Genetic covariation of pelvic organ and elbow mobility in twins and their sisters

A range of environmental risk factors, with childbirth the most notable, have been associated with the development of pelvic organ prolapse and urinary incontinence. However, indications of genetic influence (positive family histories, ethnic differences) have prompted research into the heritability of measures of pelvic organ descent and joint mobility, which have also been associated with prolapse and incontinence. Genes appear to influence about half of the variation in these measures and, furthermore, the pelvic organ measures are associated with elbow hyperextension at a phenotypic level (r approximate to .2). We examined these measures in young, nulligravid women to determine if their association is due to a common genetic source. Data were collected from 178 Caucasian female co-twins and non-twin sisters, 50 of whom returned to be retested, which allowed reliability to be estimated and unreliable variance to be isolated in the multivariate analyses. Structural equation modeling was used to estimate genetic associations between latent elbow and bladder mobility factors for which heritabilities were estimated to be 0.80 and 0.64 respectively. The association between these factors appeared to be mediated by common genes (genetic r = .48, non-shared environmental r = -.06), with genes influencing latent elbow mobility accounting for 14% of the variation in latent bladder mobility. We speculate that genes influencing connective tissue structure may underlie this association.

Using identity-by-de scent information in affected sib pairs to increase the efficiency of genetic association studies

T he aim of this study was to determine whether identity-by-descent (IBD) information for affected sib pairs (ASPs) can be used to select a sample of cases for a genetic case-control study which will provide more power for detecting association with loci in a known linkage region. By modeling the expected frequency of the disease allele in ASPs showing IBD sharing of 0, 1, or 2 alleles, and considering additive, recessive, and dominant disease models, we show that cases selected from IBD 2 families are best for this purpose, followed by those selected from IBD 1 families; least useful are cases selected from IBD 0 families.

Genetic and environmental sources of covariance between reading tests used in neuropsychological assessment and IQ subtests

In this study, we examined genetic and environmental influences on covariation among two reading tests used in neuropsychological assessment (Cambridge Contextual Reading Test [CCRT], [Beardsall, L., and Huppert, F. A. ( 1994). J. Clin. Exp. Neuropsychol. 16: 232 - 242], Schonell Graded Word Reading Test [SGWRT], [ Schonell, F. J., and Schonell, P. E. ( 1960). Diagnostic and attainment testing. Edinburgh: Oliver and Boyd.]) and among a selection of IQ subtests from the Multidimensional Aptitude Battery (MAB), [Jackson, D. N. (1984). Multidimensional aptitude battery, Ontario: Research Psychologists Press.] and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) [Wechsler, D. (1981). Manual for the Wechsler Adult Intelligence Scale-Revised (WAIS-R). San Antonio: The Psychological Corporation]. Participants were 225 monozygotic and 275 dizygotic twin pairs aged from 15 years to 18 years ( mean, 16 years). For Verbal IQ subtests, phenotypic correlations with the reading tests ranged from 0.44 to 0.65. For Performance IQ subtests, phenotypic correlations with the reading tests ranged from 0.23 to 0.34. Results of Structural Equation Modeling (SEM) supported a model with one genetic General factor and three genetic group factors ( Verbal, Performance, Reading). Reading performance was influenced by the genetic General factor ( accounting for 13% and 20% of the variance for the CCRT and SGWRT, respectively), the genetic Verbal factor ( explaining 17% and 19% of variance for the CCRT and SGWRT), and the genetic Reading factor ( explaining 21% of the variance for both the CCRT and SGWRT). A common environment factor accounted for 25% and 14% of the CCRT and SGWRT variance, respectively. Genetic influences accounted for more than half of the phenotypic covariance between the reading tests and each of the IQ subtests. The heritabilities of the CCRT and SGWRT were 0.54 and 0.65, respectively. Observable covariance between reading assessments used by neuropsychologists to estimate IQ and IQ subtests appears to be largely due to genetic effects.

