Martin A. Kennedy

A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression

The multi-drug resistance gene ABCB1 (or MDR1) encodes a P-glycoprotein (P-gp) that regulates passage of many substances across the blood–brain barrier. The antidepressant amitriptyline and its metabolites (including nortriptyline) are substrates for P-gp, and in mice lacking P-gp, penetration of amitriptyline, but not fluoxetine, into the brain is enhanced. We reasoned that polymorphic variation of P-gp may contribute to differing responses of patients to antidepressant drugs. A single nucleotide polymorphism (SNP) of ABCB1 (3435C>T) was recently correlated with expression levels and in vivo function of P-gp. We examined this SNP in patients with major depression enrolled in a randomized antidepressant treatment trial of nortriptyline and fluoxetine, and observed a significant association between nortriptyline-induced postural hypotension and 3435C>T (χ2 = 6.78, df = 2, P = 0.034). Our results suggest that homozygosity for 3435T alleles of ABCB1 is a risk factor for occurrence of nortriptyline-induced postural hypotension (OR = 1.37, P = 0.042, 95% CI 1.01–1.86).

Confirmation of association of IRGM and NCF4 with ileal Crohn's disease in a population-based cohort

Genome-wide association studies have identified PHOX2B, FAM92B, IRGM and NCF4 as candidate susceptibility factors for ileal Crohns disease (CD). Here we sought to determine whether these genes were also associated with ileal CD in New Zealand Caucasians, as well as with ileocolonic CD, colonic CD and ulcerative colitis (UC). A total of 507 CD patients, 475 UC patients and 576 controls were genotyped for the single nucleotide polymorphisms rs16853571 (PHOX2B), rs4821544 (NCF4), rs13361189 and rs4958847 (IRGM), and rs8050910 (FAM92B). NCF4 and IRGM were significantly associated with ileal CD (P-valuers4821544=0.0090, odds ratio (OR)=1.425, 95% confidence interval (CI): 1.092–1.859; P-valuers13361189=0.0017, OR=1.942, 95% CI: 1.274–2.959; P-valuers4958847=0.0022, OR=1.767, 95% CI: 1.224–2.558), but not with other forms of inflammatory bowel disease (IBD). No association of PHOX2B or FAM92B with IBD was detected. Our study has demonstrated that IRGM and NCF4 are ileal-specific CD susceptibility factors in New Zealand Caucasians.

Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine.

A 94C>A missense mutation in the ITPA gene which encodes inosine triphosphate pyrophosphatase has been associated with adverse effects from azathioprine, specifically flu-like symptoms, pancreatitis and rash. We hypothesized that this association may also be present in a larger, population-based group of inflammatory bowel disease patients intolerant of thiopurine drugs. We performed genotyping for this polymorphism and TPMT*2 and TPMT*3 in 73 such patients and 74 patients with inflammatory bowel disease who have tolerated azathioprine. We could not demonstrate a significant association between the ITPA94C>A genotype and any adverse effects (Odds ratio (OR) 1.015, 95% confidence interval (CI) 0.360-2.867, P = 0.593), flu-like symptoms (OR 1.547, 95%CI 0.368-6.496, P = 0.398), rash (no ITPA 94C>A polymorphism identified) or pancreatitis (no ITPA 94C>A polymorphism identified). We found no significant association between the ITPA 94C>A polymorphism and adverse effects to thiopurine drugs.

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.

Thiopurine S‐methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease

Background : Azathioprine and mercaptopurine (MP) are well established treatments for inflammatory bowel disease but they have severe adverse effects that prevent their use in some patients. The likelihood and type of adverse effect may relate to thiopurine methyltransferase (TPMT) enzyme activity and genotype.

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium

Objectives To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Design Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Participants Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Primary outcome measures Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. Results The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Conclusions Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Self-Mutilation and Suicide Attempts: Relationships to Bipolar Disorder, Borderline Personality Disorder, Temperament and Character

Objective: Self-mutilation has traditionally been associated with borderline personality disorder, and seldom examined separately from suicide attempts. Clinical experience suggests that self-mutilation is common in bipolar disorder. Methods: A family study was conducted on the molecular genetics of depression and personality, in which the proband had been treated for depression. All probands and parents or siblings were interviewed with a structured interview and completed the Temperament and Character Inventory. Results: Fourteen per cent of subjects interviewed reported a history of self-mutilation, mostly by wrist cutting. Self-mutilation was more common in bipolar I disorder subjects then in any other diagnostic groups. In multiple logistic regression self-mutilation was predicted by mood disorder diagnosis and harm avoidance, but not by borderline personality disorder. Furthermore, the relatives of non-bipolar depressed probands with self-mutilation had higher rates of bipolar I or II disorder and higher rates of self-mutilation. Sixteen per cent of subjects reported suicide attempts and these were most common in those with bipolar I disorder and in those with borderline personality disorder. On multiple logistic regression, however, only mood disorder diagnosis and harm avoidance predicted suicide attempts. Suicide attempts, unlike self-mutilation, were not familial. Conclusions: Self-mutilation and suicide attempts are only partially overlapping behaviours, although both are predicted by mood disorder diagnosis and harm avoidance. Self-mutilation has a particularly strong association with bipolar disorder. Clinicians need to think of bipolar disorder, not borderline personality disorder, when assessing an individual who has a history of self-mutilation.

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.