Australian Twin Research Articles

The Role of Copper and Zinc in Irritable Bowel Syndrome: A Mendelian Randomization Study.

Irritable bowel syndrome (IBS) has been associated with copper and zinc imbalance and a zinc-deficient diet. Mendelian randomization was used in this study to evaluate if genetically determined copper and zinc levels play a causal role in the development of IBS. Three single-nucleotide polymorphisms (SNPs; rs1175550, rs2769264, and rs2769270) associated with erythrocyte copper levels, and 3 SNPs associated with erythrocyte zinc levels (rs11638477, rs1532423, and rs2120019) in the Australian Twin Study (1993-1996 and 2001-2005) were used as instrumental variables for levels of these metals. The association of these SNPs with IBS was tested using summary statistics computed from data on 340,331 individuals from the UK Biobank, 5,548 of whom had IBS (2006-2010). Genetically predicted high serum copper levels were associated with a lower risk of IBS (odds ratio = 0.89; 95% confidence interval: 0.80, 0.98). Genetically predicted, high serum zinc levels were nonsignificantly associated with a higher risk of IBS (odds ratio = 1.06; 95% confidence interval: 0.95, 1.18). Sensitivity analysis did not suggest the presence of pleiotropy. These results suggest that high erythrocyte copper levels may be protective against IBS development. Targeting higher levels, therefore, may provide an avenue to reduce the likelihood of IBS development in high-risk individuals.

The genetic architecture of anterior tooth morphology in a longitudinal sample of Australian twins and families

ObjectiveThis study presents a quantitative genetic analysis of human anterior dental morphology in a longitudinal sample of known genealogy. The primary aim of this work is to generate a suite of genetic correlations within and between deciduous and permanent characters to access patterns of integration across the diphyodont dental complex. DesignData were recorded from casted tooth crowns representing participants of a long-term Australian twin and family study (deciduous n = 290, permanent n = 339). Morphological trait expression was observed and scored following Arizona State University Dental Anthropology System standards. Bivariate genetic correlations were estimated using maximum likelihood variance decomposition models in SOLAR v.8.1.1. ResultsGenetic correlation estimates indicate high levels of integration between antimeres but low to moderate levels among traits within a tooth row. Only 9% of deciduous model comparisons were significant, while pleiotropy was indicated for one third of permanent trait pairs. Canine characters stood out as strongly integrated, especially in the deciduous dentition. For homologous characters across dentitions (e.g., deciduous i1 shoveling and permanent I1 shoveling), ∼70% of model comparisons yielded significant genetic correlations. ConclusionsPatterns of genetic correlation suggest a morphological canine module that spans the primary and secondary dentition. Results also point to the existence of a genetic mechanism conserving morphology across the diphyodont dental complex, such that paired deciduous and permanent traits are more strongly integrated than characters within individual tooth rows/teeth.

Investigating Olfactory Gene Variation and Odour Identification in Older Adults.

Ageing is associated with a decrease in odour identification. Additionally, deficits in olfaction have been linked to age-related disease and mortality. Heritability studies suggest genetic variation contributes to olfactory identification. The olfactory receptor (OR) gene family is the largest in the human genome and responsible for overall odour identification. In this study, we sought to find olfactory gene family variants associated with individual and overall odour identification and to examine the relationships between polygenic risk scores (PRS) for olfactory-related phenotypes and olfaction. Participants were Caucasian older adults from the Sydney Memory and Ageing Study and the Older Australian Twins Study with genome-wide genotyping data (n = 1395, mean age = 75.52 ± 6.45). The Brief-Smell Identification Test (BSIT) was administered in both cohorts. PRS were calculated from independent GWAS summary statistics for Alzheimer’s disease (AD), white matter hyperintensities (WMH), Parkinson’s disease (PD), hippocampal volume and smoking. Associations with olfactory receptor genes (n = 967), previously identified candidate olfaction-related SNPs (n = 36) and different PRS with BSIT scores (total and individual smells) were examined. All of the relationships were analysed using generalised linear mixed models (GLMM), adjusted for age and sex. Genes with suggestive evidence for odour identification were found for 8 of the 12 BSIT items. Thirteen out of 36 candidate SNPs previously identified from the literature were suggestively associated with several individual BSIT items but not total score. PRS for smoking, WMH and PD were negatively associated with chocolate identification. This is the first study to conduct genetic analyses with individual odorant identification, which found suggestive olfactory-related genes and genetic variants for multiple individual BSIT odours. Replication in independent and larger cohorts is needed.

