Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design

Background. Children of alcoholics are significantly more likely to experience high-risk environmental exposures, including prenatal substance exposure, and are more likely to exhibit externalizing problems [e.g. attention deficit hyperactivity disorder (ADHD)]. While there is evidence that genetic influences and prenatal nicotine and/or alcohol exposure play separate roles in determining risk of ADHD, little has been done on determining the joint roles that genetic risk associated with maternal alcohol use disorder (AUD) and prenatal risk factors play in determining risk of ADHD. Method. Using a children-of-twins design, diagnostic telephone interview data from high-risk families (female monozygotic and dizygotic twins concordant or discordant for AUD as parents) and control families targeted from a large Australian twin cohort were analyzed using logistic regression models. Results. Offspring of twins with a history of AUD, as well as offspring of non-AUD monozygotic twins whose co-twin had AUD, were significantly more likely to exhibit ADHD than offspring of controls. This pattern is consistent with a genetic explanation for the association between maternal AUD and increased offspring risk of ADHD. Adjustment for prenatal smoking, which remained significantly predictive, did not remove the significant genetic association between maternal AUD and offspring ADHD. Conclusions. While maternal smoking during pregnancy probably contributes to the association between maternal AUD and offspring ADHD risk, the evidence for a significant genetic correlation suggests: (i) pleiotropic genetic effects, with some genes that influence risk of AUD also influencing vulnerability to ADHD; or (ii) ADHD is a direct risk-factor for AUD.

A genetically informed study of the association between harsh punishment and offspring behavioral problems

Conclusions about the effects of harsh parenting on children have been limited by research designs that cannot control for genetic or shared environmental confounds. The present study used a sample of children of twins and a hierarchical linear modeling statistical approach to analyze the consequences of varying levels of punishment while controlling for many confounding influences. The sample of 887 twin pairs and 2,554 children came from the Australian Twin Registry. Although corporal punishment per se did not have significant associations with negative childhood outcomes, harsher forms of physical punishment did appear to have specific and significant effects. The observed association between harsh physical punishment and negative outcomes in children survived a relatively rigorous test of its causal status, thereby increasing the authors' conviction that harsh physical punishment is a serious risk factor for children.

Effects of Variation at the ALDH2 Locus on Alcohol Metabolism, Sensitivity, Consumption, and Dependence in Europeans

Background: The low-activity variant of the aldehyde dehydrogenase 2 (ALDH2) gene found in East Asian populations leads to the alcohol flush reaction and reduces alcohol consumption and risk of alcohol dependence (AD). We have tested whether other polymorphisms in the ALDH2 gene have similar effects in people of European ancestry. Methods: Serial measurements of blood and breath alcohol, subjective intoxication, body sway, skin temperature, blood pressure, and pulse were obtained in 412 twins who took part in an alcohol challenge study. Participants provided data on alcohol reactions, alcohol consumption, and symptoms related to AD at the time of the study and subsequently. Haplotypes based on 5 single-nucleotide polymorphisms (SNPs) were used in tests of the effects of variation in the ALDH2 gene on alcohol metabolism and alcohol's effects. Results: The typed SNPs were in strong linkage disequilibrium and 2 complementary haplotypes comprised 83% of those observed. Significant effects of ALDH2 haplotype were observed for breath alcohol concentration, with similar but smaller and nonsignificant effects on blood alcohol. Haplotype-related variation in responses to alcohol, and reported alcohol consumption, was small and not consistently in the direction predicted by the effects on alcohol concentrations. Conclusions: Genetic variation in ALDH2 affects alcohol metabolism in Europeans. However, the data do not support the hypothesis that this leads to effects on alcohol sensitivity, consumption, or risk of dependence.

A Transdiagnostic Approach to Understanding Eating Disorders

Categorical models dominate the eating disorder field, but the tandem use of categorical and dimensional models has been proposed. A transdiagnostic dimensional model, number of lifetime eating disorder behaviors (LEDB), was examined with respect to (1) its relationship to a variety of indicators of the individual's functioning, (2) the degree to which it was influenced by genetic and environmental risk factors, and (3) exposure to specific environmental risk factors. Data from self-report and interview from 1002 female twins (mean age = 34.91 years, SD = 2.09) were examined. While 15.4% women met criteria for a lifetime eating disorder, 29% had at least one LEDB. The dimensional measure provided an indicator of associated functioning, and was influenced primarily by the nonshared environment. The number of LEDB was associated with the degree of impaired functioning. This impairment was associated with conflict between parents and criticism from parents when growing up.

