational attainment and intelligence emerged in toddlerhood only (e.g. receptive vocabulary and intelligence: r g=0.36(SE=0.12)). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (r g=0.23(SE=0.08)). Multivariate genetic models in the ALSPAC cohort confirmed this finding for ADHD symptoms (r g=0.54(SE=0.26)), but showed that the association effect reversed for toddler receptive vocabulary (r g=-0.74(SE=0.23)), highlighting developmental heterogeneity. CONCLUSIONS: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy and cognition-related traits.",

author = "Ellen Verhoef and Allegrini, \{Andrea G\} and Jansen, \{Philip R\} and Katherine Lange and Wang, \{Carol A\} and Morgan, \{Angela T\} and Ahluwalia, \{Tarunveer S\} and Christos Symeonides and Else Eising and Marie-Christine Franken and Elina Hypponen and Toby Mansell and Mitchell Olislagers and Emina Omerovic and Kaili Rimfeld and Fenja Schlag and Saskia Selzam and Shapland, \{Chin Yang\} and Henning Tiemeier and Whitehouse, \{Andrew J O\} and Richard Saffery and Klaus B{\o}nnelykke and Sheena Reilly and Pennell, \{Craig E\} and Melissa Wake and Cecil, \{Charlotte A M\} and Robert Plomin and Fisher, \{Simon E\} and \{St Pourcain\}, Beate and Andreassen, \{Ole A\} and Meike Bartels and Dorret Boomsma and Dale, \{Philip S\} and Erik Ehli and Dietmar Fernandez-Orth and M{\`o}nica Guxens and Christian Hakulinen and Harris, \{Kathleen Mullan\} and Simon Haworth and \{de Hoyos\}, Luc{\'i}a and Vincent Jaddoe and Liisa Keltikangas-J{\"a}rvinen and Terho Lehtim{\"a}ki and Christel Middeldorp and Min, \{Josine L\} and Mishra, \{Pashupati P\} and Nj{\o}lstad, \{P{\aa}l Rasmus\} and Jordi Sunyer and Tate, \{Ashley E\} and Nicholas Timpson and \{van der Laan\}, Camiel and Martine Vrijheid and Eero Vuoksimaa and Alyce Whipp and Eivind Ystrom and \{EAGLE working group\}",

note = "Copyright {\textcopyright} 2023. Published by Elsevier Inc.",

year = "2024",

month = may,

day = "1",

doi = "10.1016/j.biopsych.2023.11.025",

language = "English",

volume = "95",

pages = "859--869",

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Verhoef, E, Allegrini, AG, Jansen, PR , Bartels, M , Boomsma, D, Middeldorp, C, Min, JL, van der Laan, C, Vuoksimaa, E, Whipp, A, Ystrom, E & EAGLE working group 2024, 'Genome-wide analyses of vocabulary size in infancy and toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits', Biological psychiatry, vol. 95, no. 9, pp. 859-869. https://doi.org/10.1016/j.biopsych.2023.11.025

Genome-wide analyses of vocabulary size in infancy and toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits. / Verhoef, Ellen; Allegrini, Andrea G; Jansen, Philip R et al.
In: Biological psychiatry, Vol. 95, No. 9, 01.05.2024, p. 859-869.

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

TY - JOUR

T1 - Genome-wide analyses of vocabulary size in infancy and toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits

AU - Verhoef, Ellen

AU - Allegrini, Andrea G

AU - Jansen, Philip R

AU - Lange, Katherine

AU - Wang, Carol A

AU - Morgan, Angela T

AU - Ahluwalia, Tarunveer S

AU - Symeonides, Christos

AU - Eising, Else

AU - Franken, Marie-Christine

AU - Hypponen, Elina

AU - Mansell, Toby

AU - Olislagers, Mitchell

AU - Omerovic, Emina

AU - Rimfeld, Kaili

AU - Schlag, Fenja

AU - Selzam, Saskia

AU - Shapland, Chin Yang

AU - Tiemeier, Henning

AU - Whitehouse, Andrew J O

AU - Saffery, Richard

AU - Bønnelykke, Klaus

AU - Reilly, Sheena

AU - Pennell, Craig E

AU - Wake, Melissa

AU - Cecil, Charlotte A M

AU - Plomin, Robert

AU - Fisher, Simon E

AU - St Pourcain, Beate

AU - Andreassen, Ole A

AU - Bartels, Meike

AU - Boomsma, Dorret

AU - Dale, Philip S

AU - Ehli, Erik

AU - Fernandez-Orth, Dietmar

AU - Guxens, Mònica

AU - Hakulinen, Christian

AU - Harris, Kathleen Mullan

AU - Haworth, Simon

AU - de Hoyos, Lucía

AU - Jaddoe, Vincent

AU - Keltikangas-Järvinen, Liisa

AU - Lehtimäki, Terho

AU - Middeldorp, Christel

AU - Min, Josine L

AU - Mishra, Pashupati P

AU - Njølstad, Pål Rasmus

AU - Sunyer, Jordi

AU - Tate, Ashley E

AU - Timpson, Nicholas

AU - van der Laan, Camiel

AU - Vrijheid, Martine

AU - Vuoksimaa, Eero

AU - Whipp, Alyce

AU - Ystrom, Eivind

AU - EAGLE working group

PY - 2024/5/1

Y1 - 2024/5/1

N2 - BACKGROUND: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes and neurodevelopmental conditions, including Attention-Deficit/Hyperactivity Disorder (ADHD).METHODS: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 European descent children. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h 2) and genetic correlations (r g), and modelled underlying factor structures with multivariate models. RESULTS: Early-life vocabulary size was modestly heritable (SNP-h 2: 0.08(SE=0.01) to 0.24(SE=0.03)). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (r g=0.07(SE=0.10)), although each measure was moderately related to toddler expressive vocabulary (r g=0.69(SE=0.14) and r g=0.67(SE=0.16), respectively), suggesting a multi-factorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g. spelling: r g=0.58(SE=0.20) and r g=0.79(SE=0.25), respectively), underlining genetic similarity. However, genetic association of early-life vocabulary with educational attainment and intelligence emerged in toddlerhood only (e.g. receptive vocabulary and intelligence: r g=0.36(SE=0.12)). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (r g=0.23(SE=0.08)). Multivariate genetic models in the ALSPAC cohort confirmed this finding for ADHD symptoms (r g=0.54(SE=0.26)), but showed that the association effect reversed for toddler receptive vocabulary (r g=-0.74(SE=0.23)), highlighting developmental heterogeneity. CONCLUSIONS: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy and cognition-related traits.

AB - BACKGROUND: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta-genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes and neurodevelopmental conditions, including Attention-Deficit/Hyperactivity Disorder (ADHD).METHODS: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 European descent children. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h 2) and genetic correlations (r g), and modelled underlying factor structures with multivariate models. RESULTS: Early-life vocabulary size was modestly heritable (SNP-h 2: 0.08(SE=0.01) to 0.24(SE=0.03)). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (r g=0.07(SE=0.10)), although each measure was moderately related to toddler expressive vocabulary (r g=0.69(SE=0.14) and r g=0.67(SE=0.16), respectively), suggesting a multi-factorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g. spelling: r g=0.58(SE=0.20) and r g=0.79(SE=0.25), respectively), underlining genetic similarity. However, genetic association of early-life vocabulary with educational attainment and intelligence emerged in toddlerhood only (e.g. receptive vocabulary and intelligence: r g=0.36(SE=0.12)). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (r g=0.23(SE=0.08)). Multivariate genetic models in the ALSPAC cohort confirmed this finding for ADHD symptoms (r g=0.54(SE=0.26)), but showed that the association effect reversed for toddler receptive vocabulary (r g=-0.74(SE=0.23)), highlighting developmental heterogeneity. CONCLUSIONS: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy and cognition-related traits.

U2 - 10.1016/j.biopsych.2023.11.025

DO - 10.1016/j.biopsych.2023.11.025

M3 - Article

C2 - 38070845

SN - 0006-3223

VL - 95

SP - 859

EP - 869

JO - Biological psychiatry

JF - Biological psychiatry

IS - 9

ER -

Genome-wide analyses of vocabulary size in infancy and toddlerhood: Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits

Abstract

Bibliographical note

Funding

Cohort Studies

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