Allison L. Miller

IL23R R381Q and ATG16L1 T300A Are Strongly Associated With Crohn's Disease in a Study of New Zealand Caucasians With Inflammatory Bowel Disease

OBJECTIVE:Recently, separate genome-wide association analyses have identified nonsynonymous SNPs in IL23R and ATG16L1 (rs11209026; c1142G>A, R381Q, and rs2241880; c1338A>G, T300A, respectively) as strong candidate susceptibility factors for Crohns disease (CD) in whites. The aim of our study was to test whether these SNPs are associated with CD in a population-based cohort of New Zealand Caucasian inflammatory bowel disease (IBD) patients.METHODS:Allele frequencies of rs11209026 and rs2241880 were determined in 496 CD patients, 466 ulcerative colitis (UC) patients, and 591 controls. Distribution of the relevant alleles was compared between controls and IBD patients. rs11209026 and rs2241880 genotype distributions were examined both within IBD clinical subphenotypes and CARD15 genotypes.RESULTS:rs11209026 and rs2241880 were both associated with CD (P valuers11209026 = 0.0026, OR 0.54, 95% CI 0.36–0.81; P valuers2241880 = 0.0001, OR 1.41, 95% CI 1.18–1.67). In addition, there was evidence for association of rs11209026 with UC (P value = 0.037, OR 0.66, 95% CI 0.45–0.98). No significant association was observed between IL23R genotype or ATG16L1 genotype and IBD subphenotypes. IL23R was associated with CD and UC only in the absence of CARD15 mutations, whereas ATG16L1 was associated with CD in the presence and absence of CARD15 mutations.CONCLUSIONS:We replicated the previously reported associations between CD and rs11209026 and rs2241880, confirming that IL23R and ATG16L1 are susceptibility loci for CD in the New Zealand population. We also provide further evidence for association of rs11209026 with UC and a report of an additive effect between IL23R and CARD15 genotypes in CD.

Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein β3 subunit as predictors of response to fluoxetine and nortriptyline

In 169 depressed patients randomized to treatment with either fluoxetine or nortriptyline, we examined whether polymorphisms of the serotonin transporter and the G protein beta3 subunit influenced response to these antidepressants. For depressed patients under the age of 25 yr the T allele of the G protein beta3 subunit was associated with a markedly poorer response to nortriptyline, while serotonin transporter polymorphisms did not predict antidepressant response. However, in patients 25 yr or older, the G protein beta3 polymorphisms did not predict antidepressant response, while the s,s genotype of the serotonin transporter was associated with a poorer response to both fluoxetine and nortriptyline. These differential pharmacogenetic predictors of antidepressant response by age, may provide clues to understanding the discontinuities in pharmacological responsiveness of child/adolescent and adult depressive disorders.

MAOA, abuse exposure and antisocial behaviour: 30-year longitudinal study

BACKGROUND Recent studies have raised issues concerning the replicability of gene × environment (G × E) interactions involving the monoamine oxidase A (MAOA) gene in moderating the associations between abuse or maltreatment exposure and antisocial behaviour. This study attempted to replicate the findings in this area using a 30-year longitudinal study that has strong resemblance to the original research cohort. AIMS To test the hypothesis that the presence of the low-activity MAOA genotype was associated with an increased response to abuse exposure. METHOD Participants were 398 males from the Christchurch Health and Development Study who had complete data on: MAOA promoter region variable number tandem repeat genotype; antisocial behaviour to age 30; and exposure to childhood sexual and physical abuse. RESULTS Regression models were fitted to five antisocial behaviour outcomes (self-reported property offending; self-reported violent offending; convictions for property/violent offending; conduct problems; hostility) observed from age 16 to 30, using measures of childhood exposure to sexual and physical abuse. The analyses revealed consistent evidence of G × E interactions, with those having the low-activity MAOA variant and who were exposed to abuse in childhood being significantly more likely to report later offending, conduct problems and hostility. These interactions remained statistically significant after control for a range of potentially confounding factors. Findings for convictions data were somewhat weaker. CONCLUSIONS The present findings add to the evidence suggesting that there is a stable G × E interaction involving MAOA, abuse exposure and antisocial behaviour across the life course.

