Biomedical subjects
N G Martin
Publications and source records attributed to N G Martin.
Is alcohol-related flushing a protective factor for alcoholism in Caucasians?
Although alcohol-related flushing seems to be a genetically influenced protective factor for alcoholism in some Asian groups, little is known about whether this is true for Caucasians. The evidence for alcohol-related flushing as a protective factor for the development of alcoholism was examined in a sample of 5831 Australian twins (2041 men, 3790 women) who were administered a structured psychiatric interview. Twin correlations for self-reported adverse alcohol reactions (e.g., "flushing or blushing" and "feeling very sleepy" after drinking 1 or 2 drinks) were modest, suggesting minimal contribution of genetic factors, but when corrected for reliability of measurement, were consistent with moderate heritabilities. In accord with studies examining Asian samples, we found that individuals who experienced adverse reactions after drinking small amounts of alcohol drank less often and slightly less per drinking occasion than those who did not experience adverse reactions. However, those who experienced adverse reactions were more likely to have symptoms of alcoholism and to report a parental history of alcohol problems. We conclude that self-reported alcohol-related flushing is not a protective factor for alcoholism in Caucasians and may be a risk factor.
Alcohol sensitivity and smoking history in men and women.
Many studies have found genetic effects to contribute to alcoholism risk in both men and women. Based on preliminary evidence for shared genetic risk between smoking and drinking problems, a reanalysis of alcohol challenge data on 412 Australian twins was performed to explore the possibility that smoking may diminish or moderate the intoxicating effects of alcohol. We found history of smoking to be strongly associated with self-reported intoxication after alcohol challenge in women (women: r = -0.44 +/- 0.08; men: r = -0.21 +/- 0.08), comparable with self-reported average weekly consumption of alcohol, which was more strongly associated in men (women: r = -0.37 +/- 0.07; men: r = -0.54 +/- 0.06). Structural equation model-fitting indicated a strong association between heavy drinking and smoking, but the association between smoking and postalcohol intoxication remained even when the effects of heavy drinking were controlled for. These results prompt the question of whether smoking cigarettes directly influences the transition from moderate to excessive use of alcohol by diminishing feelings of alcohol intoxication.
Genetic covariance structure of incisor crown size in twins.
Previous studies of tooth size in twins and their families have suggested a high degree of genetic control, although there have been difficulties separating the various genetic and environmental effects. A genetic analysis of variation in crown size of the permanent incisors of South Australian twins was carried out, with structural equation modeling used to determine the relative contributions of genetic and environmental factors. Maximum mesiodistal crown dimensions of maxillary and mandibular permanent incisors were recorded from dental models of 298 pairs of twins, including 149 monozygous (MZ) and 149 dizygous (DZ) pairs. The analysis revealed that: (i) an adequate fit required additive genetic and unique environmental components; (ii) augmenting the model with non-additive genetic variation did not lead to a significant improvement in fit; (iii) there was evidence of shared environmental influences in the upper central incisors of males; (iv) the additive genetic component constituted a general factor loading on all eight teeth, with group factors loading on antimeric pairs of teeth; (v) unique environmental effects were mostly variable-specific; (vi) most factor loadings on antimeric tooth pairs could be constrained to be equal, indicating a symmetry of genetic and environmental influences between left and right sides; and (vii) estimated heritability of the incisor mesiodistal dimensions varied from 0.81 to 0.91.
Heterogeneity of melanoma risk in families of melanoma patients.
While it is recognized that relatives of melanoma patients are at increased risk for this disease, the source and extent of variation in melanoma risk between families of melanoma cases is unknown. Heterogeneity of familial melanoma risk was assessed among the families (comprising 7,666 first-degree relatives) of 1,149 cutaneous melanoma cases diagnosed in Queensland, Australia, between 1982 and 1987. The measure of familial melanoma risk was based on the number of cases of melanoma in the family in excess of those predicted from the age-, sex-, and birth cohort-specific cumulative incidences of melanoma among all relatives in the sample. Probands over-reported melanoma occurrence among their relatives, with a false positive reporting rate of 44.5% (216 false reports out of 485). Only medically verified cases among relatives were included in the analysis. There was statistically significant heterogeneity in family risk, with 53 (4.7%) of the total 1,116 unrelated families containing significantly more melanoma cases than expected considering the size of the family, and the age, sex, and birth cohort distributions of family members. In univariate analyses, members of the high-risk families were significantly more likely to have poor ability to tan, a propensity to sunburn, fair skin color, red hair, and many melanocytic nevi. When all variables were included simultaneously in a multiple logistic regression model, only the associations with tanning ability, skin color, and number of nevi remained significant. There were no significant differences overall between high-risk and other families in the sites and ages at diagnosis of melanoma, although melanomas on variably sun-exposed sites (trunk and legs) were diagnosed earlier in the high-risk families, independent of the stage at diagnosis.