Genetic and environmental influences on extreme personality dispositions in adolescent female twins

Background: The objective was to determine whether the pattern of environmental and genetic influences on deviant personality scores differs from that observed for the normative range of personality, comparing results in adolescent and adult female twins. Methods: A sample of 2,796 female adolescent twins ascertained from birth records provided Junior Eysenck Personality Questionnaire data. The average age of the sample was 17.0 years ( S. D. 2.3). Genetic analyses of continuous and extreme personality scores were conducted. Results were compared for 3,178 adult female twins. Results: Genetic analysis of continuous traits in adolescent female twins were similar to findings in adult female twins, with genetic influences accounting for between 37% and 44% of the variance in Extraversion (Ex), Neuroticism (N), and Social Non-Conformity (SNC), with significant evidence of shared environmental influences (19%) found only for SNC in the adult female twins. Analyses of extreme personality characteristics, defined categorically, in the adolescent data and replicated in the adult female data, yielded estimates for high N and high SNC that deviated substantially (p < .05) from those obtained in the continuous trait analyses, and provided suggestive evidence that shared family environment may play a more important role in determining personality deviance than has been previously found when personality is viewed continuously. However, multiple-threshold models that assumed the same genetic and environmental determinants of both normative range variation and extreme scores gave acceptable fits for each personality dimension. Conclusions: The hypothesis of differences in genetic or environmental factors responsible for N and SNC among female twins with scores in the extreme versus normative ranges was partially supported, but not for Ex.

Butyrylcholinesterase: Association with the metabolic syndrome and identification of 2 gene loci affecting activity

Background: Plasma cholinesterase activity is known to be correlated with plasma triglycerides, HDL- and LDL-cholesterol, and other features of the metabolic syndrome. A role in triglyceride metabolism has been proposed. Genetic variants that decrease activity have been studied extensively, but the factors contributing to overall variation in the population are poorly understood. We studied plasma cholinesterase activity in a sample of 2200 adult twins to assess covariation with cardiovascular risk factors and components of the metabolic syndrome, to determine the degree of genetic effects on enzyme activity, and to search for quantitative trait loci affecting activity. Methods and Results: Cholinesterase activity was lower in women than in men before the age of 50, but increased to activity values similar to those in males after that age. There were highly significant correlations with variables associated with the metabolic syndrome: plasma triglyceride, HDL- and LDL-cholesterol, apolipoprotein B and E, urate, and insulin concentrations; gamma-glutamyltransferase and aspartate and alanine aminotransferase activities; body mass index; and blood pressure. The heritability of plasma cholinesterase activity was 65%. Linkage analysis with data from the dizygotic twin pairs showed suggestive linkage on chromosome 3 at the location of the cholinesterase WHO gene and also on chromosome 5. Conclusions: Our results confirm and extend the connection between cholinesterase, cardiovascular risk factors, and metabolic syndrome. They establish a substantial heritability for plasma cholinesterase activity that might be attributable to variation near the structural gene and at an independent locus. (c) 2006 American Association for Clinical Chemistry.

A genome scan for epidermal skin pattern in adolescent twins reveals suggestive linkage on 12p13.31

Deterioration in stratum corneum reticular patterning (skin pattern or skin wrinkling) has been associated with increased rates of solar keratoses and skin cancer. A previous analysis of data from the twin sample used in this investigation has shown that 86% of the variation in skin pattern is genetic at age 12 and 62% in an adult sample (mean age 47.5). Variation due to genetic influences is likely to be influenced by more than one locus. Here, we present results of a genome-wide linkage scan of skin pattern in adolescent twins and siblings from 428 nuclear twin families. Sib-pair linkage analysis was performed on skin pattern data collected from twins at age 12 (378 informative families) and 14 (316 families). Suggestive linkage was found at marker D12S397 (12p13.31, logarithm of the odds (lod) 1.94), when the effect of the trait locus was modelled to influence the skin pattern equally at both ages 12 and 14. In the same analysis, a peak was seen at 4q23 with a lod score of 1.55. A possible candidate for the peak at 12p13.31 is the protease inhibitor, alpha-2-macroglobulin.

