We and others have previously shown that the dopamine D4 exon III repeat (D4DR) and the serotonin-transporter promoter region (5-HTTLPR) polymorphisms are not only associated with adult personality traits 1-7 but also with temperament in 2-week-old neonates. 8 We now report the results of a second study of these infants and their temperament at 2 months using Rothbart's Infant Behavior Questionnaire (IBQ).9 There were significant negative correlations between neonatal orientation and motor organization as measured by the Neonatal Behavioral Assessment Scale (NBAS) 10 at 2 weeks and negative emotionality, especially distress in daily situations, at 2 months of age. There were significant main effects for negative emotionality and distress when the infants were grouped by the D4DR and the 5-HTTLPR polymorphisms. Infants with long D4DR alleles had significantly lower scores on Negative Emotionality These infants showed most negative emotionality and most distress to daily situations, temperament traits that are perhaps the underpinning of adult neuroticism.The initial findings of associations between D4DR and adult Novelty Seeking 1,6 and 5-HTTLPR and Neuroticism or Harm Avoidance 5 fueled a number of similar investigations some of which did not corroborate these associations across cultural and ethnic groups. [11][12][13][14][15] We postulated that genetic effects on personality might be more clearly understood by studying the first expressions of personality, that is, infant temperament. In order to study the association between temperament and specific genetic polymorphisms, we initiated a longitudinal study of human temperament. We 8 examined a group of infants shortly after birth using the Brazelton Neonatal Assessment Scale (NBAS).10 Cord blood was collected at birth and DNA is available for these subjects. Significant multivariate and univariate main effects were observed for D4DR on four temperament clusters. Infants with long D4DR alleles received higher scores on these clusters than infants with short D4DR alleles. There was also a significant interaction between D4DR and 5-HTTLPR. The effect of s/s 5-HTTLPR was to lower the scores on the orientation cluster for the group of neonates lacking long D4DR alleles. Orientation is a behavioral cluster reflecting alertness and visual and auditory orienting behavior in neonates perhaps akin to adult Novelty Seeking.We are continuing to follow the development of these infants and have now assessed their temperament at 2 months of age using Rothbart's Infant Behavior Questionnaire (IBQ). 9 In the current report we examined the relationship between neonatal behavior and 2-month temperament and the association between two genetic polymorphisms, D4DR and 5-HTTLPR, and temperament at 2 months. All statistical tests were carried out using Statistica or SPSS for Windows. Analyses were based on the classification of the D4DR genotype into long (6-8) and short (2-5) repeats which we also used for the neonatal study. 8 We have discussed in some detail the rationale justific...
Genetic effects on behavior were evaluated at a time in early development when we hypothesized that environmental influences are minimal and least likely to confound associations between temperament and genes. The behavioral effects of two common polymorphisms linked respectively in some, but not all, studies to novelty seeking (dopamine D4 receptor -D4DR) and neuroticism and harm avoidance (serotonin transporter promoter region -STPR) were examined in a group of 81 two-week-old neonates. Neonate temperament was evaluated using the Brazelton neonatal assessment scale (NBAS). Multivariate tests of significance showed a significant association of D4DR across four behavioral clusters pertinent to temperament including orientation, motor organization, range of state and regulation of state. A significant multivariate interaction was also observed between D4DR and STPR. The effect of the homozygous short STPR genotype (s/s) was to lower the orientation score for the group of neonates lacking the long form (L) of D4DR. When adult subjects were grouped by the STPR polymorphism there is no significant effect of L-D4DR in those subjects homozygous for the STPR short form (s/s) whereas in the group without the homozygous genotype the effect of L-D4DR is significant and accounts for 13% of the variance in novelty seeking scores between groups.
The dopamine D4 receptor (DRD4) exon III polymorphism has generated interest because of its association with attention deficit hyperactivity disorder (ADHD), with an increased frequency of the seven-repeat allele being reported in children with ADHD. Deficits in sustained attention and information processing characterize ADHD, and individual differences in these functions are apparent from infancy. We found that in a structured play situation and on an information-processing task, 1-year-old infants with the 7-DRD4 allele showed less sustained attention and novelty preference than do infants without the 7-DRD4 allele. There was also a significant interaction between DRD4 and the serotonin transporter promoter (5-HTTLPR) gene on a measure of sustained attention. Our results provide evidence for a possible developmental link between DRD4 and ADHD via early sustained attention and information processing. It also points to the importance of considering the influence of more than one gene in studies of behavior.
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