Factors associated with care-seeking for low back pain when genetics and the familial environment are considered

BackgroundLow back pain (LBP) is the leading cause of disability worldwide. Care-seekers for LBP cause substantial economic burden to governments and the healthcare system. ObjectiveTo investigate lifestyle and health-related factors associated with care-seeking (including pain medication use) in individuals experiencing LBP, after controlling for important genetic and early environmental confounders through the use of a within-twin pair case-control design. DesignA secondary analysis of observational longitudinal data, derived from the Australian Twin low BACK pain (AUTBACK) study, was performed on 66 twin pairs that presented with similar symptoms of LBP at baseline but became discordant for care-seeking behaviour over one month. MethodsSubjective and objective assessment of pain intensity, disability, depression, sleep quality, physical activity and body mass index were performed. Data was analysed using stepwise conditional logistic regression in two stages: within-pair case–control for monozygotic and dizygotic twins together; and within-pair case–control analysis of monozygotic twins only. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI). ResultsHigher LBP intensity (OR 2.9; 95% CI 1.3–6.8) and poorer sleep quality (OR 10.9; 95% CI 1.5–77.7) were the main factors that increased the likelihood of care-seeking for LBP. These associations remained significant and increased in magnitude after adjusting for genetic confounding. ConclusionsIndividuals with higher LBP intensity and worse sleep quality are more likely to seek care for LBP, and this relationship is likely to be causal after adjustment of familial and genetic confounding.

Familial and Genetic Influences on the Common Pediatric Primary Pain Disorders: A Twin Family Study.

The primary pain disorders of childhood are highly prevalent but have infrequently been studied collectively. Genetic influences have been suggested to be causally implicated. Surveys were sent to 3909 Australian twin families, assessing the lifetime prevalence of growing pains, migraine, headache, recurrent abdominal pain, low back pain, and persistent pain (not otherwise specified) in pediatric twins and their immediate family members. Comparisons between monozygous (MZ) and dizygous (DZ) twin pair correlations, concordances and odds ratios were performed to assess the contribution of additive genetic influences. Random-effects logistic regression modelling was used to evaluate relationships between twin individuals and their co-twins, mothers, fathers and oldest siblings with the subject conditions. Twin analyses of responses from 1016 families revealed significant influence of additive genetic effects on the presence of growing pains, migraine, and recurrent abdominal pain. The analyses for headache, low back pain, and persistent pain overall did not conclusively demonstrate that genetic influences were implicated more than shared environmental factors. Regression analyses demonstrated varying levels of significance in relationships between family members and twin individuals for the tested conditions, with strongest support for genetic influences in growing pains and migraine. These data, together with previously published association analyses, suggest common causal influences including genes.

Are prescription misuse and illicit drug use etiologically distinct? A genetically-informed analysis of opioids and stimulants.

Drug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue. A total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use of opioids and stimulants. Univariate and bivariate biometric models partitioned variances and covariances into additive genetic, shared environmental, and unique environmental influences across drug types. Variation in the propensity to misuse prescription opioids was attributable to genes (41%) and unique environment (59%). Illicit opioid use was attributable to shared (71%) and unique (29%) environment. Prescription stimulant misuse was attributable to genes (79%) and unique environment (21%). Illicit stimulant use was attributable to genes (48%), shared environment (29%), and unique environment (23%). There was evidence for genetic influence common to both stimulant types, but limited evidence for genetic influence common to both opioid types. Bivariate correlations suggested that prescription opioid use may be more genetically similar to prescription stimulant use than to illicit opioid use. Prescription opioid misuse may share little genetic influence with illicit opioid use. Future research may consider avoiding unitary drug classifications, particularly when examining genetic influences.

