Maternal serotonin transporter genotype and offsprings' clinical and cognitive measures of ADHD and ASD

Sabrina I. Hanswijk; Daan van Rooij; Jaap Oosterlaan; Marjolein Luman; Pieter J. Hoekstra; Catharina A. Hartman; Barbara Franke; Emma Sprooten; Judith R. Homberg; Jan K. Buitelaar

doi:10.1016/j.pnpbp.2021.110354

Maternal serotonin transporter genotype and offsprings' clinical and cognitive measures of ADHD and ASD

Sabrina I. Hanswijk, Daan van Rooij, Jaap Oosterlaan, Marjolein Luman, Pieter J. Hoekstra, Catharina A. Hartman, Barbara Franke, Emma Sprooten, Judith R. Homberg, Jan K. Buitelaar^*

^*Corresponding author for this work

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Abstract

Serotonin (5-HT) is an important factor for prenatal neurodevelopment whereby its neurotrophic actions can be regulated through maternal-fetal interactions. We explored if maternal 5-HTTLPR genotype is associated with clinical and cognitive measures of attention-deficit/hyperactivity disorder (ADHD) and comorbid autism spectrum disorder (ASD) in typically-developing and ADHD-diagnosed offspring, beyond classical inheritance and environmental- and comorbidity-mediators/confounders. Family-based variance decomposition analyses were performed incorporating 6–31 year-old offsprings' as well as parental genotypes of 462 ADHD and control families from the NeuroIMAGE cohort. Dependent measures were offsprings' ADHD symptom- and ASD trait-scores and cognitive measures including executive functioning (including response inhibition and cognitive flexibility), sustained attention, reward processing, motor control, and emotion recognition. Offsprings' stereotyped behavior was predicted by an interaction between maternal 5-HTTLPR genotype and offsprings' sex. Furthermore, offspring of mothers with low-expressing genotypes demonstrated larger reward-related reductions in reaction time. While specifically adult male offspring of these mothers reported a faster reversal learning with less errors, specifically young female offspring of these mothers were more accurate in identifying happy faces. Adult offspring from the mothers with low-expressing 5-HTTLPR genotypes were also slower in identifying happy faces. However, this association seemed to be mediated by offsprings' high anxiety levels. In sum, we found some support for a role of the maternal 5-HT system in modulating fetal brain development and behavior. Offsprings' cognitive measures might be more sensitive to small alterations within the maternal 5-HT system than their ADHD and ASD clinical phenotypes. Further studies are needed to specify the association between maternal genotype and risk for neurodevelopmental disorders.

Original language	English
Article number	110354
Pages (from-to)	1-12
Number of pages	12
Journal	Progress in Neuro-Psychopharmacology and Biological Psychiatry
Volume	110
Early online date	15 May 2021
DOIs	https://doi.org/10.1016/j.pnpbp.2021.110354
Publication status	Published - 30 Aug 2021

Bibliographical note

Funding Information:
This work was supported by a Donders Center for Neuroscience Radboud Nijmegen University Medical Center junior researcher round grant [grant number N.A., 2016]. The NeuroIMAGE project was supported by grants from National Institutes of Health (grant R01MH62873 to SV Faraone) for initial sample recruitment, and from NWO Large Investment (grant 1750102007010 to JK Buitelaar), NWO Brain & Cognition (grant 433-09-242 to JK Buitelaar), and grants from Radboud University Medical Center , University Medical Center Groningen, Accare , and VU University Amsterdam for subsequent assessment waves. NeuroIMAGE also received funding from the European Community's Seventh Framework Programme ( FP7/2007–2013 ) under grant agreements n° 602805 (Aggressotype), n° 278948 (TACTICS), and n° 602450 (IMAGEMEND), and from the European Community's Horizon 2020 Programme ( H2020/2014–2020 ) under grant agreements n° 667302 (CoCA) and n° 728018 (Eat2beNICE). We would like to thank Marina Hakobjan and Angelien Heister, Radboud University Nijmegen Medical Center, for providing details regarding the genotyping procedure.