Genetic influences on alcohol consumption patterns and problem drinking: results from the Australian NH&MRC twin panel follow-up survey.
Self-report questionnaire data from 3,000 adult twin pairs participating in the 1988-1989 follow-up survey of the Australian NH&MRC twin panel were analyzed to determine (1) the contribution of genetic factors to risk of problem drinking in males and females; and (2) the magnitude of the correlation between genetic effects on problem drinking and genetic effects on alcohol consumption level. Significant genetic contributions were found both for average weekly consumption of alcohol and for problem-drinking history. For level of consumption, genetic factors accounted for approximately 58% of the variation in females and 45% of the variation in males. Heritability estimates for problem drinking, though significantly greater than zero, were variable in magnitude, ranging (under different models) from 8-44% in females and 10-50% in males. Likewise, estimates of the magnitude of the genetic correlation, whilst in all cases significantly greater than zero, ranged from 0.42-1.00 in females and 0.45-1.00 in males under different models.
Inferring the direction of causation in cross-sectional twin data: theoretical and empirical considerations.
A recent multivariate extension of the classical twin study in theory allows the inference of the direction of causation between correlated traits solely using cross-sectional data. In this paper we briefly review this model and assess its usefulness by applying it to a number of pairs of biological and psychological variables between which the nature of the causative relationship is already known. We conclude that the method has a number of biases and limitations. If a causative relationship at the phenotypic level exists between two traits, the correct direction of causation is usually identifiable, providing the reliability and validity of the measures are known. Failure to correctly specify a measurement model can lead to incorrect tests of hypotheses. Difficulties can also occur when discriminating between a direct causative relationship and a correlation due to common genetic or environmental determinants, but these occur in predictable situations. If these considerations are taken into account in interpretation of results, the true nature of the association between traits can often be correctly identified, or at least included in a subgroup of best fitting models.
A model system for analysis of family resemblance in extended kinships of twins.
The "Virginia 30,000" comprise 29,698 subjects from the extended kinships of 5670 twin pairs. Over 80 unique correlations between relatives can be derived from these kinships, comprised of monozygotic (MZ) and dizygotic (DZ) twins and their spouses, parents, siblings, and children. This paper describes the first application of a fairly general model for family resemblance to data from the Virginia 30,000. The model assesses the contributions of additive and dominant genetic effects in the presence of vertical cultural inheritance, phenotypic assortative mating, shared twin and sibling environments, and within-family environment. The genetic and environmental effects can be dependent on sex. Assortment and cultural inheritance may be based either on the phenotype as measured or on a latent trait of which the measured phenotype is an unreliable index. The model was applied to church attendance data from this study. The results show that the contributions of genes, vertical cultural inheritance, and genotype-environment covariance are all important, but their contributions are significantly heterogeneous over sexes. Phenotypic assortative mating has a major impact on family resemblance in church attendance.
Testing a model for the genetic structure of personality: a comparison of the personality systems of Cloninger and Eysenck.
Genetic analysis of data from 2,680 adult Australian twin pairs demonstrated significant genetic contributions to variation in scores on the Harm Avoidance, Novelty Seeking, and Reward Dependence scales of Cloninger's Tridimensional Personality Questionnaire (TPQ), accounting for between 54% and 61% of the stable variation in these traits. Multivariate genetic triangular decomposition models were fitted to determine the extent to which the TPQ assesses the same dimensions of heritable variation as the revised Eysenck Personality Questionnaire. These analyses demonstrated that the personality systems of Eysenck and Cloninger are not simply alternative descriptions of the same dimensions of personality, but rather each provide incomplete descriptions of the structure of heritable personality differences.
Comparability of naevus counts between and within examiners, and comparison with computer image analysis.
In the course of an investigation of melanocytic naevus development in Queensland, Australia, whole-body naevus counts of 66 adolescents were performed separately by two nurse examiners on two occasions on average 4 weeks apart. There was good agreement between the two examiners for counts of total naevi on the whole body (intra-class correlation coefficient = 0.96) and at selected subsites (face, neck, back, upper arms, lower arms). Agreement was lower when raised naevi only were counted (0.83). Intra-examiner repeatability was high for both nurses, particularly for the more experienced examiner (intra-class correlation coefficients = 0.98 and 0.91 for total naevi on the whole body), and was consistently better when all naevi were counted rather than naevi of a particular size. Independent counts of naevi on the back using a computer imaging technique were reproducible (intra-class correlation coefficient = 0.92), but showed only moderate agreement with counts by the nurse examiners. Overall, these results demonstrate high comparability of naevus counts between and within similarly trained examiners. They do not support the common practice in epidemiological studies of restricting counts to naevi larger than 2 mm, or of counting raised naevi only.