The Australian Twins Economic Preferences Survey

This paper describes the Australian Twins Economic Preferences Survey (ATEPS). The dataset comprises a wide variety of preference and behavioral measures (risk aversion, impatience, ambiguity aversion, trust, confidence) elicited using incentivised decision tasks. 1,120 Australian adult twins (560 pairs) completed the survey, making it one of the largest datasets containing incentivised preference measures of twins. As the survey was conducted during the COVID-19 pandemic, we also collected information on experiences related to the pandemic, along with a variety of questions on political attitudes and mental wellbeing. We hope that ATEPS can make a valuable contribution to social science and genetics research.

The Australian Twins Economic Preferences Survey

This paper describes the Australian Twins Economic Preferences Survey (ATEPS). The dataset comprises a wide variety of preference and behavioral measures (risk aversion, impatience, ambiguity aversion, trust, confidence) elicited using incentivised decision tasks. 1,120 Australian adult twins (560 pairs) completed the survey, making it one of the largest datasets containing incentivised preference measures of twins. As the survey was conducted during the COVID-19 pandemic, we also collected information on experiences related to the pandemic, along with a variety of questions on political attitudes and mental wellbeing. We hope that ATEPS can make a valuable contribution to social science and genetics research.

16Up: Outline of a Study Investigating Wellbeing and Information and Communication Technology Use in Adolescent Twins

The '16Up' study conducted at the QIMR Berghofer Medical Research Institute from January 2014 to December 2018 aimed to examine the physical and mental health of young Australian twins aged 16-18 years (N = 876; 371 twin pairs and 18 triplet sets). Measurements included online questionnaires covering physical and mental health as well as information and communication technology (ICT) use, actigraphy, sleep diaries and hair samples to determine cortisol concentrations. Study participants generally rated themselves as being in good physical (79%) and mental (73%) health and reported lower rates of psychological distress and exposure to alcohol, tobacco products or other substances than previously reported for this age group in the Australian population. Daily or near-daily online activity was almost universal among study participants, with no differences noted between males and females in terms of frequency or duration of internet access. Patterns of ICT use in this sample indicated that the respondents were more likely to use online information sources for researching physical health issues than for mental health or substance use issues, and that they generally reported partial levels of satisfaction with the mental health information they found online. This suggests that internet-based mental health resources can be readily accessed by adolescent Australians, and their computer literacy augurs well for future access to online health resources. In combination with other data collected as part of the ongoing Brisbane Longitudinal Twin Study, the 16Up project provides a valuable resource for the longitudinal investigation of genetic and environmental contributions to phenotypic variation in a variety of human traits.

The Association Between Chronic Disease and Psychological Distress: An Australian Twin Study.

There is a commonly observed association between chronic disease and psychological distress, but many potential factors could confound this association. This study investigated the association using a powerful twin study design that can control for unmeasured confounders that are shared between twins, including genetic and environmental factors. We used twin-paired cross-sectional data from the Adult Health and Lifestyle Questionnaire collected by Twins Research Australia from 2014 to 2017. Linear regression models fitted using maximum likelihood estimations (MLE) were used to test the association between self-reported chronic disease status and psychological distress, measured by the Kessler Psychological Distress Scale (K6). When comparing between twin pairs, having any chronic disease was associated with a 1.29 increase in K6 (95% CI: 0.91, 1.66; p < .001). When comparing twins within a pair, having any chronic disease was associated with a 0.36 increase in K6 (95% CI: 0.002, 0.71; p = .049). This within-pair estimate is of most interest as comparing twins within a pair naturally controls for shared factors such as genes, age and shared lived experiences. Whereas the between-pair estimate does not. The weaker effect found within pairs tells us that genetic and environmental factors shared between twins confounds the relationship between chronic disease and psychological distress. This suggests that associations found in unrelated samples may show exaggerated estimates.

