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Multifetal pregnancies are at risk of adverse maternal, neonatal and long-term health outcomes, and gestational weight gain (GWG) is a potentially modifiable risk factor for several of these. However, studies assessing the associations of GWG with long-term health in twins are rare, and studies which do assess these associations in twins often do not account for gestational age. Since longer gestations are likely to lead to larger GWG and lower risk of adverse outcomes, adjusting for gestational age is necessary to better understand the association of GWG with twin health outcomes. We aimed to explore long-term associations of GWG-for-gestational-age with twin anthropometric measures. The Peri/Postnatal Epigenetic Twins Study (PETS) is a prospective cohort study, which recruited women pregnant with twins from 2007 to 2009. Twins were followed-up at 18 months and 6 years of age. GWG-for-gestational-age z-scores were calculated from pre-pregnancy weight and weight at delivery. We fitted regression models to assess associations of GWG with twin weight, height and BMI at birth, 18 months, and 6 years. Of the 250 women in the PETS, 172 had GWG measured throughout pregnancy. Overall, higher GWG-for-gestational-age z-scores were associated with higher birthweight (β: 0.32 z-scores, 95% Confidence Interval (95% CI): 0.19, 0.45), BMI (β: 0.29 z-scores, 95% CI: 0.14, 0.43) and length (β: 0.27 z-scores, 95% CI: 0.09, 0.45). However, these associations were not observed at 18 months or 6 years of age. GWG was associated with twin length, weight and BMI at birth but not during childhood. Further research is needed to determine the long-term effects of GWG on twin health outcomes.

BackgroundComputed tomography (CT) scans make substantial contributions to low-dose ionizing radiation exposures, raising concerns about excess cancers caused by diagnostic radiation.MethodsDeidentified medicare records for all Australians aged 0–19 years between 1985–2005 were linked to national death and cancer registrations to 2012. The National Cancer Institute CT program was used to estimate radiation doses to the brain from CT exposures in 1985–2005, Poisson regression was used to model the dependence of brain cancer incidence on brain radiation dose, which lagged by 2 years to minimize reverse causation bias.ResultsOf 10 524 842 young Australians, 611 544 were CT-exposed before the age of 20 years, with a mean cumulative brain dose of 44 milligrays (mGy) at an average follow-up of 13.5 years after the 2-year lag period. 4472 were diagnosed with brain cancer, of whom only 237 had been CT-exposed. Brain cancer incidence increased with radiation dose to the brain, with an excess relative risk of 0.8 (95% CI 0.57–1.06) per 100 mGy. Approximately 6391 (95% CI 5255, 8155) persons would need to be exposed to cause 1 extra brain cancer.ConclusionsFor brain tumors that follow CT exposures in childhood by more than 2 years, we estimate that 40% (95% CI 29%–50%) are attributable to CT Radiation and not due to reverse causation. However, because of relatively low rates of CT exposure in Australia, only 3.7% (95% CI 2.3%–5.4%) of all brain cancers are attributable to CT scans. The population-attributable fraction will be greater in countries with higher rates of pediatric scanning.

Although twins often participate in medical research, few clinical trials are conducted entirely in twin populations. The purpose of this review is to demonstrate the substantial benefits and address the key challenges of conducting clinical trials in twin populations, or ‘twin-only trials’. We consider the unique design, analysis, recruitment and ethical issues that arise in such trials. In particular, we describe the different approaches available for randomizing twin pairs, highlight the similarity or correlation that exists between outcomes of twins, and discuss the impact of this correlation on sample size calculations and statistical analysis methods for estimating treatment effects. We also consider the role of both monozygotic and dizygotic twins for studying variation in outcomes, the factors that may affect recruitment of twins, and the ethics of conducting trials entirely in twin populations. The advantages and disadvantages of conducting twin-only trials are also discussed. Finally, we recommend that twin-only trials should be considered more often.

Background In infancy, males are at higher risk of dying than females. Birthweight and gestational age are potential confounders or mediators but are also familial and correlated, posing epidemiological challenges that can be addressed by studying male-female twin pairs. Methods We studied 28 558 male-female twin pairs born in Brazil between 2012 and 2016, by linking their birth and death records. Using a co-twin control study matched for gestational age and familial factors, we applied logistic regression with random effects (to account for paired data) to study the association between male sex and infant death, adjusting for: birthweight, within- and between-pair effects of birthweight, birth order and gestational age, including interactions. The main outcome was infant mortality (0–365 days) stratified by neonatal (early and late) and postneonatal deaths. Results Males were 100 g heavier and more at risk of infant death than their female co-twins before [odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.11–1.49, P = 0.001] and after (OR = 1.60, 95% CI: 1.39–1.83, P Conclusions After matching for gestational age and familial factors by design and controlling for birthweight and birth order, males remain at greater risk of infant death than their female co-twins. Birthweight’s role as a confounder can be partially explained by familial factors.

Birthweight has been consistently related to risk of cardiometabolic disorders in later life. Twins are at higher risk of low birthweight than singletons, so understanding the links between birthweight and cardiometabolic health may be particularly important for twins. However, evidence for the association of birthweight with childhood markers of cardiometabolic health in twins is currently lacking. Previous studies have often failed to appropriately adjust for gestational age or fully implement twin regression models. Therefore, we aimed to evaluate the association of birthweight-for-gestational-age z-scores with childhood cardiometabolic health in twins, using within-between regression models. The Peri/Postnatal Epigenetic Twins Study is a Melbourne-based prospective cohort study of 250 twin pairs. Birthweight was recorded at delivery, and childhood anthropometric measures were taken at 18-month and 6-year follow-up visits. Associations of birthweight with markers of cardiometabolic health were assessed at the individual, between- and within-pair level using linear regression with generalised estimating equations. Birthweight-for-gestational-age z-scores were associated with height, weight and BMI at 18 months and 6 years, but not with blood pressure (twins-as-individual SBP: β = 0.15, 95% CI: −0.81, 1.11; twins-as-individual DBP: β = 0.22, 95% CI: −0.34, 0.77). We found little evidence to indicate that the within-between models improved on the twins-as-individuals models. Birthweight was associated with childhood anthropometric measures, but not blood pressure, after appropriately adjusting for gestational age. These associations were consistent across the within-between and twins-as-individuals models. After adjusting for gestational age, results from the twins-as-individuals models are consistent with singleton studies, so these results can be applied to the general population.

