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Marcus R Munafò

Publications and source records attributed to Marcus R Munafò.

18 recordsLinked to original sources
PubMed2006

The endophenotype concept in psychiatric genetics.

The idea that some phenotypes bear a closer relationship to the biological processes that give rise to psychiatric illness than diagnostic categories has attracted considerable interest. Much effort has been devoted to finding such endophenotypes, partly because it is believed that the genetic basis of endophenotypes will be easier to analyse than that of psychiatric disease. This belief depends in part on the assumption that the effect sizes of genetic loci contributing to endophenotypes are larger than those contributing to disease susceptibility, hence increasing the chance that genetic linkage and association tests will detect them. We examine this assumption by applying meta-analytical techniques to genetic association studies of endophenotypes. We find that the genetic effect sizes of the loci examined to date are no larger than those reported for other phenotypes. A review of the genetic architecture of traits in model organisms also provides no support for the view that the effect sizes of loci contributing to phenotypes closer to the biological basis of disease is any larger than those contributing to disease itself. While endophenotype measures may afford greater reliability, it should not be assumed that they will also demonstrate simpler genetic architecture.

Catechol O-Methyltransferase↗
PubMed2006

Smoking cessation, weight gain, and DRD4 -521 genotype.

We investigated change in body mass index following long-term smoking cessation in a representative cohort of treatment-seeking heavy smokers in the United Kingdom, to determine the extent of long-term weight gain in successful quitters versus continuing smokers. We further investigated whether DRD4 genotype moderated any weight gain in either group. Smoking cessation was associated with an increase in BMI, and persisted up to 8 years after smoking cessation. Ex-smokers at 8-year follow-up weighed over 2.5 kg/m(3) more on average than they did at baseline, while participants who were smokers at both baseline and 8-year follow-up did not demonstrate any change in BMI. We did not observe an interaction between smoking status and DRD4 genotype. However, independently of the weight gain among those who stopped smoking during the course of the study, DRD4 genotype was significantly associated with BMI, with possession of the -521 C-allele associated with increased BMI. The magnitude of increase in BMI following smoking cessation, and the persistence of this change at 8-year follow-up, suggests that health benefits associated with smoking cessation may to some extent be negated by the detrimental effects on health of associated weight gain. Smoking cessation programmes should therefore consider incorporating follow-up support to promote weight loss among those who successfully stop smoking.

Adult↗
PubMed2005

Neuroticism mediates the association of the serotonin transporter gene with lifetime major depression.

BACKGROUND AND OBJECTIVES: An association between a polymorphism in the serotonin transporter gene (5HTT-LPR) and the personality trait of neuroticism has been reported. We sought to address the question of whether trait neuroticism mediates the putative association between this polymorphism and lifetime major depression in adults drawn from the general population. METHODS: Two hundred and fifty-one participants completed the Eysenck Personality Questionnaire and an adapted version of the depression section of the Structured Clinical Interview for DSM-III-R diagnosis, modified for implementation by a self-report questionnaire. A path method was applied to assess the mediator effect of neuroticism on the association between 5HTT-LPR genotype and lifetime major depression. RESULTS: 5HTT-LPR genotype was significantly associated with both neuroticism (p=0.02) and lifetime major depression (p=0.04), and neuroticism with lifetime major depression (p<0.001). Neuroticism accounted for 42.3% of the effect of 5HTT-LPR genotype on lifetime major depression, indicating possible mediation (p<0.001). CONCLUSIONS: These results suggest that neuroticism mediates the association between 5HTT-LPR genotype and lifetime major depression, consistent with models of the aetiology of depression which suggest that anxiety-related personality traits represent a substantial risk factor for affective disorder.

Adult↗
PubMed2005

Selective processing of social threat cues following acute tryptophan depletion.

