The catechol-O-methyltransferase (COMT) Val158Met polymorphism moderates the effect of antenatal stress on childhood behavioural problems: longitudinal evidence across multiple ages.

AIM: The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene was analysed to determine its association with maternal stress and childhood total difficulties. METHOD: Data were collected at birth from a group of infants who were born small for gestational age and a group who were born at an appropriate size for gestational age and had been enrolled in the Auckland Birthweight Collaborative Study. Children were followed up at the ages of 1 year, 3 years 6 months, 7 years, and 11 years. At the age of 11 years, DNA samples were collected from 546 children (270 females, 276 males): 227 children born small for gestational age and 319 children born at an appropriate size for gestational age. The main independent variable was perceived maternal stress at birth and at 7 and 11 years of age, assessed using the total difficulties scale of the Strength and Difficulties Questionnaire. IQ was assessed at the age of 7 years. RESULTS: Met/Met homozygotes were at a significantly increased risk of behavioural and emotional problems at the ages of 7 (p=0.002) and 11 years (p=0.003), relative to either heterozygous or homozygous carriers of the Val158Met polymorphism, but only when they were exposed to maternal stress in utero. Met/Met homozygotes had, on average, IQ scores that were four points higher than those of Val/Val homozygotes (p=0.010). INTERPRETATION: These findings emphasize the potential long-term consequences of prenatal stress for genetically susceptible individuals during neurodevelopment in utero. Our findings add to the general understanding of the aetiology and developmental nature of childhood emotional and behavioural problems.

Children born small for gestational age are not at special risk for preschool emotion and behaviour problems.

Despite the wealth of literature examining long term outcomes of preterm low birthweight children, few studies have directly assessed the developmental impact of being born full term but small for gestational age (SGA). We aim to determine whether (i) being SGA increases preschool behavioural problems and (ii) other risk factors operate differently in SGA and appropriate for gestational age (AGA) controls. 550 New Zealand European mothers and their 3.5 year old children participated in this study. All children were born at full term (>37 weeks' gestation) and approximately half were SGA (≤sex specific 10th percentile for gestation) the remainder were AGA controls. Extensive data were collected at the child's birth, 1 year and 3.5 years. Behavioural problems were measured when children were 3.5 years, using the Strengths and Difficulties Questionnaire (SDQ). Multiple regression analyses were used to examine the associations between risk factors and behavioural problems; statistical weighting was used for analyses of the total study group. There was no significant difference in behavioural problems between SGA and AGA groups. In the total sample the significant predictors of behavioural problems included: mothers' school leaving age; smoking during pregnancy; maternal alcohol use during pregnancy; and absence of the father. Predictors of behavioural problems were found to be the same for SGA and AGA groups. These results do not support the view that SGA is a risk for behavioural preschool difficulties or that SGA children are sensitised to risks known to be associated with such difficulties in the preschool years.

Initial evidence that polymorphisms in neurotransmitter-regulating genes contribute to being born small for gestational age.

Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined - that SGA marks pre-existing genetic risk for later problems.