Abstract
Background
Studies investigating the effects of prenatal alcohol exposure on childhood attention-deficit hyperactivity disorder (ADHD) symptoms using conventional observational designs have reported inconsistent findings, which may be affected by unmeasured confounding and maternal and fetal ability to metabolize alcohol. We used genetic variants from the alcohol metabolizing genes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), as proxies for fetal alcohol exposure to investigate their association with risk of offspring ADHD symptoms around age 7–8 years.
Methods
We used data from 3 longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Generation R study (GenR), and the Norwegian Mother, Father and Child Cohort study (MoBa). Genetic risk scores (GRS) for alcohol use and metabolism using 36 single nucleotide polymorphisms (SNPs) from ADH and ALDH genes were calculated for mothers (NALSPAC=8,196; NMOBA=13,614), fathers (NMOBA=13,935), and offspring (NALSPAC=8,237; NMOBA=14,112; NGENR=2,661). Associations between maternal GRS and offspring risk of ADHD symptoms were tested in the full sample to avoid collider bias. Offspring GRS analyses were stratified by maternal drinking status.
Results
The pooled estimate in maternal GRS analyses adjusted for offspring GRS in ALSPAC and MoBa was OR = 0.99, 95%CI 0.97–1.02. The pooled estimate in offspring GRS analyses stratified by maternal drinking status across all the cohorts was as follows: ORDRINKING = 0.98, 95% CI 0.94–1.02; ORNO DRINKING = 0.99, 95% CI 0.97–1.02. These findings remained similar after accounting for maternal genotype data in ALSPAC and maternal and paternal genotype data in MoBa.
Conclusions
We did not find evidence for a causal effect of fetal alcohol exposure on risk of ADHD symptoms in offspring. The results may be affected by limited power to detect small effects and outcome assessment.
Studies investigating the effects of prenatal alcohol exposure on childhood attention-deficit hyperactivity disorder (ADHD) symptoms using conventional observational designs have reported inconsistent findings, which may be affected by unmeasured confounding and maternal and fetal ability to metabolize alcohol. We used genetic variants from the alcohol metabolizing genes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), as proxies for fetal alcohol exposure to investigate their association with risk of offspring ADHD symptoms around age 7–8 years.
Methods
We used data from 3 longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Generation R study (GenR), and the Norwegian Mother, Father and Child Cohort study (MoBa). Genetic risk scores (GRS) for alcohol use and metabolism using 36 single nucleotide polymorphisms (SNPs) from ADH and ALDH genes were calculated for mothers (NALSPAC=8,196; NMOBA=13,614), fathers (NMOBA=13,935), and offspring (NALSPAC=8,237; NMOBA=14,112; NGENR=2,661). Associations between maternal GRS and offspring risk of ADHD symptoms were tested in the full sample to avoid collider bias. Offspring GRS analyses were stratified by maternal drinking status.
Results
The pooled estimate in maternal GRS analyses adjusted for offspring GRS in ALSPAC and MoBa was OR = 0.99, 95%CI 0.97–1.02. The pooled estimate in offspring GRS analyses stratified by maternal drinking status across all the cohorts was as follows: ORDRINKING = 0.98, 95% CI 0.94–1.02; ORNO DRINKING = 0.99, 95% CI 0.97–1.02. These findings remained similar after accounting for maternal genotype data in ALSPAC and maternal and paternal genotype data in MoBa.
Conclusions
We did not find evidence for a causal effect of fetal alcohol exposure on risk of ADHD symptoms in offspring. The results may be affected by limited power to detect small effects and outcome assessment.
Original language | English |
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Pages (from-to) | 2090-2102 |
Number of pages | 13 |
Journal | Alcoholism: Clinical and Experimental Research |
Volume | 45 |
Issue number | 10 |
Early online date | 6 Sept 2021 |
DOIs | |
Publication status | E-pub ahead of print - 6 Sept 2021 |
Bibliographical note
Funding Information:The general design of Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfare and Sport, and the Ministry of Youth and Families. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR‐MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The generation and management of GWAS genotype data for the Generation R Study were done at the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, The Netherlands. We would like to thank Karol Estrada, Dr. Tobias A. Knoch, Anis Abuseiris, Luc V. de Zeeuw, and Rob de Graaf, for their help in creating GRIMP, BigGRID, MediGRID, and Services@MediGRID/D‐Grid (funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A‐H, 01 IG 07015 G) for access to their grid computing resources. We thank Mila Jhamai, Manoushka Ganesh, Pascal Arp, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters for their help in creating, managing, and QC of the GWAS database. Also, we thank Karol Estrada for their support in creation and analysis of imputed data.
Funding Information:
We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant‐acknowledgements.pdf ). GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. This research was performed in the UK Medical Research Council Integrative Epidemiology Unit (grant number MC_UU_00011/7) and also supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. LZ was supported by a UK Medical Research Council fellowship (grant number G0902144). HMS is supported by the European Research Council (Grant ref: 758813 MHINT). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. This research was also conducted as part of the CAPICE (Childhood and Adolescence Psychopathology: unraveling the complex etiology by a large Interdisciplinary Collaboration in Europe) project, funded by the European Union’s Horizon 2020 research and innovation program, Marie Sklodowska Curie Actions—MSCA‐ITN‐2016—Innovative Training Networks under grant agreement number 721567.
Funding Information:
The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this ongoing cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high‐quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (NRC) (#229624). We also thank the NORMENT Centre for providing genotype data, funded by NRC (#223273), South East Norway Health Authority, and KG Jebsen Stiftelsen. Furthermore, we thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, NRC, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway health Authorities (Helse Vest). The South‐Eastern Norway Regional Health Authority supported AH (#2018059 & #2020022). The Norwegian Research Council supported EY (#262177 & #288083), OAA (RCN# 273291 & 223273), TRK (#274611), and AH (#274611 & #288083).
Publisher Copyright:
© 2021 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcoholism.
Keywords
- Fetal alcohol exposure
- ADHD
- ALSPAC
- GENR
- MOBA