Preliminary analyses were performed for age, socioeconomic status, IQ, body mass index, hand preference, and ICV by risk group, gender, and risk × gender (). Psychiatric diagnoses by risk group were also analyzed ( and ). The HR offspring from multiplex families were more likely to have a lifetime childhood/adolescent or young adult disorder than control subjects, consistent with data from the larger sample (29
Results of our primary analysis revealed a significant difference by risk group for the right/left ratios adjusting for ICV, age, hand preference, and previous SUD diagnosis [F(1,100) = 9.95, p = .002] (). The OFC ratios were larger for low-risk than HR offspring (adjusted means = 2.92 × 10−5 ± 3.33 × 10−5 cm3 versus .82 × 10−5 ± 3.32 × 10−5 cm3). Three univariate analyses were performed for right volume (total, grey, and white), adjusting for left volume, ICV, age, handedness, and SUD. For total volume, risk was significant [F(1,98) = 10.44, p = .002] as was risk × gender F [ (1,98) = 5.05, p = .02]. For grey, risk was significant [F(1,97) = 9.36, p = .003]. For white, risk was significant [F(1,97) = 4.96, p = .028], as was risk × gender [F(1,97) = 5.32, p = .023].
Figure 2 Orbitofrontal cortex (OFC) ratios were determined for each participant with the formula Right − Left/Right + Left. Volumes were adjusted for intracranial volume (ICV) before statistical analyses were performed. Depicted here are the adjusted means (more ...)
Because personal exposure to alcohol and drugs or the presence of psychiatric disorders might explain the familial risk group differences seen, analyses were performed removing cases with anxiety or depression (n = 38) or SUD (n = 22). Risk group differences remain significant for total right volume adjusting for left, age, and handedness [F(1,62) = 4.62, p = .04] and for risk × gender [F(1,62) = 4.37, p = .04] when cases with anxiety or depression are removed. Similarly, removal of SUD cases shows that risk remains significant [F(1,78) = 8.98, p = .004], as does risk × gender [F(1,78) = 4.91, p = .03].
We hypothesized that reduced volume of the right OFC in the HR group might reflect a developmental delay in reaching age-appropriate volume. To test this, right/left ratios were regressed on age and slopes were tested to determine if they differed from zero. For the female sample (n
= 50), the slope did not differ from zero, remaining approximately the same with age (see ). In contrast, the relationship between age and the OFC ratios for the male sample (n
= 57) showed a significant effect, with right/left ratios increasing with age for the HR male subjects only [t
) = 4.10, p
= .001; see ].
Regression lines for orbitofrontal cortex (OFC) ratios for female participants show a relatively flat progression from childhood to young adulthood.
Figure 4 Regression lines for orbitofrontal cortex (OFC) ratios for male participants show a relatively flat progression from childhood to young adulthood for control subjects. In contrast, high-risk male subjects appears to show increased volume in the right (more ...)
We hypothesized that genotypic variation in 5-HTT and the BDNF might explain the differing risk-group OFC ratios that reflect reduced right hemisphere volume. A significant interaction between the presence of the S allele of the 5-HTT gene and the Met allele of the VAL/Met variation of the BDNF gene was seen in association with volume of the OFC in the right hemisphere (Right − Left)/(Right + Left), corrected for ICV, for the 87 participants. For total volume, the BDNF × 5-HTT × risk interaction was significant [F(1,77) = 5.55, p = .021], although no main effects of either gene were seen. This interaction was also significant for white [F(1,77) = 4.92, p = .03] and for grey F [ (1,77) = 4.16, p = .045] volumes. An analysis restricted to the 57 HR participants was also significant [F(1,51) = 6.32, p = .015] ().
Figure 5 A statistically significant association between the presence of the S allele of the serotonin transporter (5-HTT) gene, the Met allele of the VAL/Met variation of the brain-derived neurotrophic factor gene and volume of the orbitofrontal cortex (OFC) (more ...)
To test the possible contribution of right OFC volume to behavioral disinhibition, partial correlations were performed for right OFC volume (total, white, grey) and Control scale scores adjusting for left OFC volume and age. A highly significant relationship between Control scale scores and right OFC white matter [r(74) = .36, p = .001] was seen along with a significant relationship with grey matter [r(74) = .28, p = .01], although total right OFC volume was not significantly related to Control scale scores. Because white matter volume in the right hemisphere shows a greater age-related change in HR male subjects than in low-risk control subjects (), it seems likely that delay in attaining white matter volumes for age in HR male subjects could result in greater disinhibited behavior for age. Collectively, the present results provide an empirical model () that would predict a relationship between genetic variation, right OFC volume, and Control scale scores.
Figure 6 The growth in volume seen in high-risk male subjects () is largely due to increases in white matter volume. Orbitofrontal cortex (OFC) white matter volumes show a statistically significant correlation with Multidimensional Personality Questionnaire (more ...)
Figure 7 This empirically derived model suggests that developmental change in right orbitofrontal cortex (OFC) volume is influenced by the interaction of serotonin transporter (5-HTT) and brain-derived neurotrophic factor (BDNF) genes, which leads to developmental (more ...)
A mixed model analysis was performed to test the main effect of the presence of any short allele of the 5-HTT polymorphism, any Met allele, and their interaction on Control scale scores, adjusting for age and gender. A significant relationship between the presence of the short 5-HTT allele and Control scores was seen [F(1,69) = 7.15, p = .009], as was the relationship between the BDNF allele and Control [F(1,69) = 4.51, p = .037], although the interaction of the two genes was not significant. However, including risk with the two genes showed a significant interaction between the BDNF gene and risk in prediction of Control scale scores [F(1,65) = 8.79, p = .004].