Funding Information:
This work was supported by a Donders Center for Neuroscience Radboud Nijmegen University Medical Center junior researcher round grant [grant number N.A. 2016]. The NeuroIMAGE project was supported by grants from National Institutes of Health (grant R01MH62873 to SV Faraone) for initial sample recruitment, and from NWO Large Investment (grant 1750102007010 to JK Buitelaar), NWO Brain & Cognition (grant 433-09-242 to JK Buitelaar), and grants from Radboud University Medical Center, University Medical Center Groningen, Accare, and VU University Amsterdam for subsequent assessment waves. NeuroIMAGE also received funding from the European Community's Seventh Framework Programme (FP7/2007?2013) under grant agreements n? 602805 (Aggressotype), n? 278948 (TACTICS), and n? 602450 (IMAGEMEND), and from the European Community's Horizon 2020 Programme (H2020/2014?2020) under grant agreements n? 667302 (CoCA) and n? 728018 (Eat2beNICE). We would like to thank Marina Hakobjan and Angelien Heister, Radboud University Nijmegen Medical Center, for providing details regarding the genotyping procedure.

Publisher Copyright:
© 2021

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

This work was supported by a Donders Center for Neuroscience Radboud Nijmegen University Medical Center junior researcher round grant [grant number N.A., 2016]. The NeuroIMAGE project was supported by grants from National Institutes of Health (grant R01MH62873 to SV Faraone) for initial sample recruitment, and from NWO Large Investment (grant 1750102007010 to JK Buitelaar), NWO Brain & Cognition (grant 433-09-242 to JK Buitelaar), and grants from Radboud University Medical Center , University Medical Center Groningen, Accare , and VU University Amsterdam for subsequent assessment waves. NeuroIMAGE also received funding from the European Community's Seventh Framework Programme ( FP7/2007–2013 ) under grant agreements n° 602805 (Aggressotype), n° 278948 (TACTICS), and n° 602450 (IMAGEMEND), and from the European Community's Horizon 2020 Programme ( H2020/2014–2020 ) under grant agreements n° 667302 (CoCA) and n° 728018 (Eat2beNICE). We would like to thank Marina Hakobjan and Angelien Heister, Radboud University Nijmegen Medical Center, for providing details regarding the genotyping procedure. This work was supported by a Donders Center for Neuroscience Radboud Nijmegen University Medical Center junior researcher round grant [grant number N.A. 2016]. The NeuroIMAGE project was supported by grants from National Institutes of Health (grant R01MH62873 to SV Faraone) for initial sample recruitment, and from NWO Large Investment (grant 1750102007010 to JK Buitelaar), NWO Brain & Cognition (grant 433-09-242 to JK Buitelaar), and grants from Radboud University Medical Center, University Medical Center Groningen, Accare, and VU University Amsterdam for subsequent assessment waves. NeuroIMAGE also received funding from the European Community's Seventh Framework Programme (FP7/2007?2013) under grant agreements n? 602805 (Aggressotype), n? 278948 (TACTICS), and n? 602450 (IMAGEMEND), and from the European Community's Horizon 2020 Programme (H2020/2014?2020) under grant agreements n? 667302 (CoCA) and n? 728018 (Eat2beNICE). We would like to thank Marina Hakobjan and Angelien Heister, Radboud University Nijmegen Medical Center, for providing details regarding the genotyping procedure.

Funders	Funder number
Donders Center for Neuroscience Radboud Nijmegen University Medical Center
European Community's Horizon 2020 Programme	667302
Marina Hakobjan and Angelien Heister, Radboud University Nijmegen Medical Center
National Institutes of Health
National Institute of Mental Health	R01MH062873
Chiropractic and Osteopathic College of Australasia	728018
Seventh Framework Programme	602805, 602450, 278948
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	1750102007010, 433-09-242
Seventh Framework Programme

Keywords

Maternal effects
5-HTTLPR
rs25531
Attention-deficit
hyperactivity disorder
Autism spectrum disorder