The aim of the present study was to investigate the effects of low dose tryptophan depletion on recovered depressed patients both on and off antidepressant medication on an emotional Stroop task using social threat cues.Twenty-four healthy volunteers, 24 euthymic volunteers with a history of depression not currently on antidepressant medication and 24 euthymic volunteers with a history of depression and currently on antidepressant medication were randomly allocated to double-blind treatment with either a tryptophan depleting or a balanced mixture. All participants then completed subjective mood ratings and an emotional Stroop task using social threat cues. The recovered depressed group on medication demonstrated an increase in selective processing of social threat cues on the emotional Stroop task in the tryptophan depletion compared to the control condition. This was not the case for either healthy controls or the recovered depressed group not on medication. Although none of the patients showed a clinically significant relapse following tryptophan depletion, the medicated group showed a small but statistically significant increase in self-rated depression on the Profile of Mood States (POMS). Our data indicate that low-dose acute tryptophan depletion elicits both cognitive processing typical of the depressed state and subtle changes in subjective mood in the recovered depressed group on medication, but not in the recovered depressed group not on medication. This suggests that these two groups may differ in their underlying vulnerability to compromised serotonin function.

Adult↗
PubMed2005

Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: a functional magnetic resonance imaging study.

BACKGROUND: Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity. METHODS: Twenty-six healthy right-handed volunteers (14 smokers and 12 nonsmoking controls) underwent functional magnetic resonance imaging (fMRI) during which neutral and smoking-related images were presented. Region of interest analyses were performed within the ventral striatum/nucleus accumbens (VS/NAc) for the contrast between smoking-related (SR) and nonsmoking related neutral (N) cues. RESULTS: Group activation for SR versus N cues was observed in smokers but not in nonsmokers in medial orbitofrontal cortex, superior frontal gyrus, anterior cingulate cortex, and posterior fusiform gyrus using whole-brain corrected Z thresholds and in the ventral VS/NAc using uncorrected Z-statistics (smokers Z = 3.2). Region of interest analysis of signal change within ventral VS/NAc demonstrated significantly greater activation to SR versus N cues in smokers than controls. CONCLUSIONS: This is the first demonstration of greater VS/NAc activation in addicted smokers than nonsmokers presented with smoking-related cues using fMRI. Smokers, but not controls, demonstrated activation to SR versus N cues in a distributed reward signaling network consistent with cue reactivity studies of other drugs of abuse.

Adult↗
PubMed2005

The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association.

BACKGROUND: A promoter-based length polymorphism (5-HTTLPR) of the human serotonin gene (SLC6A4) has exhibited inconsistent association with emotionality phenotypes, such as major depression (MD) and the personality trait neuroticism (N). Several explanations have been posited to account for this discrepancy, including underpowered experimental design and variation in gender ratio, age, and ethnicity. METHODS: Here, we describe three independent tests of association between the 5-HTTLPR locus and both N and MD in samples selected for extremeness of N-score from two homogenous populations (n = 88,142, and 20,921). Calculations of statistical power indicated that at a 5% alpha level, these samples retain 100% power to detect a genetic effect accounting for just .5% of phenotypic variance. Effects of age were regressed out of the phenotypic measure, and gender was included as a covariate. RESULTS: No statistically significant effects of genotype could be identified on either N or MD phenotypes (in all cases, p > or = .26), independently of the genetic mode of action applied. CONCLUSIONS: Our data do not support the hypothesis that the 5-HTTLPR variant contributes significantly toward human emotionality as indexed by either the Eysenck Personality Questionnaire N scale or the DSM-IV for MD.

Depression↗
PubMed2005

Association between the serotonin transporter gene and alcohol consumption in social drinkers.

Relatively few studies have investigated the role of the 5HTT gene in intermediate phenotypes such as alcohol consumption in non-alcohol dependent populations. A recent study reported an association with alcohol consumption in a student population. We attempted to replicate these findings and extend on this work in a representative, ethnically homogenous, non-alcohol dependent sample of social drinkers in the United Kingdom. The short allele of the 5HTT gene was significantly associated with increased alcohol consumption (P = 0.03). There was suggestive evidence of a genotype-sex interaction (P = 0.04). Post-hoc tests indicated higher alcohol consumption in men with one or more copies of the short allele, while in women consumption was highest among heterozygotes compared to both homozygote groups. Age at time of data collection and cigarette consumption were entered as covariates. These results replicate recent previous findings and suggest a possibility that this association may differ in men and women.

