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

Abstract

Keywords: DRD4 exon III VNTR polymorphism; −521 C/T promoter polymorphism; attachment disorganization; dopamineIn non-clinical low-risk populations 15% of infants show disorganized attachment behavior 1,2 with their caregivers in the Strange Situation, 3 a mildly stressful laboratory procedure testing infants' ability to cope with separation anxiety. Disorganization of early attachment has been primarily ascribed to inadequate parenting, 2,4,5 and has been associated with childhood behavior problems 6,7 and adolescent psychopathological tendencies. 5We have recently reported an association between the DRD4 exon III 48 basepair repeat polymorphism and disorganization of infants' attachment behavior towards their mother in a low-social-risk group of 1-year-old infants: 8 the risk for disorganized attachment among infants carrying the 7-repeat allele was fourfold. Here we report further evidence for the involvement of the dopamine D4 receptor gene in attachment disorganization. The same group of infants was genotyped for the functional −521 C/T single nucleotide polymorphism (SNP) in the upstream regulatory region of the DRD4 gene 9 in order to test the association with attachment disorganization both alone and in interaction with the DRD4 exon III 7-repeat allele. While the −521 C/T genotype itself had no effect on attachment status ( 2 = 0.41, df = 2, P = 0.82), there was an interaction between the structural 48-bp repeat polymorphism and the −521 C/T promoter polymorphism: the association between disorganized attachment and the 7-repeat allele was enhanced in the presence of the −521 T allele ( 2 = 6.61 and 6.67, df = 1, P Ͻ 0.025 for CT and TT genotypes, respectively). In the presence of both risk alleles the odds ratio for disorganized attachment increased tenfold. This result supports our previous postulation that the DRD4 gene plays a role in the development of attachment behavior in low-risk, non-clinical populations. Molecular Psychiatry (2002) 7, 27-31. DOI: 10.1038/ sj/mp/4000986The role of dopamine receptor and transporter genes in both normal traits and psychopathology has been intensively studied in the past decade.10,11 One of the most frequently targeted candidate genes is the highly polymorphic dopamine D4 receptor (DRD4) gene. 12,13A 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. 19-21Recently, we found that the 7-repeat DRD4 allele was 2.5 times more frequent among one-year-old infants who showed disorganized attachment behavior, ie were unable to cope with the stress elicited by the two brief separations from the caregiver in the Strange Situation exper...

An Attachment Perspective on Borderline Personality Disorder: Advances in Gene–Environment Considerations

“…The attachment disorganization and DRD4 work was recently summarized well by Bernier and Meins [43], who posited a threshold approach to disorganization, arguing that when enough risk factors are encountered (genetic and environmental), disorganization results. A sample of Hungarian infants reported on by Gervai et al [44] and Lakatos et al [45,46] suggested that the 7-repeat DRD4 gene polymorphism could be a risk factor for disorganized attachment; specifically, the 7-repeat allele was observed in 71% of disorganized children in this sample, compared with only 29% of nondisorganized children. Further examination of the same sample revealed that this association was substantially enhanced when children also carried the -521T allele in the promoter region of the DRD4 gene [46].…”

“…A sample of Hungarian infants reported on by Gervai et al [44] and Lakatos et al [45,46] suggested that the 7-repeat DRD4 gene polymorphism could be a risk factor for disorganized attachment; specifically, the 7-repeat allele was observed in 71% of disorganized children in this sample, compared with only 29% of nondisorganized children. Further examination of the same sample revealed that this association was substantially enhanced when children also carried the -521T allele in the promoter region of the DRD4 gene [46]. Children carrying both the 7-repeat allele and the -521T allele were 10 times more likely to present with disorganized attachment than their counterparts who carried neither risk allele.…”

“…Children carrying both the 7-repeat allele and the -521T allele were 10 times more likely to present with disorganized attachment than their counterparts who carried neither risk allele. Thus far, two Dutch reports have attempted to replicate the findings of Lakatos et al [46], and both failed to find a direct link between the DRD4 gene and disorganized attachment, whether with twin infants [47] or singletons [48]. However, van IJzendoorn and Bakermans-Kranenburg [48] reported provocative findings showing how parental features measured via the AAI can interact with genetic risk in a child to make disorganization much more likely.…”

Mesocorticolimbic dopamine functioning in primary psychopathy: A source of within-group heterogeneity

“…Infants carrying 7R-alleles might have more difficulty in adapting flexibly to irregular, abusive, or erratic parenting, which can then result in confusion and disorganization of attachment schemas. Indeed, prevalence of disorganized attachment is more than fourfold increased in children carrying the 7R-allele (Lakatos et al, 2000(Lakatos et al, , 2002Gervai et al, 2005;Van Ijzendoorn and Bakermans-Kranenburg, 2006;Gervai et al, 2007;Bakermans-Kranenburg et al, 2011). These findings are not consistent, however, and some studies report no associations between DRD4 genotypes and attachment (Luijk et al, 2011), while other demonstrate a positive association between the 7R-allele and secure attachment (Reiner and Spangler, 2010;Das et al, 2011).…”

Polymorphic Markers of the Dopamine D4 Receptor Gene Promoter Region and Personality Traits in Mentally Healthy Individuals from the Russian Population

“…Studying markers VNTR and -521 C/T and the novelty seeking trait in the Korean population including only females, Lee et al [9] showed that these parameters were higher in carriers of the C allele in the presence of the long VNTR allele. Lakatos et al [10] reported joint effect of these polymorphic markers on temperament traits in their study of attachment disorganization in infants. In a study of the combined effect of polymorphic markers -616 G/T and -521 C/T on variation of another trait correlating with novelty seeking, extraversion, in African Americans, Bookman et al [11] detected association of the CC genotype ( -521 C/T ) only in women.…”