Maternal and child genetic liability for smoking and caffeine consumption and child mental health: An intergenerational polygenic risk score analysis in the ALSPAC cohort

Background and aims: Previous studies suggest an association between maternal tobacco and caffeine consumption during and outside of pregnancy and offspring mental health. We used an intergenerational polygenic risk scores (PRS) approach to disentangle effects of the maternal environment (intrauterine or postnatal) and pleiotropic genetic effects. Specifically, we 1) validated smoking and caffeine PRS derived from published GWAS for use during pregnancy, 2) compared estimated effects of maternal and offspring PRS on childhood mental health outcomes, and 3) tested associations between maternal and offspring PRS on their own outcomes. Design: PRS were created for smoking and caffeine consumption for 8,196 mothers and 8,237 offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC). Outcomes included mostly mental health and some non-mental health phenotypes (I.e. substance use, personality, BMI and sociodemographic variables). For mothers, 79 phenotypes assessed during and outside of pregnancy, and for offspring, 71 phenotypes assessed in childhood (<10 years) and adolescence (11-18 years) were included. Linear and logistic regressions were run to assess PRS in relation to maternal and offspring phenotypes. Findings: First, the maternal smoking and caffeine PRS were associated with these behaviours during pregnancy. Second, the maternal and offspring smoking PRS both showed evidence (permutation corrected P < 0.05) of association with reduced anxiety symptoms in childhood ({beta}maternal = -0.033; {beta}offspring= -0.031) and increased conduct disorder symptoms ({beta}maternal= 0.024; {beta}offspring= 0.030). Finally, the maternal and offspring smoking PRS were associated with own sensation seeking phenotypes in mothers and adolescence (e.g. increased symptoms of externalising disorders, extraversion, and monotony avoidance), but the caffeine PRS showed weaker evidence for associations with mental health outcomes. Our results indicate that the smoking PRS is most likely pleiotropic with sensation seeking personality traits. However, these results need replication in independent samples, using techniques more robust to pleiotropy.