Alcohol consumption and alcohol pharmacokinetics: interactions within the normal population.
We have analyzed the interrelationships between habitual alcohol consumption, peak blood alcohol concentration after a standard dose, and rate of alcohol metabolism in a group of 199 male and 213 female twins. Both peak concentration and rate of metabolism are strongly associated with alcohol consumption levels, even in the range of 0-10 g of alcohol/day. The peak concentration and rate of metabolism were strongly correlated in both men and women; this is not due to their common dependence on alcohol intake nor to experimental error. These results show that the threshold for effects of habitual consumption on alcohol pharmacokinetics is much lower than previously suspected, and that there are factors that reduce preabsorptive or first-pass metabolism but increase postabsorptive metabolism.
Sources of individual differences in depressive symptoms: analysis of two samples of twins and their families.
OBJECTIVE: Self-reported symptoms of depression are commonly used in mental health research to assess current psychiatric state, yet wide variation in these symptoms among individuals has been found in both clinical and epidemiologic populations. The authors sought to understand, from a genetic-epidemiologic perspective, the sources of individual differences in depressive symptoms. METHODS: Self-reported symptoms of depression were assessed in two samples of twins and their spouses, parents, siblings, and offspring: one sample contained volunteer twins recruited through the American Association of Retired Persons and their relatives (N = 19,203 individuals) and the other contained twins from a population-based twin registry in Virginia and their relatives (N = 11,242 individuals). Model fitting by an iterative, diagonal, weighted least squares method was applied to the 80 different family relationships in the extended twin-family design. RESULTS: Independent analyses of the two samples revealed that the level of depressive symptoms was modestly familial, and familial resemblance could be explained solely by genetic factors and spousal resemblance. The estimated heritability of depressive symptoms was between 30% and 37%. There was no evidence that the liability to depressive symptoms was environmentally transmitted from parents to offspring or was influenced by environmental factors shared either generally among siblings or specifically between twins. With correction for unreliability of measurement, genetic factors accounted for half of the stable variance in depressive symptoms. CONCLUSIONS: Depressive symptoms in adulthood partly reflect enduring characteristics of temperament that are substantially influenced by hereditary factors but little, or not at all, by shared environmental experiences in the family of origin.
Genetic effects on alcohol consumption patterns and problems in women.
We review evidence that genetic factors play no less important a role in the etiology of alcoholism in women than in men. Potential mediators of this genetic influence (differences in personality or alcohol sensitivity) exhibit equal heritability in men and women. Genetically determined differences in alcohol preference (or consumption level), a phenotype widely used in animal models of alcoholism, have been neglected as a mechanism of alcoholism inheritance. Using data from the 1992-3 interview survey of the Australian twin panel (N = 5995 twins), we have reexamined the mediating role of personality and alcohol consumption variables. By comparing the non-alcoholic co-twins of alcoholic twins, and twins from concordant unaffected pairs (separately for MZ and DZ pairs), we have avoided the problem of obtaining consumption and personality assessments that are contaminated by history of alcoholism. In MZ pairs, in both genders, co-twin's heavy alcohol exposure (drinking 5+ drinks in one day) and co-twin's Novelty Seeking score, are both predictive of alcoholism in the respondent. The effect of co-twin's heavy alcohol exposure remains significant even when the respondent's personality variables are controlled for, implying that there are genetic effects on alcoholism risk mediated through consumption pattern that are independent of those mediated through personality differences.
Risk factors for atherosclerosis in twins.
We performed multivariate genetic analyses of cardiovascular risk factors from two sets of data on US and Australian female twins. Similar models for body mass index (BMI), serum low density (LDL) and high density (HDL) lipoproteins, including age as a covariate, were fitted successfully to both groups. These suggested that BMI, or genes responsible for a significant proportion of the variance of BMI, explained correlations between lipid subfractions, as well as those between blood pressure and lipid subfractions, especially HDL.
Reproductive hormone genes in mothers of spontaneous dizygotic twins: an association study.
