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Maternal and offspring genetic risk score (GRS) analyses of fetal alcohol exposure and ADHD risk in offspring

By Elis Haan, Hannah M Sallis, Eivind Ystrom, Pal Rasmus Njolstad, Ole Andreassen, Ted Reichborn-Kjennerud, Marcus R Munafo, Alexandra Havdahl, Luisa Zuccolo

Posted 04 Apr 2021
medRxiv DOI: 10.1101/2021.03.30.21254492

Background: Studies investigating the effects of prenatal alcohol exposure on childhood ADHD symptoms using conventional observational designs have reported inconsistent findings, which may be affected by unmeasured confounding and maternal and fetal ability to metabolise alcohol. We used genetic variants from alcohol metabolising genes (alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)) as proxies for fetal alcohol exposure to investigate their association with offspring ADHD risk around age 7-8. Methods: We used data from three 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/ALDH genes were calculated for mothers (N_ALSPAC=8,196; N_MOBA=13,614), fathers (N_MOBA=13,935) and offspring (N_ALSPAC=8,237; N_MOBA=14,112; N_GENR=2,661). Associations between maternal GRS and offspring ADHD risk 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 the cohorts was: OR_DRINKING=0.98, 95%CI 0.94-1.02; OR_NO 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 ADHD risk in offspring. The results may be affected by low power and outcome assessment.

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