Adult↗
PubMed2005

A family smoking index to capture genetic influence in smoking: rationale and two validation studies.

Despite a growing appreciation that genetic factors may impart vulnerability toward smoking behavior, only a modest consensus has been created about the specific genetic mechanisms that may underlie various aspects of smoking. A core feature of genetic contribution toward any complex human behavior is familial resemblance. Most previous attempts to index familial smoking have classified individuals into discrete categories, based on the number of smokers in a family. We discuss the development of a continuous measure of familial smoking, the Family Smoking Index (FSI), which is based on the proportion of smokers in first- and second-degree family members and provides a more precise weighting according to genetic proximity. We present the psychometric characteristics of the FSI as well as initial validation data from two studies. We also describe current and future directions for continued FSI validation and application.

Adult↗
PubMed2005

Association of serotonin transporter genotype with selective processing of smoking-related stimuli in current smokers and ex-smokers.

We sought to determine whether polymorphism in the serotonin transporter (5HTT) gene is associated with attentional bias toward smoking-related stimuli in current smokers and ex-smokers, using a modified Stroop task and an attentional blink task to measure selective processing of smoking-related stimuli. All participants attended a single testing session during which they completed the modified Stroop and attentional blink tasks to index attentional bias for smoking-related stimuli, in counterbalanced order. The experimental design included two between-subjects factors of smoking status (current smoker, ex-smoker) and 5HTT genotype (short, long). Smoking status x genotype interactions were significant on both the modified Stroop (p = .046) and the attentional blink (p = .006) tasks. On the modified Stroop task, we found a significant effect of 5HTT genotype on color-naming interference among ex-smokers (p = .018) but not current smokers (p = .989). On the attentional blink task, we found a significant effect of 5HTT genotype for current smokers (p = .028), whereas among ex-smokers this effect did not reach statistical significance, although it constituted a trend (p = .086). Our data provide tentative support for a moderating influence of 5HTT genotype on attentional bias for smoking-related stimuli in ex-smokers. This finding may account for inconsistent reports of attentional bias among ex-smokers.

Adult↗
PubMed2005

Longitudinal analysis of the effect of prenatal nicotine exposure on subsequent smoking behavior of offspring.

We explored the influence of maternal smoking during pregnancy on the likelihood of smoking among offspring in adolescence and adulthood using data from two similar British birth cohort surveys, the 1958 National Child Development Study and the 1970 British Birth Survey. Similar information was available in each cohort on maternal age at delivery, offspring sex, maternal smoking during pregnancy, parental and offspring socioeconomic status, and parental smoking at the time offspring smoking was assessed at age 16 years. Offspring smoking at 16 years and at 30/33 years were the primary outcomes of interest. Our data support an association between maternal smoking during pregnancy and an increased risk of offspring smoking later in life among female offspring but not among male offspring. Female offspring of mothers who smoked during pregnancy were more likely to smoke at 16 years than were their male counterparts. Moreover, in this same subgroup, female offspring smoking at 16 years was associated with an increased likelihood of smoking at 30/33 years. Further investigation in larger studies with greater detail of factors shaping smoking in childhood and adulthood and biochemically verified outcome measures would be desirable to clarify the relationship.

Adolescent↗
PubMed2005

Pharmacogenetics and nicotine addiction treatment.

This review focuses on the current status of, and future directions for, pharmacogenetic research on nicotine dependence and smoking cessation treatment. Pharmacological treatment involving nicotine replacement therapy and bupropion for nicotine addiction and smoking cessation has been shown to be efficacious when provided in combination with behavioral support. Cessation rates remain somewhat modest, however, and one possibility is that success rates may be enhanced by offering treatments tailored to an individual's genotype. Nonetheless, research on this issue remains in its infancy, and although the scope for individualized treatment tailored to genotype is promising, there are substantial practical, ethical and social considerations that must be addressed before such research is translated into clinical practice.

Bupropion↗
PubMed2005

Smoking cessation treatment: pharmacogenetic assessment.