Sex differences in risk factors for white matter hyperintensities in non-demented older individuals

White matter hyperintensities (WMH) are generally considered to be associated with cerebral small vessel disease, especially, in older age. Although significant sex differences have been reported in the severity of WMH, it is not yet known if the risk factors for WMH differ in men and women. In this study, magnetic resonance imaging brain scans from 2 Australian cohorts were analyzed to extract WMH volumes. The objective of this study is to examine the moderation effect by sex in the association between known risk factors and WMH. The burden of WMH was significantly higher in women compared to men, especially in the deep WMH (DWMH). In the generalized linear model that included the interaction between sex and body mass index (BMI), there was a differential association of BMI with DWMH in men and women in the exploratory sample, that is, the Sydney Memory and Aging Study, n = 432, aged between 70 and 90. The finding of a higher BMI associated with a higher DWMH in men compared to women was replicated in the Older Australian Twins Study sample, n = 179, aged between 65 and 90. The risk factors of WMH pathology are suggested to have a different impact on the aging brains of men and women.

The role of locus of control in adulthood outcomes: Evidence from Australian twins

Abstract We study the impact of locus of control on adulthood outcomes. We address the issue of omitted shared family background and genetic factors using data on monozygotic (MZ) and dizygotic (DZ) twins from Australia. Estimation results are highly sensitive to controlling adequately for shared background and genes. While the associations between locus of control and most adulthood outcomes are statistically significant and similar across OLS and DZ twins fixed effect models, they are insignificant in the MZ twins fixed effect models. Two important exceptions emerge. Locus of control remains significantly associated with regular physical exercise and occupational rank, in line with the previous literature. We discuss the implications of our findings.

Sex differences in the relative influence of marital status and parenthood on alcohol use disorder symptoms: A multilevel discordant twin design.

Marriage and parenthood are associated with alcohol use and use disorder (AUD), although they are confounded such that many studies struggle to identify their unique and/or causal effects. The present study utilized a genetically informed discordant twin design that strengthens the putative causal role of marital and parental status in the presentation of AUD symptoms by using each individual's cotwin as their own control while simultaneously modeling both predictors among men and women. Participants were 980 complete same-sex twin pairs from the Australian Twin Registry (Mage = 31.70 [SD = 2.48]; 71% women). Marital status, parental status, and past year AUD symptoms were assessed via semistructured interview. Three random-intercept generalized linear mixed models were fit in men and women including (a) marital status only, (b) parental status only, and (c) both marital and parental status; demographics, past year pregnancy, age of first drink, age of regular drinking, personality traits, and antisociality were included as covariates. Models tested for quasi-causal and familial effects. The sole-predictor marital status model (Model 1) provided the best fit among men, while the simultaneous-predictor marital and parental status model (Model 3) provided the best fit among women. Sole-predictor models showed familial effects of both predictors among men and quasi-causal and familial effects of both predictors among women; the simultaneous-predictor model revealed familial effects of marital status only among men and quasi-causal effects of parental status only among women. The present study elucidates important sex differences in the presentation of AUD among midlife adults in the context of notable developmental milestones. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Typologies of illicit drug use in mid-adulthood: a quasi-longitudinal latent class analysis in a community-based sample of twins.