Adult socioeconomic status (SES) has been consistently associated with body mass index (BMI), but it is unclear whether it is linked to BMI independently of childhood SES or other potentially confounding factors. Twin studies can address this issue by implicitly controlling for childhood SES and unmeasured confounders. This co-twin control study used cross-sectional data from Twins Research Australia’s Health and Lifestyle Questionnaire (N = 1918 twin pairs). We investigated whether adult SES, as measured by both the Index of Relative Socioeconomic Disadvantage (IRSD) and the Australian Socioeconomic Index 2006 (AUSEI06), was associated with BMI after controlling for factors shared by twins within a pair. The primary analysis was a linear mixed-effects model that estimated effects both within and between pairs. Between pairs, a 10-unit increase in AUSEI06 was associated with a 0.29 kg/m2 decrease in BMI (95% CI [−.42, −.17], p < .001), and a 1-decile increase in IRSD was associated with a 0.26 kg/m2 decrease in BMI (95% CI [−.35, −.17], p < .001). No association was observed within pairs. In conclusion, higher adult SES was associated with lower BMI between pairs, but no association was observed within pairs. Thus, the link between adult SES and BMI may be due to confounding factors common to twins within a pair.

Children undergoing computed tomography (CT) scans have an increased risk of cancer in subsequent years, but it is unclear how much of the excess risk is due to reverse causation bias or confounding, rather than to causal effects of ionising radiation. An examination of the relationship between excess cancer risk and organ dose can help to resolve these uncertainties. Accordingly, we have estimated doses to 33 different organs arising from over 900 000 CT scans between 1985 and 2005 in our previously described cohort of almost 12 million Australians aged 0–19 years. We used a multi-tiered approach, starting with Medicare billing details for government-funded scans. We reconstructed technical parameters from national surveys, clinical protocols, regulator databases and peer-reviewed literature to estimate almost 28 000 000 individual organ doses. Doses were age-dependent and tended to decrease over time due to technological improvements and optimisation.

PURPOSE: We studied individual variability in exercise responses in twins. We hypothesized that 1) endurance (END) training would reduce fat mass whereas resistance (RES) training would increase lean mass, 2) individuals who did not respond to one modality would respond to the other, and 3) cross-sectional heritability estimates would be higher than estimates based on training responses. METHODS: DXA was undertaken in 84 same-sex untrained twins (30 monozygotic [MZ], 12 dizygotic [DZ]). Participants underwent 3 months of END and RES training, separated by 3 months washout. Twins trained in pairs. RESULTS: RES (P < 0.001) and END (P = 0.002) increased lean mass, with a greater change in RES (P < 0.001). Similarly, RES (P = 0.04) and END (P = 0.006) decreased fat mass. Eighty-four percent of subjects responded positively to RES for lean mass and 58% to END (P < 0.001). For fat mass, RES and END induced 56% and 66% responder rates, respectively (P = 0.28). Cross-sectional intraclass correlations, used to assess the similarity in twin responses, were higher for MZ than DZ pairs for all variables. Following training, only MZ pairs were significantly correlated (P < 0.001) for change in lean mass to RES. CONCLUSION: To our knowledge, this study is the first to report individual responsiveness in body composition to both RES and END in the same subjects. Although RES and END induced favorable changes in fat mass, RES was superior for lean mass. The frequency of lean mass responders to RES exceeded that for END, whereas response rates for fat mass were similar. Cross-sectional heritability estimates were higher than training response estimates, and shared environment had the largest influence on changes in body composition. This study suggests that exercise professionals should consider modality and environmental factors when optimizing exercise interventions.

Gestational weight gain (GWG) has been associated with maternal and child health outcomes, but knowledge of appropriate GWG for twin gestations is limited.The Peri/Postnatal Epigenetic Twins Study is a prospective twin cohort study of 250 women and their twin children in Melbourne, Australia. We modeled trajectories of GWG using group-based growth modeling and compared these trajectories to GWG categories (within, above, or below current GWG recommendations for twin pregnancy). We fitted robust linear and Poisson regression models to assess associations of maternal pre-pregnancy and gestational exposures with risk of gaining weight outside the recommendations.Of the 250 women enrolled in the PETS, GWG measures were available for 172 women. Forty-seven percent of women had GWG within the current recommendations. We identified three GWG trajectories - 23.6% of women had low GWG throughout pregnancy, 34.5% had average GWG throughout pregnancy, and 42.0% had average initial GWG, followed by high GWG from trimester two until delivery. Gestational diabetes mellitus (GDM) was associated with increased risk of inadequate GWG (RR: 2.40, 95%CI: 1.53, 3.75). Pre-pregnancy obesity (RR: 1.88, 95%CI: 1.09, 3.26) and hypertensive disorders of pregnancy (RR: 2.64, 95%CI: 1.20, 5.81) were associated with increased risk of excessive GWG.More than half of the women in the PETS did not meet the current GWG recommendations. Women with GDM or hypertensive disorders were more likely to gain weight outside these guidelines. More research is needed to establish comprehensive guidelines for twin pregnancies.