Do the Genetic or Environmental Determinants of Anxiety and Depression Change with Age? A Longitudinal Study of Australian Twins

Because the determinants of anxiety and depression in late adolescence and early adulthood may differ from those in later life, we investigated the temporal stability and magnitude of genetic and environmental correlates of symptoms of anxiety and depression across the life span. Data were collected from a population-based Australian sample of 4364 complete twin pairs and 777 singletons aged 20 to 96 years who were followed-up over three studies between 1980 and 1996. Each study contained the 14-item self-report DSSI/sAD scale which was used to measure recently experienced symptoms of anxiety and depression. Symptom scores were then divided and assigned to age intervals according to each subject's age at time of participation. We fitted genetic simplex models to take into account the longitudinal nature of the data. For male anxiety and depression, the best fitting simplex models comprised a single genetic innovation at age 20 which was transmitted, and explained genetic variation in anxiety and depression at ages 30, 40, 50 and 60. Most of the lifetime genetic variation in female anxiety and depression could also be explained by innovations at age 20 which were transmitted to all other ages; however, there were also smaller age-dependent genetic innovations at 30 for anxiety and at 40 and 70 for depression. Although the genetic determinants of anxiety and depression appear relatively stable across the life-span for males and females, there is some evidence to support additional mid-life and late age gene action in females for depression. The fact that mid-life onset for anxiety occurs one decade before depression is also consistent with a causal relationship (anxiety leading to depression) between these conditions. These findings have significance for large scale depression prevention projects.

Genetic assignment methods for the direct, real-time estimation of migration rate: a simulation-based exploration of accuracy and power

Genetic assignment methods use genotype likelihoods to draw inference about where individuals were or were not born, potentially allowing direct, real-time estimates of dispersal. We used simulated data sets to test the power and accuracy of Monte Carlo resampling methods in generating statistical thresholds for identifying F-0 immigrants in populations with ongoing gene flow, and hence for providing direct, real-time estimates of migration rates. The identification of accurate critical values required that resampling methods preserved the linkage disequilibrium deriving from recent generations of immigrants and reflected the sampling variance present in the data set being analysed. A novel Monte Carlo resampling method taking into account these aspects was proposed and its efficiency was evaluated. Power and error were relatively insensitive to the frequency assumed for missing alleles. Power to identify F-0 immigrants was improved by using large sample size (up to about 50 individuals) and by sampling all populations from which migrants may have originated. A combination of plotting genotype likelihoods and calculating mean genotype likelihood ratios (D-LR) appeared to be an effective way to predict whether F-0 immigrants could be identified for a particular pair of populations using a given set of markers.

Defining nicotine dependence for genetic research: evidence from Australian twins

Background. Whether current criteria used to define nicotine dependence are informative for genetic research is an important empirical question. The authors used items of the DSM-IV and of the Heaviness of Smoking Index to characterize the nicotine dependence phenotype and to identify salient symptoms in a genetically informative community sample of Australian young adult female and mate twins. Method. Phenotypic and genetic factor analyses were performed on nine dependence symptoms (the seven DSM-IV substance dependence criteria and the two Heaviness of Smoking Index (HSI) items derived from the Fagerstrom Tolerance Questionnaire, time to first cigarette in the morning and number of cigarettes smoked per day). Phenotypic and genetic analyses were restricted to ever smokers. Results. Phenotypic nicotine dependence symptom covariation was best captured by two factors with a similar pattern of factor loadings for women and men. In genetic factor analysis item covariation was best captured by two genetic but one shared environmental factor for both women and men; however, item factor loadings differed by gender. All nicotine dependence symptoms were substantially heritable, except for the DSM-IV criterion of 'giving up or reducing important activities in order to smoke', which was weakly familial. Conclusions. The salient behavioral indices of nicotine dependence are similar for women and men. DSM-IV criteria of tolerance, withdrawal, and experiencing difficulty quitting and HSI items time to first cigarette in the morning and number of cigarettes smoked per day may represent the most highly heritable symptoms of nicotine dependence for both women and men.

Genetic Simplex Modeling of Eysenck's Dimensions of Personality in a Sample of Young Australian Twins

The relative stability and magnitude of genetic and environmental effects underlying major dimensions of adolescent personality across time were investigated. The Junior Eysenck Personality Questionnaire was administered to over 540 twin pairs at ages 12, 14 and 16 years. Their personality scores were analyzed using genetic simplex modeling which explicitly took into account the longitudinal nature of the data. With the exception of the dimension lie, multivariate model fitting results revealed that familial aggregation was entirely explained by additive genetic effects. Results from simplex model fitting suggest that large proportions of the additive genetic variance observed at ages 14 and 16 years could be explained by genetic effects present at the age of 12 years. There was also evidence for smaller but significant genetic innovations at 14 and 16 years of age for male and female neuroticism, at 14 years for male extraversion, at 14 and 16 years for female psychoticism, and at 14 years for male psychoticism.

Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments

After initial infection, human cytomegalovirus remains in a persistent state with the host. Immunity against the virus controls replication, although intermitent viral shedding can still take place in the seropositive immunocompetent person. Replication of cytomegalovirus in the absence of an effective immune response is central to the pathogenesis of disease. Therefore, complications are primarily seen in individuals whose immune system is immature, or is suppressed by drug treatment or coinfection with other pathogens. Although our increasing knowledge of the host-virus relationship has lead to the development of new pharmacological strategies for cytomegalovirus-associated infections, these strategies all have limitations-eg, drug toxicities, development of resistance, poor oral bioavailability, and low potency. Immune-based therapies to complement pharmacological strategies for the successful treatment of virus-associated complications should be prospectively investigated.

Global genetic diversity of human metapneumovirus fusion gene

We analyzed 64 human metapneumovirus strains from eight countries. Phylogenetic analysis identified two groups (A and B, amino acid identity 93%-96%) and four subgroups. Although group A strains predominated, accounting for 69% of all strains, as many B as A strains were found in persons greater than or equal to3 years of age.

Case-only study of interactions between genetic polymorphisms of GSTM1, P1, T1 and Z1 and smoking in Parkinson's disease

Current opinion contends that complex interactions between genetic and environmental factors play a role in the etiology of Parkinson's disease (PD). Cigarette smoking is thought to reduce risk of PD, and emerging evidence suggests that genetic factors may modulate smoking's effect. We used a case-only design, an approach not previously used to study gene-environment interactions in PD, specifically to study interactions between glutathione-S-transferase (GST) gene polymorphisms and smoking in relation to PD. Four-hundred PD cases (age at onset: 60.0 +/- 10.7 years) were genotyped for common polymorphisms in GSTM1, PI, T1 and Z1 using well-established methods. Smoking exposure data were collected in face-to-face interviews. The independence of the studied GST genotypes and smoking exposure was confirmed by studying 402 healthy, aged individuals. No differences were observed in the distributions of GSTM1, T1 or Z1 polymorphisms between ever-smoked and never-smoked PD cases using logistic regression (all P > 0.43). However, GSTP1 *C haplotypes were over-represented among PD cases who ever smoked (odds ratio for interaction (ORi) = 2.00 (95% Cl: 1.11-3.60, P = 0.03)). Analysis revealed that ORi between smoking and the GSTP1-114Val carrier status increased with increasing smoking dose (P = 0.02 for trend). These data suggest that one or more GSTP1 polymorphisms may interact with cigarette smoking to influence the risk for PD. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Virus-specific CD8+ T lymphocytes within the normal human liver

The frequency and phenotype of human antiviral memory CD8(+) T cells in blood are well studied, yet little is known about their distribution within tissues. Analysis of antiviral CD8(+) T cell populations derived from a unique set of normal liver and blood samples identified a consistent population of virus-specific cells within the liver. In comparison to the circulating T cells, the liver-derived T cells were present at frequencies which were variably enriched compared to that in the blood, and showed significant differences with regard to the expression of CD45RA, CD45RO, CD95, CCR7, CD27 and CD28. The differences in these cell surface markers are consistent with a mature 'effector memory' phenotype of antigen-specific CD8(+) T cells within the liver. An enrichment of an activated subset of NKT cells (Valpha24/Vbeta11) was also observed, a finding which may be relevant to the regulation of the antiviral population:.

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor ( CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.

Genetic effects on alcohol dependence risk: re-evaluating the importance of psychiatric and other heritable risk factors

Background. Genetic influences have been shown to play a major role in determining the risk of alcohol dependence (AD) in both women and men; however, little attention has been directed to identifying the major sources of genetic variation in AD risk. Method. Diagnostic telephone interview data from young adult Australian twin pairs born between 1964 and 1971 were analyzed. Cox regression models were fitted to interview data from a total of 2708 complete twin pairs (690 MZ female, 485 MZ male, 500 DZ female, 384 DZ male, and 649 DZ female/male pairs). Structural equation models were fitted to determine the extent of residual genetic and environmental influences on AD risk while controlling for effects of sociodemographic and psychiatric predictors on risk. Results. Risk of AD was increased in males, in Roman Catholics, in those reporting a history of major depression, social anxiety problems, and conduct disorder, or (in females only) a history of suicide attempt and childhood sexual abuse; but was decreased in those reporting Baptist, Methodist, or Orthodox religion, in those who reported weekly church attendance, and in university-educated males. After allowing for the effects of sociodemographic and psychiatric predictors, 47 % (95 % CI 28-55) of the residual variance in alcoholism risk was attributable to additive genetic effects, 0 % (95 % CI 0-14) to shared environmental factors, and 53 % (95 % CI 45-63) to non-shared environmental influences. Conclusions. Controlling for other risk factors, substantial residual heritability of AD was observed, suggesting that psychiatric and other risk factors play a minor role in the inheritance of AD.