To identify drug use typologies based on substances used and persistence of use over two time points, use a genetically informed design to explore twin concordance of and genetic influence on the use typologies and compare patterns of declined/discontinued ("desistant") and persistent drug use on drug use correlates. Latent class analysis was applied to data from a cross-sectional self-report survey on current and past drug use. Use characteristics, use disorder, and psychiatric problems were compared across classes. Computer-assisted telephone interview in respondents' homes. A total of 3785 individual twins and siblings (1365 men, 2420 women; Mage =32) from the Australian Twin Registry Cohort III. A comprehensive interview assessed prior to past year and past year use of cannabis, stimulants, cocaine/crack, hallucinogens, opioids, sedatives, inhalants, dissociatives, and solvents; age of first use; opportunity to use; peer drug use; attention deficit/hyperactivity, conduct, antisocial personality, depressive, and substance use disorders; and suicidality. A five-class solution emerged: no/low use (50%), desistant cannabis use (23%), desistant party drug use (18%), persistent prescription drug misuse (4%), and persistent polydrug use (5%). Twin concordances were higher among monozygotic (k =0.30-0.35) than dizygotic pairs (same-sex k =0.19-0.20; opposite sex k =0.07), and biometric modeling suggested that the persistent polydrug use class, in particular, was highly heritable (a2 =0.94). Conduct disorder (OR=2.40), antisocial personality disorder (OR=3.27), and suicidal ideation (OR=1.98) increased persistent polydrug use risk; depression (OR=2.38) and lifetime suicide attempt (OR=2.31) increased persistent prescription misuse risk. Relative to persistent prescription drug misuse, persistent polydrug use was associated with higher rates of cannabis and stimulant use disorder (OR=6.14-28.01), younger first substance use (OR=0.82-0.83), more drug use opportunity (OR=10.66-66.06), and more drug-using peers (OR=4.66-9.20). Unique patterns of declined/discontinued ("desistant") and persistent drug use are differentially heritable and differentially associated with risk factors, psychiatric symptoms, and substance use disorder outcomes.

Diverse phenotypic measurements of wellbeing: Heritability, temporal stability and the variance explained by polygenic scores.

Wellbeing, a key aspect of mental health, is moderately heritable with varying estimates reported from independent studies employing a variety of instruments. Recent genome-wide association studies (GWAS) have enabled the construction of polygenic scores (PGS) for wellbeing, providing the opportunity for direct comparisons of the variance explained by PGS for different instruments commonly employed in the field. Nine wellbeing measurements (multi-item and single-item), two personality domains (NEO-FFI neuroticism and extraversion), plus the depression domain of the DASS-42 were drawn from a larger self-report battery applied to the TWIN-E study-an Australian longitudinal twin cohort (N = 1660). Heritability was estimated using univariate twin modeling and 12-month test-retest reliability was estimated using intra-class correlation. PGS were constructed using wellbeing GWAS summary-statistics from Baselmans et al. (Nat Genet. 2019), and the variance explained estimated using linear models. Last, a GWAS was performed using COMPAS-W, a quantitative composite wellbeing measure, to explore its utility in genomic studies. Heritability estimates ranged from 23% to 47% across instruments, and multi-item measures showed higher heritability and test-retest reliability than single-item measures. The variance explained by PGS was ~0.5% to 1.5%, with considerable variation between measures, and within each measure over 12 months. Five loci with suggestive association (p < 1 × 10-5 ) were identified from this initial COMPAS-W wellbeing GWAS. This work highlights the variability across measures currently employed in wellbeing research, with multi-item and composite measures favored over single-item measures. While wellbeing PGS are useful in a research setting, they explain little of the phenotypic variance, highlighting gaps for improved gene discovery.

Childhood maltreatment and disordered gambling in adulthood: disentangling causal and familial influences.