Changes in left ventricular mass (LVM) and end-diastolic volume (EDV) in response to exercise training are important determinants of functional capacity in health and disease, but the impact of different exercise modalities remains unclear.Using a randomized crossover design we studied the impact of resistance (RES) and endurance (END) training using cardiac magnetic resonance imaging in previously untrained monozygotic (MZ) and dizygotic (DZ) twin pairs (n = 72; 22 MZ pairs, 14 DZ same-sex pairs; 26.1 ± 5.4 yr). Twins, as pairs, undertook 3 months of RES and 3 months of END training (order randomized), separated by a 3-month washout.Group results revealed that END increased LVM (P0.001) and EDV (P = 0.007), whereas RES did not (P0.05). A higher proportion of individuals responded to END than RES for LVM (72% vs 38%, P0.001) and EDV (67% vs 40%, P = 0.003). Baseline cross-sectional intraclass correlations were higher for MZ than DZ twin pairs for all variables (e.g., LVM heritability = 0.42), but no significant correlations were apparent between pairs for change in any variable in response to either RES or END (P0.05).Our findings indicate that cardiac adaptation in response to exercise is modality-specific and that low responders to one mode of exercise can be high responders to an alternative. Heritability estimates based on cross-sectional data, which suggested a genetic contribution to LVM, do not accord with estimates based on training effects, which indicated limited genetic impact on adaptation in this 3-month study of exercise training. This study has implications for understanding the physiological and health impacts of typically used exercise modalities on cardiac adaptation in previously untrained individuals.

We welcome the recent South Korean cohort study by Hong et al . (1), which estimated cancer risks following low-dose diagnostic radiation exposure before age 20. This study captured 12,068,821 patients from a nationally representative sample of South Korean residents. The study is larger than previous paediatric CT cohort studies (2-7), exceeding the number of CT exposed individuals (n=1,179,021) of all previous studies combined; though this advantage is offset by relatively short follow-up time. Including all forms of diagnostic radiation (not just CT scans), this study had a total of 1,275,829 individuals exposed to at least one low-dose medical radiation procedure. This important study of paediatric imaging is the first from South Korea, and the second from Asia, following the work of Huang et al . (4). Our commentary compares and contrasts this new study with earlier studies, highlighting advantages, potential limitations and outstanding questions.

Twins Research Australia (TRA) is a community of twins and researchers working on health research to benefit everyone, including twins. TRA leads multidisciplinary research through the application of twin and family study designs, with the aim of sustaining long-term twin research that, both now and in the future, gives back to the community. This article summarizes TRA’s recent achievements and future directions, including new methodologies addressing causation, linkage to health, economic and educational administrative datasets and to geospatial data to provide insight into health and disease. We also explain how TRA’s knowledge translation and exchange activities are key to communicating the impact of twin studies to twins and the wider community. Building researcher capability, providing registry resources and partnering with all key stakeholders, particularly the participants, are important for how TRA is advancing twin research to improve health outcomes for society. TRA provides researchers with open access to its vibrant volunteer membership of twins, higher order multiples (multiples) and families who are willing to consider participation in research. Established four decades ago, this resource facilitates and supports research across multiple stages and a breadth of health domains.

Low socioeconomic status (SES) has been established as a risk factor for poor mental health; however, the relationship between SES and mental health problems can be confounded by genetic and environmental factors in standard regression analyses and observational studies of unrelated individuals. In this study, we used a within-pair twin design to control for unmeasured genetic and environmental confounders in investigating the association between SES and psychological distress. We also employed within–between pair regression analysis to assess whether the association was consistent with causality. SES was measured using the Index of Relative Socio-economic Disadvantage (IRSD), income and the Australian Socioeconomic Index 2006 (AUSEI06); psychological distress was measured using the Kessler 6 Psychological Distress Scale (K6). Data were obtained from Twins Research Australia’s Health and Lifestyle Questionnaire (2014–2017), providing a maximum sample size of 1395 pairs. Twins with higher AUSEI06 scores had significantly lower K6 scores than their co-twins after controlling for shared genetic and environmental traits (βW [within-pair regression coefficient] = −0.012 units, p = .006). Twins with higher income had significantly lower K6 scores than their co-twins after controlling for familial confounders (βW = −0.182 units, p = .002). There was no evidence of an association between the IRSD and K6 scores within pairs (βW, p = .6). Using a twin design to eliminate the effect of potential confounders, these findings further support the association between low SES and poor mental health, reinforcing the need to address social determinants of poor mental health, in addition to interventions targeted to individuals.

AIM To assess educational outcomes of twins and quantify the degree this is mediated by gestational age and other perinatal factors. METHODS We conducted a population-based record-linkage cohort study of all live births ≥24 weeks gestation in New South Wales, Australia with a corresponding standardised school test result for grade 3 in 2008-2014. The primary outcome was whether a child met the National Minimum Standard (NMS) cut-off in literacy and numeracy domains. Robust multivariable Poisson models were used to obtain adjusted relative risks (aRRs), and mediation analysis conducted to assess contributing factors on the causal pathway. RESULTS Of 351 791 liveborn infants, 10 365 (2.9%) were twins. After adjusting for maternal covariates and compared with singletons, twins had an increased risk of not meeting the NMS for all five literacy and numeracy domains (aRR 1.27-1.45, P

Focus of Presentation Males and females differ substantially in their exposures and outcomes across the life-course. Previous research into sex differences has been limited by an inability to account for inter-individual differences in genetic factors and in their early-life environment. Studying within male-female twin pair differences offers a unique opportunity to address these weaknesses that has not yet been exploited. Findings We studied linked health administrative data for 28,054 newborn Brazilian male-female twin pairs. Using random-effects logistic regression, we found that males had 1.61 (95% CI: 1.38– 1.90, P From analysing within-pair differences in genome-wide DNA methylation in blood samples for 55 Australian adolescent male-female twin pairs, we found that 1,227 DNA methylation sites were more methylated in females while only 157 sites were more methylated in males (P Conclusions/Implications Sex differences not explained by familial confounders exist for neonatal mortality in newborns and for DNA methylation in blood during adolescence. Key messages Analysing the within-pair differences of male-female twin pairs brings novel and important strengths to the study of sex differences, helping mitigate bias from uncontrolled familial confounding caused by genetic and environmental factors.

