Bibian van der Voorn

115 GR/MR VARIATION ON IQ & BEHAVIOR AFTER PREMATURITY a poorer IQ-score. In addition, the R23K SNP was associated with a more favorable parent-reported total problembehavior score and the I180VSNPwithamore favorable internalizing behavior score. Interaction between the GR and MR polymorphisms and antenatal exposure to synthetic glucocorticoids was observed, with poorer IQ-scores for exposed N363S carriers and I180V carriers and more favorable total problem behavior score for exposed R23K carriers. Antenatal glucocorticoid treatment was associated with more unfavorable behavior, especially internalizing behavior, but not with IQ. Previous follow-up studies in this cohort 23,24 showed, similar to other studies in preterm survivors 2,27,28 , poorer cognitive functioning and more unfavorable internalizing behavior, with male subjects being disadvantaged. In animals, antenatal glucocorticoid treatment was found to affect the limbic system, primarily the hippocampus 3,4,12 . Antenatal exposure to synthetic glucocorticoids was associated with a decreased hippocampal volume, degeneration and depletion of hippocampal neurons, reduced levels of GR and MR mRNA, cognitive deficits and increased anxiety- like and hypoactive behavior 12,29-31 . In humans, longitudinal studies assessing neurodevelopment after antenatal glucocorticoid treatment for fetal lung maturation are scarce 5 . The present study is the first to show that variation in GR and MR signaling contributes to cognitive and behavioral outcomes after preterm birth and might be augmented by the effects of antenatal glucocorticoid exposure. In human fetuses, both GRs and MRs are expressed in the limbic system as early as 24 weeks gestational age 30 . The MR mRNA expression appears to be high at the end of the second trimester and decreases through the third trimester. In contrast, the GR mRNA expression is low at the end of the second trimester and increases during the third trimester. These dissimilarities in the spatiotemporal distribution of GRs and MRs, as well as person-specific affinity for synthetic glucocorticoids, have the potential to affect neurodevelopment 12,13,32,33 . In general, GR and MR SNPs have been associated with depression, dementia, metabolism and body composition 14,15,34-38 . At 19 years of age, we found already associations between GR and MR SNPs and neurobiological outcomes in a population with a high risk of cognitive impairments and psychopathology. Furthermore, we found that a single antenatal course of glucocorticoids had an additional effect on these outcomes. Yet it is unknown whether these could be modulated by subsequent functioning of the HPA axis. The major strength of this study lies in the relatively large size of the cohort, given its unique nature. Another strength is that we assessed both parent- as well as self-