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.pnpbp.2021.110354

Maternal serotonin transporter genotype and offsprings clinical and cognitive measures of ADHD and ASDFinal published version, 1.52 MBLicence: Article 25fa Dutch Copyright Act

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Hanswijk, S. I., van Rooij, D., Oosterlaan, J., Luman, M., Hoekstra, P. J., Hartman, C. A., Franke, B., Sprooten, E., Homberg, J. R., & Buitelaar, J. K. (2021). Maternal serotonin transporter genotype and offsprings' clinical and cognitive measures of ADHD and ASD. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 110, 1-12. Article 110354. https://doi.org/10.1016/j.pnpbp.2021.110354

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abstract = "Serotonin (5-HT) is an important factor for prenatal neurodevelopment whereby its neurotrophic actions can be regulated through maternal-fetal interactions. We explored if maternal 5-HTTLPR genotype is associated with clinical and cognitive measures of attention-deficit/hyperactivity disorder (ADHD) and comorbid autism spectrum disorder (ASD) in typically-developing and ADHD-diagnosed offspring, beyond classical inheritance and environmental- and comorbidity-mediators/confounders. Family-based variance decomposition analyses were performed incorporating 6–31 year-old offsprings' as well as parental genotypes of 462 ADHD and control families from the NeuroIMAGE cohort. Dependent measures were offsprings' ADHD symptom- and ASD trait-scores and cognitive measures including executive functioning (including response inhibition and cognitive flexibility), sustained attention, reward processing, motor control, and emotion recognition. Offsprings' stereotyped behavior was predicted by an interaction between maternal 5-HTTLPR genotype and offsprings' sex. Furthermore, offspring of mothers with low-expressing genotypes demonstrated larger reward-related reductions in reaction time. While specifically adult male offspring of these mothers reported a faster reversal learning with less errors, specifically young female offspring of these mothers were more accurate in identifying happy faces. Adult offspring from the mothers with low-expressing 5-HTTLPR genotypes were also slower in identifying happy faces. However, this association seemed to be mediated by offsprings' high anxiety levels. In sum, we found some support for a role of the maternal 5-HT system in modulating fetal brain development and behavior. Offsprings' cognitive measures might be more sensitive to small alterations within the maternal 5-HT system than their ADHD and ASD clinical phenotypes. Further studies are needed to specify the association between maternal genotype and risk for neurodevelopmental disorders.",

keywords = "Maternal effects, 5-HTTLPR, rs25531, Attention-deficit, hyperactivity disorder, Autism spectrum disorder",

author = "Hanswijk, {Sabrina I.} and {van Rooij}, Daan and Jaap Oosterlaan and Marjolein Luman and Hoekstra, {Pieter J.} and Hartman, {Catharina A.} and Barbara Franke and Emma Sprooten and Homberg, {Judith R.} and Buitelaar, {Jan K.}",