Birthweight has been consistently related to risk of cardiometabolic disorders in later life. Twins are at higher risk of low birthweight than singletons, so understanding the links between birthweight and cardiometabolic health may be particularly important for twins. However, evidence for the association of birthweight with childhood markers of cardiometabolic health in twins is currently lacking. Previous studies have often failed to appropriately adjust for gestational age or fully implement twin regression models. Therefore, we aimed to evaluate the association of birthweight-for-gestational-age

Introduction Perinatal outcomes for singleton pregnancies are poorer, on average, for Aboriginal people than non-Aboriginal people, but little is known about Aboriginal multifetal pregnancies. Yet multifetal pregnancies and births are often more complicated and have poorer outcomes than singleton pregnancies. We describe the pregnancies, births and perinatal outcomes for Aboriginal twins born in Western Australia (WA) and New South Wales (NSW) with comparisons to Aboriginal singletons in both states and to non-Aboriginal births in NSW. Materials and methods Whole-population birth records and birth and death registrations were linked for all births during 2000–2013 (WA) and 2002–2008 (NSW). Hospital records and the WA Register of Developmental Anomalies - Cerebral Palsy were linked for all WA births and hospital records for a subset of NSW births. Descriptive statistics are reported for maternal and child demographics, maternal health, pregnancy complications, births and perinatal outcomes. Results Thirty-four thousand one hundred twenty-seven WA Aboriginal, 32,352 NSW Aboriginal and 601,233 NSW non-Aboriginal births were included. Pregnancy complications were more common among mothers of Aboriginal twins than Aboriginal singletons (e.g. 17% of mothers of WA twins had hypertension/pre-eclampsia/eclampsia vs 8% of mothers of singletons) but similar to mothers of NSW non-Aboriginal twins. Most Aboriginal twins were born in a principal referral, women’s or large public hospital. The hospitals were often far from the mother’s home (e.g. 31% of mothers of WA Aboriginal twins gave birth at hospitals located more than 3 h by road from their home). Outcomes were worse for Aboriginal liveborn twins than Aboriginal singletons and non-Aboriginal twins (e.g. 58% of NSW Aboriginal twins were preterm compared to 9% of Aboriginal singletons and 49% non-Aboriginal twins). Conclusions Mothers of Aboriginal twins faced significant challenges during the pregnancy, birth and the postnatal period in hospital and, in addition to accessible specialist medical care, these mothers may need extra practical and psychosocial support throughout their journey.

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.

As most common oral conditions and diseases have complex genetic and environmental etiologies, twin and family studies have been utilized for decades to explore the relative contribution of each to disease susceptibility. In the omic-era they offer exciting potential to utilize emerging scientific and analytical techniques to give valuable insight into disease mechanisms and develop novel approaches to disease prevention and management. This chapter will review the application of twin and family studies to understanding risk, etiology, disease mechanisms and epigenetics and several aspects of oral health, including childhood dental caries, periodontal disease, and craniofacial development; and identify future directions for research.

IntroductionMultifetal pregnancies and births tend to be more complicated and have poorer outcomes than singleton pregnancies. Singleton pregnancies and perinatal outcomes are worse, on average, for Indigenous people than non-Indigenous people, but little is known about Indigenous multifetal pregnancies. Objectives and ApproachWe comprehensively describe and compare Indigenous twin and singleton pregnancies and births in Western Australia (WA) and New South Wales (NSW) and compare to NSW non-Indigenous pregnancies and births. Birth records and infant and maternal hospital records were linked for births during 2000-2013 (WA) and 2002-2008 (NSW). Time travelled for the birth was based on the distance from the hospital to the centroid of the mother’s geographical residential area. ResultsIn the Indigenous populations, mothers of twins had poorer health than mothers of singletons (e.g. in WA, 19% of mothers of twins had hypertension/pre-eclampsia/eclampsia vs 9% of mothers of singletons). They were more likely to have antenatal care during the first trimester (e.g. 69% vs 64% in NSW), though less likely than non-Indigenous mothers of both twins (80%) and singletons (75%).The majority of Indigenous twins were born in a hospital with a neonatal intensive care unit (NICU) (e.g. 66% vs 26% in WA) and many mothers of twins travelled further for the birth (e.g. 8% of mothers of Indigenous twins in NSW travelled 3 hours or more vs 4% of mothers of singletons). In both jurisdictions, outcomes were worse for twins than singletons (e.g. 67% of twins in WA were preterm vs 13% of singletons and 30% of twins were admitted to a NICU vs 6% of singletons). Conclusion / ImplicationsMothers of Indigenous twins faced significant challenges during the pregnancy, birth and the postnatal period in hospital and, in addition to accessible specialist medical care, these mothers may need practical and psychosocial support throughout their journey.

Background: Familial confounding is confounding due to genetics or environmental exposures shared by family members. We aimed to study whether familial confounding explains the association between body mass index (BMI) and severe hip osteoarthritis (OA). Methods: We linked data from the Norwegian Arthroplasty Registry with the Norwegian Twin Registry on the National ID-number in 2014, generating a population-based prospective cohort study of same-sex twins born between 1915 and 1960 (53.4% females). BMI was calculated from self-reported height/weight. The outcome was incident hip arthroplasty due to OA (follow-up time, 1987-2014; 424 914 person-years). We performed sex-specific co-twin control analyses of dizygotic (N = 5,226) and monozygotic (MZ, N = 3,803) twin pairs using Cox regression models and explored reasons for any familial confounding using bivariate twin models. Results: The mean (SD) BMI was 22.6 (2.96), peak lifetime BMI 25.6 (2.61), and N = 614 had hip surgery due to OA. In cohort analyses, BMI was associated with hip OA for women and men (hazard ratio [HR] = 1.09, 95% confidence intervals [CIs] = 1.06 to 1.11 and HR = 1.08, 95% CI = 1.04 to 1.12, respectively). When adjusting for familial confounding within MZ twins, the association got stronger for women (HR = 1.19; 95% CI = 1.05 to 1.36) but weaker for men (HR = 0.93; 95% CI = 0.75 to 1.16). There was no genetic overlap between BMI and hip OA, yet the familial confounding in men provides suggestive evidence that the association could be explained by shared environmental factors. Conclusion: The association between BMI and hip OA may be explained by familial confounding for men. For women, there was no evidence for familial confounding, consistent with a causal association. See video abstract at, http://links.lww.com/EDE/B336.