Cognitive modelling and the behaviour genetics of reading

While it is well known that reading is highly heritable, less has been understood about the bases of these genetic influences. In this paper, we review the research that we have been conducting in recent years to examine genetic and environmental influences on the particular reading processes specified in the dual-route cognitive model of reading. We argue that a detailed understanding of the role of genetic factors in reading acquisition requires the delineation and measurement of precise phenotypes, derived from well-articulated models of the reading process. We report evidence for independent genetic influences on the lexical and nonlexical reading processes represented in the dual-route model, based on studies of children with particular subtypes of dyslexia, and on univariate and multivariate genetic modelling of reading performance in the normally reading population.

Heritability and nineteen-year stability of long and short EPQ-R Neuroticism scales

The heritability and stability over a 19 year period of long (23-item) and short (12-item) versions of Eysenck's Neuroticism scale were compared in a large Australian twin-family sample. Stability over 19 years of the 23-item Neuroticism scale was 0.62 and for the 12-item scale 0.59. Correlations between scores obtained by mailed questionnaire and telephone interview a few weeks apart were 0.87 for the long scale and 0.85 for the short scale; scores obtained by mail were slightly higher, particularly for females. The 12-item scale had slightly reduced power to discriminate both high and low scoring individuals on the full 23-item scale. Mean Neuroticism score for the 12-item scale was atypically low when compared to the distribution of the complete set of scores for all possible combinations (> 1 million) of 12-items drawn from the full 23-item EPQ-R. Mean heritabilities for the lowest and highest 300,000 of these combinations were 43.2% and 42.7%, respectively, somewhat higher than the 41.0% for the actual EPQ-R-S 12-item scale. Heritability for the 23-item scale was 46.5%. We conclude that there is little loss of either stability or heritability in using the short EPQ-R scale, but the choice of which 12-items could have been better. (c) 2005 Elsevier Ltd. All rights reserved.

The heritability of conscientiousness facets and their relationship to IQ and academic achievement

The heritability of conscientiousness has been one of the least explored of the NEO PI domains. Here we focus on the facet scales of the conscientiousness domain, estimating both their heritability and their correlations with measures of IQ and academic achievement (Queensland Core Skills Test; QCST) in a sample of adolescent twins and their non-twin siblings. Our findings confirmed positive associations between IQ and the facets of Competence and Dutifulness (ranging 0.11-0.27), with academic achievement showing correlations of 0.27 and 0.15 with these same facets and 0.15 with Deliberation. All conscientiousness facets were influenced by genes (broad sense heritabilities ranging 0.18-0.49) and unique environment, but common environment was judged unimportant. A multivariate genetic analysis including Competence, Dutifulness, IQ (verbal, performance) and QCST scores showed that common variance was primarily explained by a general additive genetic factor (loadings ranging 0.15-0.84). Future multivariate genetic analysis which incorporates Openness to Experience dimensions may improve the interpretation of these findings. (c) 2005 Elsevier Ltd. All rights reserved.

Assumption-free estimation of heritability from genome-wide identity-by-descent sharing between full siblings

The study of continuously varying, quantitative traits is important in evolutionary biology, agriculture, and medicine. Variation in such traits is attributable to many, possibly interacting, genes whose expression may be sensitive to the environment, which makes their dissection into underlying causative factors difficult. An important population parameter for quantitative traits is heritability, the proportion of total variance that is due to genetic factors. Response to artificial and natural selection and the degree of resemblance between relatives are all a function of this parameter. Following the classic paper by R. A. Fisher in 1918, the estimation of additive and dominance genetic variance and heritability in populations is based upon the expected proportion of genes shared between different types of relatives, and explicit, often controversial and untestable models of genetic and non-genetic causes of family resemblance. With genome-wide coverage of genetic markers it is now possible to estimate such parameters solely within families using the actual degree of identity-by-descent sharing between relatives. Using genome scans on 4,401 quasi-independent sib pairs of which 3,375 pairs had phenotypes, we estimated the heritability of height from empirical genome-wide identity-by-descent sharing, which varied from 0.374 to 0.617 (mean 0.498, standard deviation 0.036). The variance in identity-by-descent sharing per chromosome and per genome was consistent with theory. The maximum likelihood estimate of the heritability for height was 0.80 with no evidence for non-genetic causes of sib resemblance, consistent with results from independent twin and family studies but using an entirely separate source of information. Our application shows that it is feasible to estimate genetic variance solely from within- family segregation and provides an independent validation of previously untestable assumptions. Given sufficient data, our new paradigm will allow the estimation of genetic variation for disease susceptibility and quantitative traits that is free from confounding with non-genetic factors and will allow partitioning of genetic variation into additive and non-additive components.