Association of D4 dopamine receptor gene and serotonin transporter promoter polymorphisms with infants' response to novelty

Abstract

Effects of DRD4 and 5-HTTLPR length polymorphisms have been reported on neonatal and infant temperament as well as adult personality traits. The 7-repeat form of the DRD4 III exon VNTR polymorphism has been associated with childhood ADHD, and recently we have reported its link with attachment disorganization in a nonclinical population of infants. Here, we report associations of these polymorphisms with infant temperament at 12 months of age. Maternal accounts of temperament and observed response to novelty were investigated for 90 infants, who were independently genotyped for the DRD4 III exon, and for 5-HTT-linked promoter region length polymorphisms. Maternal rating of temperament was not affected by these polymorphisms, but we found combined genotype effects for infants' observed responses to a novel, anxiety-provoking stimulus: the appearance of, and approach by, a stranger. Infants with at least one copy of both the 7-repeat DRD4 allele and the long variant of 5-HTTLPR (7 + , l/l&l/s) responded with significantly less anxiety than infants with other genotypes. However, infants with the 7-repeat DRD4 allele and homozygous for the short form of 5-HTTLPR (7 + , s/s) showed more anxiety and resistance to the stranger's initiation of interaction. These genotype effects were not redundant with the previously reported association between the 7-repeat DRD4 allele and disorganized attachment behavior. Although both temperament and attachment behavior were affected by the DRD4 repeat polymorphism, the effect on temperament measures was modified by the infants' 5-HTTLPR genotype. Molecular Psychiatry (2003) 8, 90-97.

Further evidence for the role of the dopamine D4 receptor (DRD4) gene in attachment disorganization: interaction of the exon III 48-bp repeat and the −521 C/T promoter polymorphisms

“…15 Evidence linking the 7-repeat allele of the DRD4 gene with infant temperament traits of negative emotionality [16][17][18] and maladaptive behavioral problems, especially attention deficit hyperactivity disorder (ADHD) in children, is being accumulated.…”

“…26,27 We have previously speculated about the role of potential genetic interaction between the structural and regulatory polymor- phisms in the mixed results of replication studies of effects of the DRD4 exon III VNTR polymorphism. 28 To investigate the possible effects of such an interaction on attachment behavior, 95 children (41 girls and 54 boys) participating in the longitudinal Budapest Infant Parent Study (BIPS), already genotyped for the 48-basepair repeat polymorphism in the third exon of the DRD4 gene, 8,17 were also genotyped for the −521 C/T SNP. Frequencies of the C and T alleles in the BIPS sample were 0.489 and 0.511, respectively (Table 1).…”

“…12,13 A 48-bp VNTR polymorphism has been identified in exon III with the 4-repeat allele being the most common, followed by the 7-repeat form 14 which is 2-3 times less potent in dopamine-mediated coupling to adenylyl cyclase than the 4-repeat form. 15 Evidence linking the 7-repeat allele of the DRD4 gene with infant temperament traits of negative emotionality [16][17][18] and maladaptive behavioral problems, especially attention deficit hyperactivity disorder (ADHD) in children, is being accumulated.…”

The molecular genetic architecture of human personality: beyond self-report questionnaires

“…117,[160][161][162][163][164][165] As we first noted, 164,165 the study of temperament traits in children offers the opportunity to study gene effects at a time in development when environmental effects are conjectured to be minimal and genetic associations might be more robustly demonstrated.…”

“…who examined a two-locus haplotype consisting of the exon III repeat and the C-521T promoter polymorphism in family trios studied for disorganized attachment (see Lakatos et al [115][116][117] for their earlier work and a Dutch study 118 that reported a failure to replicate the association between attachment and DRD4), an early behavioral measure related to temperament. These authors showed that the transmission bias in the larger secure attachment group of infants was because of the low-rate transmission of the C-521T 'T':exon 3 seven repeat haplotype, suggesting that not carrying this haplotype may act as a resilience factor in the optimal development of early attachment.…”