note = "Funding Information: This work was supported by a Donders Center for Neuroscience Radboud Nijmegen University Medical Center junior researcher round grant [grant number N.A., 2016]. The NeuroIMAGE project was supported by grants from National Institutes of Health (grant R01MH62873 to SV Faraone) for initial sample recruitment, and from NWO Large Investment (grant 1750102007010 to JK Buitelaar), NWO Brain & Cognition (grant 433-09-242 to JK Buitelaar), and grants from Radboud University Medical Center , University Medical Center Groningen, Accare , and VU University Amsterdam for subsequent assessment waves. NeuroIMAGE also received funding from the European Community's Seventh Framework Programme ( FP7/2007–2013 ) under grant agreements n° 602805 (Aggressotype), n° 278948 (TACTICS), and n° 602450 (IMAGEMEND), and from the European Community's Horizon 2020 Programme ( H2020/2014–2020 ) under grant agreements n° 667302 (CoCA) and n° 728018 (Eat2beNICE). We would like to thank Marina Hakobjan and Angelien Heister, Radboud University Nijmegen Medical Center, for providing details regarding the genotyping procedure. Funding Information: This work was supported by a Donders Center for Neuroscience Radboud Nijmegen University Medical Center junior researcher round grant [grant number N.A. 2016]. The NeuroIMAGE project was supported by grants from National Institutes of Health (grant R01MH62873 to SV Faraone) for initial sample recruitment, and from NWO Large Investment (grant 1750102007010 to JK Buitelaar), NWO Brain & Cognition (grant 433-09-242 to JK Buitelaar), and grants from Radboud University Medical Center, University Medical Center Groningen, Accare, and VU University Amsterdam for subsequent assessment waves. NeuroIMAGE also received funding from the European Community's Seventh Framework Programme (FP7/2007?2013) under grant agreements n? 602805 (Aggressotype), n? 278948 (TACTICS), and n? 602450 (IMAGEMEND), and from the European Community's Horizon 2020 Programme (H2020/2014?2020) under grant agreements n? 667302 (CoCA) and n? 728018 (Eat2beNICE). We would like to thank Marina Hakobjan and Angelien Heister, Radboud University Nijmegen Medical Center, for providing details regarding the genotyping procedure. Publisher Copyright: {\textcopyright} 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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Hanswijk, SI, van Rooij, D, Oosterlaan, J , Luman, M, Hoekstra, PJ, Hartman, CA, Franke, B, Sprooten, E, Homberg, JR & Buitelaar, JK 2021, 'Maternal serotonin transporter genotype and offsprings' clinical and cognitive measures of ADHD and ASD', Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 110, 110354, pp. 1-12. https://doi.org/10.1016/j.pnpbp.2021.110354

TY - JOUR

T1 - Maternal serotonin transporter genotype and offsprings' clinical and cognitive measures of ADHD and ASD

AU - Hanswijk, Sabrina I.

AU - van Rooij, Daan

AU - Oosterlaan, Jaap

AU - Luman, Marjolein

AU - Hoekstra, Pieter J.

AU - Hartman, Catharina A.

AU - Franke, Barbara

AU - Sprooten, Emma

AU - Homberg, Judith R.

AU - Buitelaar, Jan K.

N1 - Funding Information: This work was supported by a Donders Center for Neuroscience Radboud Nijmegen University Medical Center junior researcher round grant [grant number N.A., 2016]. The NeuroIMAGE project was supported by grants from National Institutes of Health (grant R01MH62873 to SV Faraone) for initial sample recruitment, and from NWO Large Investment (grant 1750102007010 to JK Buitelaar), NWO Brain & Cognition (grant 433-09-242 to JK Buitelaar), and grants from Radboud University Medical Center , University Medical Center Groningen, Accare , and VU University Amsterdam for subsequent assessment waves. NeuroIMAGE also received funding from the European Community's Seventh Framework Programme ( FP7/2007–2013 ) under grant agreements n° 602805 (Aggressotype), n° 278948 (TACTICS), and n° 602450 (IMAGEMEND), and from the European Community's Horizon 2020 Programme ( H2020/2014–2020 ) under grant agreements n° 667302 (CoCA) and n° 728018 (Eat2beNICE). We would like to thank Marina Hakobjan and Angelien Heister, Radboud University Nijmegen Medical Center, for providing details regarding the genotyping procedure. Funding Information: This work was supported by a Donders Center for Neuroscience Radboud Nijmegen University Medical Center junior researcher round grant [grant number N.A. 2016]. The NeuroIMAGE project was supported by grants from National Institutes of Health (grant R01MH62873 to SV Faraone) for initial sample recruitment, and from NWO Large Investment (grant 1750102007010 to JK Buitelaar), NWO Brain & Cognition (grant 433-09-242 to JK Buitelaar), and grants from Radboud University Medical Center, University Medical Center Groningen, Accare, and VU University Amsterdam for subsequent assessment waves. NeuroIMAGE also received funding from the European Community's Seventh Framework Programme (FP7/2007?2013) under grant agreements n? 602805 (Aggressotype), n? 278948 (TACTICS), and n? 602450 (IMAGEMEND), and from the European Community's Horizon 2020 Programme (H2020/2014?2020) under grant agreements n? 667302 (CoCA) and n? 728018 (Eat2beNICE). We would like to thank Marina Hakobjan and Angelien Heister, Radboud University Nijmegen Medical Center, for providing details regarding the genotyping procedure. Publisher Copyright: © 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/8/30

