Abstract:
Background: Being small for gestational age (SGA) is a risk factor for a wide range of adverse neurobiological outcomes, including Attention Deficit Hyperactivity Disorder (ADHD). It is currently unclear how exposure to a suboptimal prenatal environment (proxy for SGA) moderates genetic risk for ADHD. In childhood, symptoms of ADHD have been reported as unstable, with limited knowledge on what contributes to this instability. This study involved two primary aims: (1) to investigate whether being born SGA moderated associations between single nucleotide polymorphisms (SNP) within the dopamine transporter gene (SLC6A3/DAT1) and increased symptoms of ADHD (sADHD); and (2) to ascertain predictors of ADHD symptoms over two time periods (age 7 and age 11). Method: Data were obtained via the Auckland Birth weight Collaborative longitudinal study. In the first study, a total of 546 children of white European descent were successfully genotyped at age 11 for seven DAT1 SNPs (rs6347, rs11564774, rs40184, rs1042098, rs2702, rs8179029 and rs3863145). The parent version of the Strengths and Difficulties Questionnaire was used to measure sADHD at ages 3.5, 7 and 11. An ANCOVA was used to determine associations between DAT1SNPs and sADHD in each age group. The second study used the parent version of the Conner’s Behavioral Rating Scale Revised Long format to measure sADHD at ages 7 and 11. A repeated measures ANCOVA was used to determine predictors at two time points (age 7 and age 11) and a logistic regression was used to determine predictors of sADHD at age 11. Results: The results found significant gene-environment interactions between birth weight status and DAT1 SNPs (rs40184, rs3863145, rs6347 and rs1042098) on sADHD at 3.5 years. A novel finding that certain DAT1 genotypes in SGA infants may confer a potential protective effect against sADHD in early childhood was also found. In the second study the following variables were found to significantly explain a decrease in sADHD from age 7 to 11: maternal age; gender; marital status; and behaviour problems at 3.5 years. In an adjusted analysis, ii behavioural problems at age 3.5 and low average sleep duration at 7 were found to significantly predict increased sADHD at age 11. Conclusion: Taken together, these findings may suggest that exposure to a suboptimal prenatal environment moderates the effect of DAT1 variants on the risk for sADHD in early childhood. These results are discussed in terms of the differential susceptibility framework, whereby certain DAT1 genotypes may be more responsive to particular environmental influences. Early detection of emotional and behavioural problems as predictors of sADHD at age 11, imply the potential to use early detection measures to identify at risk children. The explanation of decreasing sADHD according to biological and maternal variables could provide insights into the cumulative impact of these variables throughout development. Overall, these findings help to explain some of the heterogeneity in ADHD outcomes for children born SGA and add to the current knowledge of pre and postnatal determinants of sADHD.