Estimation of individual genetic and environmental profiles in longitudinal designs

Parameter estimates obtained in the genetic analysis of longitudinal data can be used to construct individual genetic and environmental profiles across time. Such individual profiles enable the attribution of individual phenotypic change to changes in the underlying genetic or environmental processes and may lead to practical applications in genetic counseling and epidemiology. Simulations show that individual estimates of factor scores can be reliably obtained. Decomposition of univariate, and to a lesser extent of bivariate, phenotypic time series may yield estimates of independent individual G(t) and E(t), however, that are intercorrelated. The magnitude of these correlations depends somewhat on the autocorrelation structure of the underlying series, but to obtain completely independent estimates of genetic and environmental individual profiles, at least three measured indicators are needed at each point in time. KEY WORDS: longitudinal genetic analysis; environmental profiles; genetic profiles; factor scores; Kalman filter

Implementation of a combined association-linkage model for quantitative traits in linear mixed model procedures of statistical packages

Atransmission disequilibrium test for quantitative traits which combines association and linkage analyses is currently available in several dedicated software packages. We describe how to implement such models in linear mixed model procedures that are available in widely used statistical packages such as SPSS. We also briefly mention a few extensions of the model that become naturally available once the model is implemented in such procedures. Genotyping of many microsatellite markers or single nucleotide polymorphisms (SNPs) over the entire genome is becoming increasingly common in human genetics. In those high-resolution maps the average distance between microsatellite markers may be as small as 5 cM and between SNPs one half cM or less. At those small distances it becomes fairly likely that some markers in the set are in linkage disequilibrium (LD) with a gene affecting the trait (a so-called quantitative trait locus or QTL if the trait or the vulnerability distribution is quantitative). Different alleles or combinations of alleles of the markers or SNPs can then be associated with different trait means. Association studies are conducted to discover such allelic effects. Abecasis et al. (2000) generalized the model proposed by Fulker et al. (1999) for combined linkage and association tests, within and between families. The Fulker-Abecasis or F-A model is implemented in the program QTD

Evidence for genetic factors explaining the association between birth weight and low-density lipoprotein cholesterol and possible intrauterine factors influencing the association between birth weight and high-density lipoprotein cholesterol: Analysis in twins

Recent studies have demonstrated an association between low weight at birth and an atherogenic lipid profile in later life. To examine the influences of intrauterine and genetic factors, we investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. Regression analysis demonstrated that low birth weight was associated with high levels of total cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (-0.17 mmol/liter per kg, P = 0.07; -0.18 mmol/liter per kg, P = 0.04; and -0.07 g/liter per kg, P = 0.02, respectively) and with low levels of high-density lipoprotein (HDL) cholesterol (+0.04 mmol/liter per kg, P = 0.1), after adjustment for age, sex, and body mass index. Intrapair differences in birth weight were significantly associated with differences in total cholesterol, LDL cholesterol, and apolipoprotein B in dizygotic twins after adjustment for differences in current body mass index (-0.49 mmol/liter per kg, P = 0.02; -0.51 mmol/liter per kg, P = 0.01; and -0.10 g/liter per kg, P = 0.04, respectively), demonstrating that the larger the difference in birth weight, the higher these risk factors in the twin with the lower birth weight, compared with the cotwin with the higher birth weight. In monozygotic twins, however, the associations between intrapair differences in birth weight and differences in total cholesterol, LDL cholesterol, and apolipoprotein B were in the opposite direction (+0.32 mmol/liter per kg, P = 0.03; +0.23 mmol/liter per kg, P = 0.08; and +0.06 g/liter per kg, P = 0.04, respectively). The association between intrapair differences in birth weight and differences in HDL cholesterol was not significant in dizygotic twins (+0.04 mmol/liter per kg, P = 0.6) and of borderline significance in monozygotic twins (+0.11 mmol/liter per kg, P = 0.05). These data suggest that genetic factors account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association between birth weight and HDL cholesterol

Heritability of testosterone levels in 12-year-old twins and its relation to pubertal development

The aim of this study was to estimate the heritability of variation in testosterone levels in 12-year-old children, and to explore the overlap in genetic and environmental influences on circulating testosterone levels and androgen dependent pubertal development. Midday salivary testosterone samples were collected on two consecutive days in a sample of 183 unselected twin pairs. Androgen induced pubertal development was assessed using self report Tanner scales of pubic hair development (boys and girls) and genital development (boys). A significant contribution of genetic effects to the variance in testosterone levels was found. Heritability was approximately 50% in both boys and girls. The remaining proportion of the variance in testosterone levels could be explained by non-shared environmental influences. The relatively high correlation between testosterone levels of opposite sex dizygotic twins suggests that sex differences in genes influencing variation in testosterone levels have not yet developed in pre- and early puberty. Variance in pubertal development was explained by a large genetic component, moderate shared environmental influences, and a small non-shared environmental effect. Testosterone levels correlated moderately (r = .31) with pubertal development; the covariance between testosterone levels and pubertal development was entirely accounted for by genetic influences

A genetic analysis of coffee consumption in a sample of Dutch twins

Caffeine is by far the most commonly used psycho-active substance. Caffeine is consumed regularly as an ingredient of coffee. Coffee consumption and coffee preference was explored in a sample of 4,495 twins (including 1,231 pairs) registered with the Netherlands Twin Registry. Twin resemblance was assessed by tetrachoric correlations and the influence of both genetic and environmental factors was explored with model fitting analysis in MX. Results showed moderate genetic influences (39%) on coffee consumption. The remaining variance was explained by shared environmental factors (21%) and unique environmental factors (40%). The variance in coffee preference (defined as the proportion of coffee consumption relative to the consumption of coffee and tea in total) was explained by genetic factors (62%) and unique environmental factors (38%)

An exploration of gene-environment interaction and asthma in a large sample of 5-year-old Dutch twins.