Moderating role of the MAOA genotype in antisocial behaviour

BACKGROUND Recent studies have examined gene×environment (G×E) interactions involving the monoamine oxidase A (MAOA) gene in moderating the associations between exposure to adversity and antisocial behaviour. The present study examined a novel method for assessing interactions between a single gene and multiple risk factors related to environmental and personal adversity. AIMS To test the hypothesis that the presence of the low-activity MAOA genotype was associated with an increased response to a series of risk factors. METHOD Participants were 399 males from the Christchurch Health and Development Study who had complete data on: (a) MAOA promoter region variable number tandem repeat genotype; (b) antisocial behaviour (criminal offending) to age 30 and convictions to age 21; and (c) maternal smoking during pregnancy, IQ, childhood maltreatment and school failure. RESULTS Poisson regression models were fitted to three antisocial behaviour outcomes (property/violent offending ages 15-30; and convictions ages 17-21), using measures of exposure to adverse childhood circumstances. The analyses revealed consistent evidence of G x E interactions, such that those with the low-activity MAOA variant who were exposed to adversity in childhood were significantly more likely to report offending in late adolescence and early adulthood. CONCLUSIONS The present findings add to the evidence suggesting that there is a stable G x E interaction involving MAOA, a range of adverse environmental and personal factors, and antisocial behaviour across the life course. These analyses also demonstrate the utility of using multiple environmental/personal exposures to test G×E interactions.

Association of a duplicated repeat polymorphism in the 5′‐untranslated region of the DRD4 gene with novelty seeking

Novelty Seeking (NS) is a human personality trait in which impulsive, exploratory, and thrill‐seeking behaviors are displayed. Dopaminergic genes have been prime candidates in the search for the genetic factors underlying NS because of the central role that dopamine plays in the brains reward system. We have investigated whether there is an association between a polymorphic 120 base pairs (bp) repeat that is located in the 5′‐untranslated region of the dopamine D4 receptor gene (DRD4) and NS. We genotyped four separate groups from psychiatric clinical studies for the repeat polymorphism. There were significant associations with NS in the groups of bipolar (P = 0.01) and alcoholic (P = 0.006) families containing 267 and 172 subjects, respectively. Subjects who were homozygous for the single‐copy allele (SS genotype) had higher mean NS scores. This trend was also observed in the two other studies that contained unrelated subjects diagnosed with depression (N = 143 and N = 148) but the associations between DRD4 duplication genotype and NS were not significant in these groups. In the data combined from all four clinical groups those genotyped as SS had higher mean scores for all four NS subscales with significant associations for impulsivity (P = 0.0006), extravagance (P = 0.04), disorderliness (P = 0.02), and total NS (P = 0.0003). However, given the low frequency of the single‐copy allele, this polymorphism would account for only a small proportion of the variance of NS in the population.

Polymorphisms of DRD4 and DRD3 and risk of avoidant and obsessive personality traits and disorders

We investigated whether polymorphisms of the dopamine D4 receptor (DRD4) and polymorphisms of the dopamine D3 receptor (DRD3) were associated with personality disorder symptomatology rather than with personality traits such as novelty seeking. DNA was obtained from 145 depressed patients in a clinical trial. These patients were assessed for the presence of personality disorder symptoms and disorders. The 2-repeat allele of the DRD4 exon III polymorphism was associated with increased rates of avoidant and obsessive personality disorder symptomatology. The T,T genotype of the DRD4 -521 C>T polymorphism was also associated with increased rates of avoidant and obsessive personality disorder symptomatology. The Gly9,Gly9 genotype of the DRD3 Ser9Gly polymorphism was associated with increased rates of obsessive personality disorder symptomatology. None of these three polymorphisms were associated with novelty seeking or other temperament traits on the Temperament and Character Inventory. Our results suggest that genetic polymorphisms of DRD4 and DRD3 may well be associated with personality traits, and that conflicting findings to date may arise from the problem of phenotype definition.

A polymorphism in the dopamine β-hydroxylase gene is associated with paranoid ideation in patients with major depression

Abstract Background: Increased dopaminergic activity may play a primary role in psychotic depression. Dopamine β-hydroxylase (DβH) catalyses the key step in biosynthesis of the neurotransmitter noradrenaline from dopamine, and low DβH activity is a possible risk factor for developing psychotic depression. An exon 2 polymorphism (DBH∗444 g/a) of the DβH gene (DBH) is significantly associated with both serum and cerebrospinal fluid levels of DβH. Methods: We determined the genotype of the DBH∗444g/a polymorphism in a cohort of 164 patients with major depression and examined the association of this polymorphism with paranoid ideation, interpersonal sensitivity, and psychoticism on the Hopkins Symptom Checklist. Results: Patients who possessed the A allele were significantly more likely to have higher scores for interpersonal sensitivity and paranoia than patients without the A allele ( p = .004 and p = .048, respectively), suggesting that this allele may predispose patients to paranoia in major depression. In addition, we found an association between prolactin levels in men and DBH∗444 g/a genotype such that homozygous G individuals displayed significantly higher levels than homozygous A or heterozygote individuals. Conclusions: Depressed patients with the GG genotype of DβH have lower scores for interpersonal sensitivity and paranoid ideation. The GG genotype may be protective against the development of psychosis in the presence of a major depressive episode.