OBJECTIVES: Hypomineralised second primary molars (HSPM) are common developmental enamel defects. The aims of this study were to use surface-level data to explore the clustering of HSPM at four levels (family, child, tooth, surface).METHODS: This study of 172 twin pairs was nested within the Peri/postnatal Epigenetic Twin Study. HSPM was measured by standardised oral examinations at age 6 years. Multilevel logistic regression models were fitted to assess the correlation structure of surface level data and variation in HSPM. The associations between surface level risk factors and HSPM were then explored using the multilevel logistic regression model using the best fitting correlation structure.RESULTS: The prevalence of HSPM was 68 (19.8%) children, with a total of 141 (10.3%) teeth and 264 tooth surfaces (6.3%) affected. Multilevel models revealed that a hierarchical structure accounting for correlation at the family, child and tooth level best accounted for the variation in HSPM. The estimated variances from the best fitting model (Model 3) were largest at the family level (12.27, 95% CI 6.68, 22.51) compared with 5.23 at the child level and 1.93 at the tooth level. Application of regression analysis utilising this three-level correlation structure identified tooth/surface level factors in addition to the previously identified familial and individual risk factors for HSPM.CONCLUSION: In addition to familial (environmental and genetic) and unique child-level factors, the aetiology of HSPM is likely to be influenced by local tooth-level factors.

Objective: To evaluate the contributions of shared but unmeasured genetic and environmental factors to hallux valgus (HV). Methods: Between 2011-2012, 74 monozygotic (MZ) and 56 dizygotic (DZ) female twin pairs self-reported HV and putative risk factors, including footwear use across their lifespan. Estimates of casewise concordance (PC), correlation (ρ) and odds ratios (OR) were calculated, adjusting for age and other risk factors, and compared between MZ and DZ pairs using logistic regression, generalised estimating equations and a maximum likelihood-based method, respectively. Results: 70 participants (27%) reported HV, with 12 MZ and 7 DZ pairs being concordant. After adjusting for age, twins were correlated (ρ = 0.27; 95%CI 0.08-0.46) and concordant (PC = 0.45, 95%CI 0.29-0.61 at mean age 58 years) with no difference between MZ and DZ pairs (p = 0.7). HV was associated with regularly wearing footwear with a constrictive toe-box during the fourth decade (adjusted OR = 2.73; 95%CI 1.12-6.67). This risk factor was correlated in MZ (ρ = 0.38; 95%CI = 0.15-0.60) but not DZ (ρ = -0.20; 95%CI = -0.43-0.03) pairs. These correlations were significantly different (p = 0.002). Conclusion: Twins are correlated for HV but we found no evidence that this was due to shared genetic factors. We identified an environmental risk factor, footwear with a constrictive toe-box, that is not shared to the same extent by MZ and DZ pairs, contrary to the assumption of the classic twin model. Footwear, and possibly genetic factors and unknown shared environmental factors could contribute to developing HV. This article is protected by copyright. All rights reserved.

Background and aims Studies of twins can reduce confounding and provide additional evidence about the causes of disease, due to within-pair matching for measured and unmeasured factors. Although findings from twin studies are typically applicable to the general population, few studies have taken full advantage of the twin design to explore the developmental origins of cardiometabolic health outcomes. We aimed to systematically review the evidence from twin studies and generate pooled estimates for the effects of early-life risk factors on later-life cardiometabolic health. Methods and results An initial search was conducted in March 2018, with 55 studies of twins included in the review. Risk of bias was assessed using the Newcastle–Ottawa Scale, and eligible studies were included in a meta-analysis, where pooled estimates were calculated. Twenty-six studies analysed twins as individuals, and found that higher birthweight was associated with lower SBP (β = −2.02 mmHg, 95%CI: −3.07, −0.97), higher BMI (β = 0.52 kg/m2, 95%CI: 0.20, 0.84) and lower total cholesterol (β = −0.07 mmol/L, 95%CI: −0.11, −0.04). However, no associations were reported in studies which adjusted for gestational age. Few of the included studies separated their analyses into within-pair and between-pair associations. Conclusions Early-life risk factors were associated with cardiometabolic health outcomes in twin studies. However, many estimates from studies in this review were likely to have been confounded by gestational age, and few fully exploited the twin design to assess the developmental origins of cardiometabolic health outcomes.

Neurodevelopment is sensitive to genetic and pre/postnatal environmental influences. These effects are likely mediated by epigenetic factors, yet current knowledge is limited. Longitudinal twin studies can delineate the link between genetic and environmental factors, epigenetic state at birth and neurodevelopment later in childhood. Building upon our study of the Peri/postnatal Epigenetic Twin Study (PETS) from gestation to 6 years of age, here we describe the PETS 11-year follow-up in which we will use neuroimaging and cognitive testing to examine the relationship between early-life environment, epigenetics and neurocognitive outcomes in mid-childhood. Using a within-pair twin model, the primary aims are to (1) identify early-life epigenetic correlates of neurocognitive outcomes; (2) determine the developmental stability of epigenetic effects and (3) identify modifiable environmental risk factors. Secondary aims are to identify factors influencing gut microbiota between 6 and 11 years of age to investigate links between gut microbiota and neurodevelopmental outcomes in mid-childhood. Approximately 210 twin pairs will undergo an assessment at 11 years of age. This includes a direct child cognitive assessment, multimodal magnetic resonance imaging, biological sampling, anthropometric measurements and a range of questionnaires on health and development, behavior, dietary habits and sleeping patterns. Data from complementary data sources, including the National Assessment Program — Literacy and Numeracy and the Australian Early Development Census, will also be sought. Following on from our previous focus on relationships between growth, cardiovascular health and oral health, this next phase of PETS will significantly advance our understanding of the environmental interactions that shape the developing brain.