There are important genetic influences on the tendency to dizygotic (DZ) twinning and it is a plausible hypothesis that these reside in one or more of the genes coding for the major reproductive hormones. We used Southern analysis of DNA from 50 young (< 32) mothers of DZ twins, who also had a family history of DZ twinning, and 50 controls, to examine allele frequencies of five restriction fragment length polymorphisms (RFLPs) in four hormone genes coding for follicle stimulating hormone beta (FSH beta), chorionic gonadotropin beta (CG beta), inhibin beta B and gonadotropin releasing hormone (GnRH). Comparison of allele frequencies revealed no significant differences between DZ twin mothers and controls. However this does not rule out the role of these genes in the hereditary tendency of multiple ovulation in humans, since absence of linkage disequilibrium does not imply absence of linkage.
Genetic and environmental covariance of serum cholesterol and blood pressure in female twins.
Blood pressure elevation is frequently associated with elevated cholesterol, triglyceride or low density lipoprotein (LDL-C) or low high density lipoprotein (HDL-C). The relative importance of genetic and environmental factors in these associations is unclear. We examined the relative contribution of genetic and environmental influences to the association between blood pressure and serum lipids in 75 pairs of female twins using path analysis and maximum-likelihood model fitting. Associations between systolic blood pressure and total cholesterol (r = 0.44, P < 0.001), and LDL-C (r = 0.38, P < 0.001), but not HDL-C (r = 0.05, N.S.), remained significant after age and body mass index adjustment. Univariate models suggested genetic effects contributed 60-70% to the variance of total cholesterol, LDL-C, HDL-C and systolic blood pressure. The remaining variance was explained by age and/or unique environmental influences. Using bivariate models, we demonstrated genetic (P = 0.017) and unique environmental covariance (P = 0.011) of cholesterol and systolic blood pressure. Significant genetic covariance (P = 0.038) was observed between LDL-C and systolic blood pressure. The association between blood pressure and total cholesterol in these twins results from shared genetic and similar unique environmental influences. The association between LDL-C and blood pressure is partly due to shared genetic influences. We conclude that both additive genetic and environmental factors unique to the individual are important determinants of the relationships between serum lipids and blood pressure.
Psoriasis in Australian twins.
BACKGROUND: Occurrence of psoriasis has been found to be strongly genetically controlled in Northern European and U.S. twin and family studies. OBJECTIVE: Our purpose was to assess cumulative incidence and heritability of psoriasis in the Australian population. METHODS: Australian twins reporting psoriasis on a screening questionnaire received from 3808 pairs were mailed a detailed instrument designed to validate the diagnosis, supplemented by telephone interview and examination of medical records. RESULTS: Only 94 of 160 subjects who screened positive were confirmed to have psoriasis. The cumulative incidence of confirmed psoriasis was 2% in 30- to 60-year-old subjects. The monozygotic twin casewise concordance for confirmed psoriasis was 35% (12 of 34 pairs), and the dizygotic twin concordance 12% (5 of 43 pairs), giving an estimated heritability of 80%, was similar to that found in a genetic reanalysis of three previous twin studies. A case-control analysis of psoriasis-discordant twin pairs found no evidence for influences of alcohol or coffee intake, overweight, birth weight, or personality in the origin of psoriasis. CONCLUSION: Occurrence of psoriasis in the Australian population is highly heritable, but identical twins are often discordant; the factor responsible for the onset of disease in one twin and not the other is unclear.
Genetic contribution to risk of smoking initiation: comparisons across birth cohorts and across cultures.
Self-report data on smoking initiation (whether the respondent admitted ever having smoked) were obtained from three large adult twin samples (Australia, N = 3,808 pairs; Virginia, N = 2,145 pairs; AARP, N = 3,620 pairs). Data were broken down into birth cohorts, and genetic models were fitted to test whether the decline, in more recent birth cohorts, in the percentage of individuals becoming smokers has led to a change in the relative contributions of genes and environment to risk of becoming a smoker. Despite a marked change in the proportion of male respondents who reported ever having smoked, we found no evidence for cohort differences in genetic and environmental effects (no Genotype x Cohort interaction). Significant differences in genetic and environmental parameters were found between sexes, and between the Australian and the two U.S. samples. In the U.S. samples, estimates of the genetic contribution to risk of becoming a smoker were 60% in men, 51% in women. In the Australian sample, heritability estimates were 33% in men, but 67% in women. Significant shared environmental effects on smoking initiation also were found, accounting for 23% of the variance in U.S. men, 28% of the variance in U.S. women, 39% of the variance in Australian men, and 15% of the variance in Australian women. In models that allowed for the environmental impact of cotwin smoking on a twin's risk of smoking initiation, estimates of the direct genetic contribution to risk of smoking initiation were comparable or higher (49-58% in U.S. women and 71% in Australian women; 58-61% in U.S. men, and 37% in Australian men).