An association study of DRD2 and COMT polymorphisms with novelty seeking and harm avoidance scores, in two independent samples of depressed patients

BackgroundIt was recently reported that an interaction of the dopamine D2 receptor (DRD2) and catechol-O-methyltransferase (COMT) influences the behavioural approach system – as measured using Carver and Whites Behavioural Inhibition and Behavioural Approach System (BIS/BAS) scales – in a sample of healthy German subjects. The Temperament and Character Inventory (TCI), in particular the novelty seeking (NS) and harm avoidance (HA) scales, correlates moderately with the BIS/BAS measure. This study aimed to examine support for an association of DRD2 and COMT with behavioural activation, using the TCI within two independent samples of depressed outpatients (for both samples n = 146).MethodsTwo clinical samples of depressed patients were ascertained to assess the efficacy of two different pharmacotherapy and psychotherapy treatments. Analysis of variance (ANOVA) was used to analyse NS and HA scale and subscale scores with respect to gene loci within each clinical sample. Analysis of covariance were undertaken to examine the association of age and gender with NS and HA scores. An association of age group or gender with gene loci were explored using chi-squared tests, in each sample.ResultsNo significant effect of DRD2 or COMT, either independently or as an interaction, on NS or HA scores was observed, within either sample. Whilst age was significantly negatively associated with NS scores, including age in the two- and three-way interactions did not affect the significance of the association of personality with gene loci.ConclusionThis study suggests that the COMT-DRD2 Equilibrium Model of Positive Emotionality recently proposed by Reuter and his colleagues is not applicable amongst currently depressed individuals, whose behavioural approach and inhibition tendencies have been assessed using the TCI.

Preliminary evidence for an association between a dopamine D3 receptor gene variant and obsessive-compulsive personality disorder in patients with major depression

We have previously reported that the Ser9Gly dopamine D3 receptor (DRD3) polymorphism was associated with increased rates of obsessive‐compulsive personality disorder (OCPD) symptomology. We tested the replicability of this association within a further two independent groups of individuals with a history of depression, from a clinical sample (n = 149) and a family study (n = 213). The data from the replication samples and the original sample, within which the association was found, were compiled within a meta‐analysis. Although the independent samples did not replicate the original finding, the meta‐analysis elucidated significant evidence supporting the association. An individual with Gly/Gly genotype is 2.4 (P = 0.017) times more likely to be diagnosed with OCPD. Male gender was also found to be a significant predictor of OCPD diagnosis (OR = 2.82, P = 0.001). An exploration of an association of DRD3 with Axis I anxiety disorder diagnoses and Temperament and Character Inventory (TCI) traits, in particular persistence, revealed no support for an association. We conclude that DRD3 may contribute to the development of OCPD.

Relationships Between Angry-Impulsive Personality Traits and Genetic Polymorphisms of the Dopamine Transporter

BACKGROUND The 9-repeat variable number tandem repeat allele of the dopamine transporter has recently been associated with borderline personality disorder (BPD) in depressed patients. METHODS We investigated the association between the 9-repeat allele of the dopamine transporter and angry-impulsive personality traits in a family study with 512 subjects on the molecular genetics of depression and personality. RESULTS Across the whole sample, the 9-repeat allele of the dopamine transporter was associated with angry-impulsive personality traits (p = .002). This association was stronger in subjects with no history of mood disorders or BPD (odds ratio [OR] = 4.85, p = .008) than in subjects with a history of mood disorders (OR = 1.73, p = .033). Angry-impulsive traits were also associated with lifetime mood disorder diagnoses and with BPD. CONCLUSIONS The associations reported in this article suggest that the 9-repeat allele of the dopamine transporter is associated with angry-impulsive personality traits, independent of any link to mood disorder or BPD. This could form the basis of a dopaminergic neurobiological model of angry-impulsive personality traits.