Sub-optimal nutrition and dental caries are both common with significant short and long-term implications for child health and development. We applied twin statistical methods to explore the relationship between body mass index (BMI) and dental caries. We measured BMI at 18 months and six years of age and cumulative dental caries experience at six years in 344 twin children. Dental caries in primary teeth was categorised into ‘any’ or ‘advanced’ and BMI was analysed as both a continuous and categorical variable. Statistical analyses included multiple logistic regression using generalized estimating equations and within/between-pair analyses. There was no association between BMI and ‘any’ dental caries experience at either time-point, neither overall nor in within/between pair analyses. However, ‘advanced’ dental caries at six years was associated with a within-pair difference in BMI of −0.55 kg/m2 (95% CI −1.00, −0.11, p = 0.015). A within-pair increase of 1 kg/m2 in BMI was associated with a lower within-pair risk of advanced dental caries (OR 0.68, 95% CI 0.52, 0.90, p = 0.007). These findings reveal a possible causal relationship between lower BMI and dental caries. As dental outcomes were only measured at one time point, the direction of this potentially causal relationship is unclear.

OBJECTIVES: To explore the relative contributions of genetic and environmental influences on dental caries risk and to investigate fetal and developmental risk factors for dental caries. METHODS: We recruited children from 250 twin pregnancies midgestation and collected demographic, health, and phenotypic data at recruitment, 24 and 36 weeks’ gestational age, birth and 18 months, and 6 years of age. 25-hydroxyvitamin D was quantified in mothers at 28 weeks’ gestation and in infants at birth. Dental caries and enamel defects were measured at six years of age. We compared concordance for the presence of any caries and advanced caries in monozygotic and dizygotic twin pairs. To investigate environmental risk factors for caries, we fitted multiple logistic regression models using generalized estimating equations to adjust for twin correlation. RESULTS: A total of 345 twins underwent dental assessment, with 111 (32.2%) showing signs of any caries and 83 (24.1%) having advanced caries. There was no evidence of higher concordance in monozygotic twins compared with dizygotic twins, with a difference of 0.05 (95% confidence interval −0.14 to 0.25; P = .30) and 0.00 (95% confidence interval −0.26 to 0.26; P = .50) for any caries and advanced caries, respectively, suggesting that environmental factors, rather than genetics, are the predominant determinant of caries risk. After adjusting for potential confounders, lack of community water fluoridation, hypomineralized second primary molars, dichorionic placenta, and maternal obesity were associated with caries. CONCLUSIONS: Environmental rather than genetic factors drive dental caries risk and arise as early as prenatal life.

Background Ionizing radiation is a cause of cancer. This paper examines the effects of radiation dose and age at exposure on the incidence of brain cancer using data from the Life Span Study (LSS) of atomic bomb survivors. Methods The Radiation Effects Research Foundation website provides demographic details of the LSS population, estimated radiation doses at time of bomb in 1945, person years of follow-up and incident cancers from 1958 to 1998. We modelled brain cancer incidence using background-stratified Poisson regression, and compared the excess relative risk (ERR) per Gray (Gy) of brain dose with estimates from follow-up studies of children exposed to diagnostic CT scans. Results After exposure to atomic bomb radiation at 10 years of age the estimated ERR/Gy was 0.91 (90%CI 0.53, 1.40) compared with 0.07 (90%CI −0.27, 0.56) following exposure at age 40. Exposure at 10 years of age led to an estimated excess of 17 brain tumors per 100,000 person year (pyr) Gy by 60 years of age. These LSS estimates are substantially less than estimates based on follow-up of children exposed to CT scans. Conclusion Estimates of ERR/Gy for brain cancers in the LSS and haemangioma cohorts seem much smaller than estimates of risk for young persons in the early years after exposure to CT-scans. This could be due to reverse causation bias in the CT cohorts, diagnostic error, measurement error with radiation doses, loss of early follow-up in the LSS, or non-linearity of the dose-response curve.

Background Excess brain cancers observed after computed tomography (CT) scans could be caused by ionizing radiation. However, as scans are often used to investigate symptoms of brain cancer, excess cancers could also be due to reverse causation bias. We used finite mixture models (FMM) to differentiate CT exposures that are plausibly causal from those due to reverse causation. Methods Persons with at least one CT scan exposure and a subsequent diagnosis of brain cancer were selected from a cohort of 11 million young Australians. We fitted FMMs and used the posterior probability to inform the choice of exclusion periods. We validated our findings using a separate clinical dataset describing the time between first symptoms and brain cancer diagnosis (pre-diagnostic symptomatic interval; PSI). Results The cohort included 1028 persons with a diagnosed brain tumor and exposed to a total of 1,450 CT scans. The best-fitting model was a generalized linear mixture model using the exponential distribution with three latent classes and two covariates (age at exposure and year of exposure). The 99th percentile classifier cutoff was 18.9 months. The sample-size weighted mean of the 99th percentile of the PSI, derived from clinical data, was 15.6 months. Conclusions To minimize reverse causation bias in studies of CT scan and brain cancer, the optimal exclusion period is one to two years (depending on the choice of classifier). This information will inform the interpretation of current and future studies.