A consistent finding from twin studies is that the environment shared by family members does not contribute to the variation in susceptibility to asthma. At the same time, it is known that environmental risk factors that are shared by family members are associated with the liability for asthma. We hypothesize that the absence of a main effect of shared environmental factors in twin studies can be explained by gene-environment interaction, that is, that the effect of an environmental factor shared by family members depends on the genotype of the individual. We explore this hypothesis by modeling the resemblance in asthma liability in twin pairs as a function of various environmental risk factors and test for gene-environment interaction. Asthma data were obtained by parental report for nearly 12,000 5-year-old twin pairs. A series of environmental risk factors was examined: birth cohort, gestational age, time spent in incubator, breastfeeding, maternal educational level, maternal smoking during pregnancy, current smoking of parents, having older siblings, and amount of child care outside home. Results revealed that being a boy, born in the 1990s, premature birth, longer incubator time, and child care outside home increased the risk for asthma. With the exception of premature birth, however, none of these factors modified the genetic effects on asthma. In very premature children shared environmental influences were important. In children born after a gestation of 32 weeks or more only genetic factors were important to explain familial resemblance for asthma

Anesthesia and cognitive performance in children: No evidence for a causal relationship

* Both authors contributed evenly to the manuscript Recent findings of an association between anesthesia administration in the first three years of life and later learning disabilities have created concerns that anesthesia has neurotoxic effects on synaptogenesis, causing later learning problems. An alternative hypothesis is that those children who are likely to undergo surgery early in life have significant medical problems that are associated with a vulnerability to learning disabilities. These two hypotheses were evaluated in a monozygotic concordant–discordant twin design. Data on anesthesia administration and learning abilities and disabilities were available for 1,143 monozygotic twin pairs (56 % female) from the Netherlands Twin Registry. Parents of the twins reported on anesthesia use before age 3 and again between ages 3 and 12 years. Near age 12, educational achievement and cognitive problems were assessed with standardized tests and teacher ratings. Results showed that twins who were exposed to anesthesia before age 3 had significantly lower educational achievement scores and significantly more cognitive problems than twins not exposed to anesthesia. However, there was one important exception: the unexposed co-twin from discordant pairs did not differ from their exposed cotwin. Thus, there is no evidence for a causal relationship between anesthesia administration and later learning-related outcomes in this sample. Rather, there is evidence for early anesthesia being a marker of an individual’s vulnerability for later learning problems, regardless of their exposure to anesthesia

The etiology of mathematical and reading (dis)ability covariation in a sample of Dutch twins

The genetic etiology of mathematical and reading (dis)ability has been studied in a number of distinct samples, but the true nature of the relationship between the two remains unclear. Data from the Netherlands Twin Register was used to determine the etiology of the relationship between mathematical and reading (dis)ability in adolescent twins. Ratings of mathematical and reading problems were obtained from parents of over 1500 twin pairs. Results of bivariate structural equation modeling showed a genetic correlation around .60, which explained over 90% of the phenotypic correlation between mathematical and reading ability. The genetic model was the same for males and females

Low birth weight is associated with increased sympathetic activity

Background - Low birth weight may be associated with high blood pressure in later life through genetic factors, an association that may be explained by alterations in sympathetic and parasympathetic activity. We examined the association of birth weight with cardiac pre-ejection period and respiratory sinus arrhythmia (indicators of cardiac sympathetic and parasympathetic activity, respectively) and with blood pressure in 53 dizygotic and 61 monozygotic adolescent twin pairs. Methods and Results - Birth weight of the twins was obtained from the mothers. Pre-ejection period and respiratory sinus arrhythmia were measured with electrocardiography and impedance cardiography at rest, during a reaction time task, and during a mental arithmetic task. In the overall sample, lower birth weight was significantly associated with shorter pre-ejection period at rest, during the reaction time task, and during the mental arithmetic task (P=0.0001, P<0.0001, and P=0.0001, respectively) and with larger pre-ejection period reactivity to the stress tasks (P=0.02 and P=0.06, respectively). In within-pair analyses, differences in birth weight were associated with differences in pre-ejection period at rest and during both stress tasks in dizygotic twin pairs (P=0.01, P=0.06, and P=0.2, respectively) but not in monozygotic twin pairs (P=0.9, P=1.0, and P=0.5, respectively). Shorter pre-ejection period explained approximately 63% to 84% of the birth weight and blood pressure relation. Conclusions - Low birth weight is associated with increased sympathetic activity, and this explains a large part of the association between birth weight and blood pressure. In addition, our findings suggest that the association between birth weight and sympathetic activity depends on genetic factors