Catechol-O-methyltransferase Val158Met genotype moderates the effect of disorganized attachment on social development in young children

Children with histories of disorganized attachment exhibit diverse problems, possibly because disorganization takes at least two distinctive forms as children age: controlling–punitive and controlling–caregiving. This variation in the developmental legacy of disorganization has been attributed primarily to variations in children's rearing experiences. Here an alternative explanation of these divergent sequelae of disorganization is evaluated: one focused on genotype. Structural equation modeling was applied to data on 704 Norwegian children to test whether the catechol-O-methyltransferase Val158Met genotype moderates the effect of disorganized attachment, which was measured dimensionally at 4 years of age using the Manchester Child Attachment Story Task, on changes in aggressive behavior and social competence from ages 4 to 6. Children who scored high on disorganization and were homozygous for the valine allele displayed significantly greater increases in aggression and decreases in self-oriented social skills (e.g., self-regulation and assertiveness) over time than did their disorganized counterparts carrying the methionine allele, whereas disorganized children carrying the methionine allele increased their other-oriented social skill (e.g., cooperation and responsibility) scores more than did valine-homozygous children. These results are consistent with the controlling–punitive and controlling–caregiving behaviors observed in disorganized children, suggesting that the children's genotype contributed to variations in the social development of disorganized children.

The Valine Allele of the V89L Polymorphism in the 5-α-Reductase Gene Confers a Reduced Risk for Hypospadias

Context: Hypospadias is one of the most common malformations in man, with an incidence of 1:300 in newborn boys. No gene has been identified that causes isolated hypospadias, but the androgenic influence is important during male genital development. Objective: A key enzyme for the androgenic function is steroid 5-α-reductase (SRD5A2). The V89L polymorphism in the SRD5A2 gene has been studied and found to be of functional importance. The leucine version of the enzyme is 30% less efficient than the valine variant. Design, Setting, Patients, and Results: We have genotyped 158 hypospadias cases and 96 unaffected controls for this polymorphism and found a significant negative association for the V89 allele in hypospadias (odds ratio, 0.24; 95% confidence interval, 0.14–0.41 for homozygous individuals). This indicates that a fully functional 5-α-reductase enzyme (homozygous for V89) protects the male urethral development. This association is shown regardless of heredity, ethnicity, and severity of phenotype. We have also sequenced a selected material of 37 sporadic cases of more severe hypospadias for mutations in the androgen receptor AR, SRD5A2, and 17β-hydroxysteroid dehydrogenase HSD17B3 genes and found only two previously described mutations, one in the AR and one in the SRD5A2 gene. Conclusion: This finding is in accordance with the assumption that functional polymorphisms may play an important role in complex disorders such as hypospadias when several genes as well as environmental factors contribute to the etiology.