The etiology of hypomineralized second primary molars (HSPM) is unclear, but genetic and environmental factors have been proposed. The aim of this study was to investigate the relative contribution of genes and environment to the etiology of HSPM and to identify potential environmental risk factors in a longitudinal twin cohort. Children from twin pregnancies ( N = 250) were recruited antenatally, and detailed demographic, health, and phenotypic data were collected at recruitment, 24- and 36-wk gestation, birth, and 18 mo of age. 25-Hydroxyvitamin D was quantified for mothers at 28-wk gestation and infants at birth. Dental examinations were conducted on the twins at 6 y of age to determine the presence, severity, and extent of HSPM per standardized criteria. To investigate associations of environmental risk factors with HSPM, multiple logistic regression models were fitted with generalized estimating equations to adjust for twin correlation. Within- and between-pair analyses were performed for unshared continuous variables: birthweight and birth 25-hydroxyvitamin D. Twin-twin concordance for monozygotic (MZ) and dizygotic (DZ) pairs was calculated and compared after adjusting for identified risk factors. A total of 344 twins underwent the 6-y-old dental assessment; HSPM occurred in 68 (19.8%). After adjusting for potential confounders, vitamin D levels at birth, infantile eczema, dizygosity, in vitro fertilization, socioeconomic position, and maternal smoking beyond the first trimester of pregnancy demonstrated the strongest associations with HSPM. Overall concordance for HSPM was 0.47 (95% CI, 0.32 to 0.62) with weak evidence ( P = 0.078) of higher concordance in MZ twins (0.63; 95% CI, 0.38 to 0.89) as compared with DZ twins (0.41; 95% CI, 0.24 to 0.58). After adjusting for known risk factors, there was no evidence ( P = 0.172) for an additive genetic influence. These findings suggest that shared and unshared environmental factors, such as maternal smoking later in pregnancy and infantile eczema, are important in the etiology of HSPM.

Aim: To investigate the influence of genetic and environmental factors on physical activity levels. Methods: Data from 134 twins from Twins Research Australia, self-report and objective measures of physical activity were obtained by the International Physical Activity Questionnaire (IPAQ) (n = 110) and Actigraph (n = 120), respectively. Correlations were calculated for twin pairs stratified by zygosity (Monozygotic, MZ; Dizygotic, DZ) and using Spearman's correlation (rs) Results: Within-pair correlations were usually higher in MZ for the Actigraph (rs ranging from 0.34 [0.0 to 0.57] to 0.48 [0.22 to 0.68]) compared to IPAQ (rs ranging from -0.15 [-0.44 to 0.17] to 0.52 [0.25 to 0.72]. Correlations in DZ were lower for the Actigraph (rs ranging from -0.03 [-0.55 to 0.51] to 0.16 [-0.41 to 0.64]) compared to IPAQ (rs ranging from -0.11 [-0.59 to 0.43] to 0.50 [-0.01 to 0.81]). Correlations between Actigraph and IPAQ for all individuals were small for sedentary vs sitting time (rs = 0.28) and vigorous physical activity (rs = 0.27), but moderate for total physical activity (rs = 0.35). Conclusion: Within-family correlation of physical activity levels depends on the assessment, with less consistent results when its assessed by self-reported methods.

A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (Pinteraction=0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.

BACKGROUND: Low socioeconomic position (SEP) is associated with increased cardiovascular (CV) disease risk, but the relative importance of SEP in childhood and adulthood, and of changes in SEP between these two life stages, remains unclear. Studies of families may help clarify these issues. We aimed to assess whether SEP in young adulthood, or change in SEP from childhood to young adulthood, was associated with five continuously measured CV risk factors. METHODS: We used data from 286 adult Australian families from the Victorian Family Heart Study (VFHS), in which some offspring have left home (n = 364) and some remained at home (n = 199). SEP (defined as the Index of Relative Socioeconomic Disadvantage) was matched to addresses. We fitted variance components models to test whether young adult SEP and/or change in SEP was associated with systolic blood pressure, diastolic blood pressure, body mass index (BMI), total cholesterol or high-density lipoprotein cholesterol, after adjustment for parental SEP and within-family correlation. RESULTS: An increase in SEP of 100 SEIFA units from childhood to adulthood was associated with a lower BMI (β = -0.49 kg/m(2), P < 0.01) only. CONCLUSIONS: These results suggest that a change in SEP in young adulthood is an important predictor of BMI, independent of childhood SEP.

Methods to examine whether genetic and/or environmental sources can account for the residual variation in ordinal family data usually assume proportional odds. However, standard software to fit the non-proportional odds model to ordinal family data is limited because the correlation structure of family data is more complex than for other types of clustered data. To perform these analyses we propose the non-proportional odds multivariate logistic regression model and take a simulation-based approach to model fitting using Markov chain Monte Carlo methods, such as partially collapsed Gibbs sampling and the Metropolis algorithm. We applied the proposed methodology to male pattern baldness data from the Victorian Family Heart Study.

Background— Renin–angiotensin–aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene–gene interactions (epistasis). Methods and Results— We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin ( REN ), angiotensinogen ( AGT ), angiotensin-converting enzyme ( ACE ), angiotensin II type 1 receptor ( AGTR1 ), and aldosterone synthase ( CYP11B2 ), including sex–SNP or SNP–SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at ACE and rs12721297 at AGTR1 ) were individually associated with lower systolic blood pressure with significant ( P AGT and rs11658531 at ACE ) and 1 SNP in women (rs12451328 at ACE ). SNP–SNP interaction was suggested ( P REN , 1 for AGT , and 1 for AGTR1 ). The SNP rs3097 at CYP11B2 was represented in 5 separate pairs. Conclusions— SNPs at key renin–angiotensin–aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype.