This review focuses on the current status and future directions of pharmacogenetics research into responses to treatments for nicotine dependence and smoking cessation. Research remains in its infancy and, although the potential for individualized treatment tailored to genotype is promising, there are practical, ethical and social considerations that must be addressed before such research is translated into clinical practice. In particular, future studies that need to be conducted before such research is translated into clinical practice and potential limitations and barriers to this translation are described.

Genotype↗
PubMed2004

Assessing publication bias in genetic association studies: evidence from a recent meta-analysis.

Publication bias may exist when nonsignificant findings remain unpublished, thereby artificially inflating the apparent magnitude of an effect. This concern is not new, but it is particularly current in relation to genetic association studies. Data from a recent meta-analysis of association studies of personality were used to assess the potential of different graphical and statistical methods for assessing evidence of publication bias. The results suggest that no single method is sufficient for assessing evidence of publication bias, and that such methods may also offer insight into potential sources of heterogeneity, which may in turn guide the design of future studies.

Humans↗
PubMed2004

Meta-analysis of genetic association studies.

Meta-analysis, a statistical tool for combining results across studies, is becoming popular as a method for resolving discrepancies in genetic association studies. Persistent difficulties in obtaining robust, replicable results in genetic association studies are almost certainly because genetic effects are small, requiring studies with many thousands of subjects to be detected. In this article, we describe how meta-analysis works and consider whether it will solve the problem of underpowered studies or whether it is another affliction visited by statisticians on geneticists. We show that meta-analysis has been successful in revealing unexpected sources of heterogeneity, such as publication bias. If heterogeneity is adequately recognized and taken into account, meta-analysis can confirm the involvement of a genetic variant, but it is not a substitute for an adequately powered primary study.

Animals↗
PubMed2003

Selective processing of threat-related cues in day surgery patients and prediction of post-operative pain.

OBJECTIVE: To investigate the use of a measure of selective processing bias associated with anxiety as a predictor of post-operative pain independently of self-report measures of anxiety. METHODS: Forty-seven women admitted for minor gynaecological surgical procedures completed a selective processing task (modified Stroop) and the State-Trait Anxiety Inventory immediately prior to surgery. Following surgery they completed the McGill Short-Form Pain Questionnaire. Intraoperative analgesia consumption was also recorded. RESULTS: Participants demonstrated significantly slower colour-naming times for physical threat cues than control cues. This was not due to an emotionality effect, as colour-naming times for neutral and positive cues were not significantly different. This bias was congruent with the participants' current concerns, as colour-naming times were significantly slower for physical threat words than for social threat words. This index of selective processing bias significantly predicted post-operative pain independently of self-reported state and trait anxiety. CONCLUSIONS: The advantages of measures of psychological constructs that are not reliant on self-reporting are discussed.

Adolescent↗
PubMedDate not supplied

Selective processing of gastrointestinal symptom-related stimuli in irritable bowel syndrome.

OBJECTIVES: We sought to determine whether irritable bowel syndrome (IBS) was associated with attentional bias toward symptom-related cues in IBS patients versus healthy controls, using a modified Stroop task to measure selective processing of gastrointestinal symptom-related cues. METHODS: Fifteen patients with a clinical diagnosis of IBS and 15 healthy controls were recruited into the study. All participants attended a single testing session, during which they completed a modified Stroop task using gastrointestinal symptom-related and neutral control words. RESULTS: Results indicated a significant main effect of word type (p = .013), with slower color-naming times for IBS-related compared with neutral words, and a significant main effect of exposure (p = .001), with slower color-naming times in the unmasked condition compared with the masked condition. The group x word type x exposure interaction was significant (p = .048). A series of post hoc tests indicated that among patients there was significant interference of symptom-related words in the masked condition but not in the unmasked condition, whereas among controls, the reverse was true. CONCLUSIONS: These results indicate that IBS patients selectively process gastrointestinal symptom-related words compared with neutral words when they are presented subliminally but not when they are presented supraliminally. In contrast, healthy controls demonstrate the opposite pattern. Implications for the cognitive mechanisms in IBS, and future research directions, are discussed.

Adult↗