Disentangling polygenic associations between attention-deficit/hyperactivity disorder, educational attainment, literacy and language

iPSYCH-Broad-PGC ADHD Consortium, Ellen Verhoef, Ditte Demontis, Stephen Burgess, Chin Yang Shapland, Philip S. Dale, Aysu Okbay, Benjamin M. Neale, Stephen V. Faraone, Evie Stergiakouli, George Davey Smith, Simon E. Fisher, Anders D. Børglum, Beate St Pourcain, Esben Agerbo, Thomas Damm Als, Marie Bækved-Hansen, Rich Belliveau, Anders D. Børglum, Jonas Bybjerg-Grauholm & 37 others Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Søren Dalsgaard, Mark J. Daly, Ditte Demontis, Ashley Dumont, Jacqueline Goldstein, Jakob Grove, Christine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, David M. Hougaard, Daniel P. Howrigan, Hailiang Huang, Julian Maller, Alicia R. Martin, Joanna Martin, Manuel Mattheisen, Jennifer Moran, Ole Mors, Preben Bo Mortensen, Benjamin M. Neale, Merete Nordentoft, Jonatan Pallesen, Duncan S. Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Elise B. Robinson, F. Kyle Satterstrom, Christine Stevens, Patrick Turley, Raymond K. Walters, Thomas Werge

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

LanguageEnglish
Article number35
JournalTranslational Psychiatry
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

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Aptitude
Attention Deficit Disorder with Hyperactivity
Language
Reading
Intelligence
Literacy
Genome

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@article{190cefd2276b4f779725cab0c4d61cd1,
title = "Disentangling polygenic associations between attention-deficit/hyperactivity disorder, educational attainment, literacy and language",
abstract = "Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6{\%} phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.",
author = "{iPSYCH-Broad-PGC ADHD Consortium} and Ellen Verhoef and Ditte Demontis and Stephen Burgess and Shapland, {Chin Yang} and Dale, {Philip S.} and Aysu Okbay and Neale, {Benjamin M.} and Faraone, {Stephen V.} and Evie Stergiakouli and {Davey Smith}, George and Fisher, {Simon E.} and B{\o}rglum, {Anders D.} and {St Pourcain}, Beate and Esben Agerbo and Als, {Thomas Damm} and Marie B{\ae}kved-Hansen and Rich Belliveau and B{\o}rglum, {Anders D.} and Jonas Bybjerg-Grauholm and Felecia Cerrato and Kimberly Chambert and Claire Churchhouse and S{\o}ren Dalsgaard and Daly, {Mark J.} and Ditte Demontis and Ashley Dumont and Jacqueline Goldstein and Jakob Grove and Hansen, {Christine S.} and Hauberg, {Mads Engel} and Hollegaard, {Mads V.} and Hougaard, {David M.} and Howrigan, {Daniel P.} and Hailiang Huang and Julian Maller and Martin, {Alicia R.} and Joanna Martin and Manuel Mattheisen and Jennifer Moran and Ole Mors and Mortensen, {Preben Bo} and Neale, {Benjamin M.} and Merete Nordentoft and Jonatan Pallesen and Palmer, {Duncan S.} and Pedersen, {Carsten B{\o}cker} and Pedersen, {Marianne Gi{\o}rtz} and Timothy Poterba and Poulsen, {Jesper Buchhave} and Stephan Ripke and Robinson, {Elise B.} and Satterstrom, {F. Kyle} and Christine Stevens and Patrick Turley and Walters, {Raymond K.} and Thomas Werge",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41398-018-0324-2",
language = "English",
volume = "9",
journal = "Translational Psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",
number = "1",

}

Disentangling polygenic associations between attention-deficit/hyperactivity disorder, educational attainment, literacy and language. / iPSYCH-Broad-PGC ADHD Consortium.

In: Translational Psychiatry, Vol. 9, No. 1, 35, 01.12.2019.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Disentangling polygenic associations between attention-deficit/hyperactivity disorder, educational attainment, literacy and language

AU - iPSYCH-Broad-PGC ADHD Consortium

AU - Verhoef, Ellen

AU - Demontis, Ditte

AU - Burgess, Stephen

AU - Shapland, Chin Yang

AU - Dale, Philip S.

AU - Okbay, Aysu

AU - Neale, Benjamin M.

AU - Faraone, Stephen V.

AU - Stergiakouli, Evie

AU - Davey Smith, George

AU - Fisher, Simon E.

AU - Børglum, Anders D.

AU - St Pourcain, Beate

AU - Agerbo, Esben

AU - Als, Thomas Damm

AU - Bækved-Hansen, Marie

AU - Belliveau, Rich

AU - Børglum, Anders D.

AU - Bybjerg-Grauholm, Jonas

AU - Cerrato, Felecia

AU - Chambert, Kimberly

AU - Churchhouse, Claire

AU - Dalsgaard, Søren

AU - Daly, Mark J.

AU - Demontis, Ditte

AU - Dumont, Ashley

AU - Goldstein, Jacqueline

AU - Grove, Jakob

AU - Hansen, Christine S.

AU - Hauberg, Mads Engel

AU - Hollegaard, Mads V.

AU - Hougaard, David M.

AU - Howrigan, Daniel P.

AU - Huang, Hailiang

AU - Maller, Julian

AU - Martin, Alicia R.

AU - Martin, Joanna

AU - Mattheisen, Manuel

AU - Moran, Jennifer

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Neale, Benjamin M.

AU - Nordentoft, Merete

AU - Pallesen, Jonatan

AU - Palmer, Duncan S.

AU - Pedersen, Carsten Bøcker

AU - Pedersen, Marianne Giørtz

AU - Poterba, Timothy

AU - Poulsen, Jesper Buchhave

AU - Ripke, Stephan

AU - Robinson, Elise B.

AU - Satterstrom, F. Kyle

AU - Stevens, Christine

AU - Turley, Patrick

AU - Walters, Raymond K.

AU - Werge, Thomas

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

AB - Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

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