Y1 - 2021/8/30

N2 - Serotonin (5-HT) is an important factor for prenatal neurodevelopment whereby its neurotrophic actions can be regulated through maternal-fetal interactions. We explored if maternal 5-HTTLPR genotype is associated with clinical and cognitive measures of attention-deficit/hyperactivity disorder (ADHD) and comorbid autism spectrum disorder (ASD) in typically-developing and ADHD-diagnosed offspring, beyond classical inheritance and environmental- and comorbidity-mediators/confounders. Family-based variance decomposition analyses were performed incorporating 6–31 year-old offsprings' as well as parental genotypes of 462 ADHD and control families from the NeuroIMAGE cohort. Dependent measures were offsprings' ADHD symptom- and ASD trait-scores and cognitive measures including executive functioning (including response inhibition and cognitive flexibility), sustained attention, reward processing, motor control, and emotion recognition. Offsprings' stereotyped behavior was predicted by an interaction between maternal 5-HTTLPR genotype and offsprings' sex. Furthermore, offspring of mothers with low-expressing genotypes demonstrated larger reward-related reductions in reaction time. While specifically adult male offspring of these mothers reported a faster reversal learning with less errors, specifically young female offspring of these mothers were more accurate in identifying happy faces. Adult offspring from the mothers with low-expressing 5-HTTLPR genotypes were also slower in identifying happy faces. However, this association seemed to be mediated by offsprings' high anxiety levels. In sum, we found some support for a role of the maternal 5-HT system in modulating fetal brain development and behavior. Offsprings' cognitive measures might be more sensitive to small alterations within the maternal 5-HT system than their ADHD and ASD clinical phenotypes. Further studies are needed to specify the association between maternal genotype and risk for neurodevelopmental disorders.

AB - Serotonin (5-HT) is an important factor for prenatal neurodevelopment whereby its neurotrophic actions can be regulated through maternal-fetal interactions. We explored if maternal 5-HTTLPR genotype is associated with clinical and cognitive measures of attention-deficit/hyperactivity disorder (ADHD) and comorbid autism spectrum disorder (ASD) in typically-developing and ADHD-diagnosed offspring, beyond classical inheritance and environmental- and comorbidity-mediators/confounders. Family-based variance decomposition analyses were performed incorporating 6–31 year-old offsprings' as well as parental genotypes of 462 ADHD and control families from the NeuroIMAGE cohort. Dependent measures were offsprings' ADHD symptom- and ASD trait-scores and cognitive measures including executive functioning (including response inhibition and cognitive flexibility), sustained attention, reward processing, motor control, and emotion recognition. Offsprings' stereotyped behavior was predicted by an interaction between maternal 5-HTTLPR genotype and offsprings' sex. Furthermore, offspring of mothers with low-expressing genotypes demonstrated larger reward-related reductions in reaction time. While specifically adult male offspring of these mothers reported a faster reversal learning with less errors, specifically young female offspring of these mothers were more accurate in identifying happy faces. Adult offspring from the mothers with low-expressing 5-HTTLPR genotypes were also slower in identifying happy faces. However, this association seemed to be mediated by offsprings' high anxiety levels. In sum, we found some support for a role of the maternal 5-HT system in modulating fetal brain development and behavior. Offsprings' cognitive measures might be more sensitive to small alterations within the maternal 5-HT system than their ADHD and ASD clinical phenotypes. Further studies are needed to specify the association between maternal genotype and risk for neurodevelopmental disorders.

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KW - 5-HTTLPR

KW - rs25531

KW - Attention-deficit

KW - hyperactivity disorder

KW - Autism spectrum disorder

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Maternal serotonin transporter genotype and offsprings' clinical and cognitive measures of ADHD and ASD

Abstract

Bibliographical note

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Keywords

UN SDGs

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