Despite abundant research on the potential causal influence of childhood maltreatment (CM) on psychological maladaptation in adulthood, almost none has implemented the discordant twin design as a means of examining the role of such experiences in later disordered gambling (DG) while accounting for genetic and family environmental confounds. The present study implemented such an approach to disentangle the potential causal and familial factors that may account for the association between CM and DG. Participants were 3750 twins from the Australian Twin Registry [Mage = 37.60 (s.d. = 2.31); 58% female]. CM and DG were assessed separately via two semi-structured telephone interviews. Random-intercept generalized linear mixed models were fit to the data; zygosity, sex, educational attainment, childhood psychiatric disorder, adult antisocial behavior, and alcohol use disorder (AUD) were included as covariates. Neither quasi-causal nor familial effects of CM predicted DG after adjusting for covariates. Educational attainment appeared to reduce the risk of DG while AUD appeared to increase risk; evidence also emerged for familial effects of antisocial behavior on DG. Post-hoc analyses revealed a familial effect of CM on antisocial behavior, indicating that the association between CM and DG identified in unadjusted models and in prior studies may be accounted for by genetic and shared family environmental effects of antisociality. These findings add to the meager literature showing that CM does not exert a causal effect on DG, and present novel evidence that familial effects of antisocial behavior may account for the association between CM and DG identified in extant non-twin research.

Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins.

The critical role of blood lipids in a broad range of health and disease states is well recognised but less explored is the interplay of genetics and environment within the broader blood lipidome. We examined heritability of the plasma lipidome among healthy older-aged twins (75 monozygotic/55 dizygotic pairs) enrolled in the Older Australian Twins Study (OATS) and explored corresponding gene expression and DNA methylation associations. 27/209 lipids (13.3%) detected by liquid chromatography-coupled mass spectrometry (LC-MS) were significantly heritable under the classical ACE twin model (h2 = 0.28-0.59), which included ceramides (Cer) and triglycerides (TG). Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for variability in some non-heritable lipids. We reveal a complex interplay of genetic and environmental influences on the ageing plasma lipidome.

Cohort profile: the AUstralian Twin BACK pain and physical activity study (AUTBACK study)

PurposeDespite the growing evidence that physical activity and familial factors play a role in low back pain (LBP), there is a lack of robust longitudinal studies that (1) investigate the...

The Academic Development Study of Australian Twins (ADSAT): Research Aims and Design

The Academic Development Study of Australian Twins was established in 2012 with the purpose of investigating the relative influence of genes and environments in literacy and numeracy capabilities across two primary and two secondary school grades in Australia. It is the first longitudinal twin project of its kind in Australia and comprises a sample of 2762 twin pairs, 40 triplet sets and 1485 nontwin siblings. Measures include standardized literacy and numeracy test data collected at Grades 3, 5, 7 and 9 as part of the National Assessment Program: Literacy and Numeracy. A range of demographic and behavioral data was also collected, some at multiple longitudinal time points. This article outlines the background and rationale for the study and provides an overview for the research design, sample and measures collected. Findings emerging from the project and future directions are discussed.

Genetic contribution to palatal morphology variation using three-dimensional analysis in Australian twins

ObjectiveThis study aimed to provide insight into the relative contributions of genetic and environmental factors to palatal morphology variation in a cohort of Australian twins. MethodsHealthy Australian twins, aged 12–15 years (45 monozygotic, 46 same sex dizygotic, and 32 opposite-sex dizygotic) were included in the study groups. A scanner was used to obtain three-dimensional data of the maxillary arch. Palatal depth was defined by a line to the deepest point measured from the reference plane at the mid-point of the inter-pre-molar or inter-molar line. This line was then divided into 10 equal sections in order to created 10 different depths for each palatal width. Each palatal width was divided into anterior and posterior areas. Univariate genetic analysis, using the OpenMx structural equation modelling package in R, was carried out on the quantitative data using the normal assumptions of a twin model. ResultsHeritability estimates for anterior palatal width ranged from 0.75 to 0.80, and from 0.78 to 0.86 for posterior palatal width. Estimates for anterior and posterior palatal depth were 0.72 and 0.86, respectively. ConclusionsPalatal morphology tends to have a moderate to relatively high genetic contribution overall. Palate height has a higher genetic contribution posteriorly than anteriorly. The width of the deep palate is under marginally less stringent genetic regulation than the width of the shallow palate.