To evaluate the contributions of shared but unmeasured genetic and environmental factors to hallux valgus (HV).Between 2011 and 2012, 74 monozygotic (MZ) and 56 dizygotic (DZ) female twin pairs self-reported HV and putative risk factors, including footwear use across their lifespan. Estimates of casewise concordance (PA total of 70 participants (27%) reported HV, with 12 MZ and 7 DZ pairs being concordant. After adjusting for age, twins were correlated (ρ = 0.27 [95% confidence interval (95% CI) 0.08, 0.46]) and concordant (PTwins are correlated for HV, but we found no evidence that correlation was due to shared genetic factors. We identified an environmental risk factor, footwear with a constrictive toe-box, that is not shared to the same extent by MZ and DZ pairs, contrary to the assumption of the classic twin model. Footwear, and possibly genetic factors and unknown shared environmental factors, could contribute to developing HV.

The P2X4 receptor is involved in endothelium-dependent changes in large arterial tone in response to shear stress and is, therefore, potentially relevant to arterial compliance and pulse pressure. Four identified nonsynonymous polymorphisms in P2RX4 were reproduced in recombinantly expressed human P2X4. Electrophysiological studies showed that one of these, the Tyr315>Cys mutation (rs28360472), significantly reduced the peak amplitude of the ATP-induced inward current to 10.9% of wild-type P2X4 receptors in transfected HEK-293 cells (10 μmol/L of ATP; n=4–8 cells; P 50 value for both ligands. Mutation of Tyr315>Cys likely disrupts the agonist binding site of P2X4 receptors, a finding supported by molecular modeling based on the zebrafish P2X4 receptor crystal structure. We tested inheritance of rs28360472 encoding the Tyr315>Cys mutation in P2RX4 against pulse pressure in 2874 subjects from the Victorian Family Heart Study. The minor allele frequency was 0.014 (1.4%). In a variance components analysis we found significant association with pulse pressure ( P =0.023 for total association) where 1 minor allele increased pulse pressure by 2.84 mm Hg (95% CI: 0.41–5.27). This increase in pulse pressure associated with inheritance of 315Cys-P2X4 receptors might reflect reduced large arterial compliance as a result of impaired endothelium-dependent vasodilation in large arteries.

Variants in the gene encoding the γ-subunit of the epithelial sodium channel ( SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G ( rs13331086 ) was significantly associated with age-, sex-, and body mass index–adjusted blood pressure in each of the 4 populations ( P P =0.002 for systolic blood pressure; SE=0.21, P =0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion ( P =0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant ( P =0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.

We have demonstrated that familial genetic and shared environmental factors influence postural responses of blood pressure, such that some families show a fall and others show a rise in systolic pressure on standing. These differences might reflect programmed differences in the underlying responses in mean arterial pressure and pulse pressure that together determine systolic pressure. Using variance components modelling techniques, we assessed familial aggregation of postural changes in mean arterial pressure and pulse pressure in 767 adult families from the Victorian Family Heart Study. On average mean arterial pressure rose (P < 0.001) and pulse pressure fell (P < 0.001) on standing, but there were no significant correlations between the two. We found little evidence of genetic effects on changes in either mean arterial pressure or pulse pressure, although significant spouse correlations indicated that some shared environmental effects might be present. The majority of variation in postural responses of mean arterial pressure (69.5%) and pulse pressure (81.2%) was attributable to individual-specific factors. These findings were not altered by adjustments for height or body mass index. Total variance was greater for males than females for both change in mean arterial pressure (33.7 versus 30.2, P = 0.04) and change in pulse pressure (70.7 versus 56.8, P < 0.001), differences also attributable to individual rather than familial factors. These findings suggest that the postural autoregulatory responses in peripheral arterial resistance and cardiac output that determine mean arterial and pulse pressure are not programmed by familial factors.

Objectives Molar incisor hypomineralization (MIH) is a common developmental dental defect of permanent teeth, which can increase the risk of dental caries, infection and hospitalization. The etiology is currently unclear although prenatal or early childhood health factors are suspected. The aim of this systematic review was to assess the strength of evidence linking etiological factors with MIH. Methods A systematic search was conducted using the Medline and Embase electronic databases for studies investigating environmental etiological factors of MIH. Two reviewers assessed the eligibility of studies. The level of evidence and bias was determined for all eligible studies according to Australian National Health and Medical Research Council guidelines for systematic reviews of etiology and the Newcastle–Ottawa Scale. Results From a total of 2254 studies identified through electronic and hand searching, 28 were eligible for inclusion. Twenty-five of these investigated MIH and three investigated a related condition in primary teeth, hypomineralized second primary molars (HSPM), and these were analysed separately. A limited number of studies reported significant associations between MIH and pre- and perinatal factors such as maternal illness and medication use in pregnancy, prematurity and birth complications. Early childhood illness was implicated as an etiological factor in MIH in several studies, in particular fever, asthma and pneumonia. The studies investigating HSPM revealed an association with maternal alcohol consumption, infantile fever and ethnicity. However, the validity of these findings is impaired by study design, lack of adjustment for confounders, lack of detail and consistency of exposures investigated and poor reporting. Conclusions Childhood illness is likely to be associated with MIH. Further prospective studies of the etiology of MIH/HSPM are needed.

Systolic blood pressure is determined in large part by genes. Six independent studies have reported evidence of linkage between systolic pressure and chromosome 16p12 that incorporates SCNN1G , the gene encoding the γ-subunit of the epithelial sodium channel. We undertook the first comprehensive association analysis of SCNN1G and systolic pressure. To achieve genetic contrast, we sampled unrelated subjects within the upper (mean: 166 mm Hg; n=96) and lower (mean: 98 mm Hg; n=94) 10% of the systolic pressure distribution of 2911 subjects from the Victorian Family Heart Study. We examined genotypes and haplotypes related to 26 single nucleotide polymorphisms across SCNN1G and its promoter. Each of 3 single nucleotide polymorphisms ( rs13331086 , rs11074553 , and rs4299163 ) in introns 5 and 6 showed evidence of association with systolic pressure in logistic regression analyses adjusted for age, sex, and body mass index. Considered as a haplotype block, these single nucleotide polymorphisms were significantly associated with systolic pressure (haplo.score global: P =0.0001). In permutation analyses to account for multiple testing, a result such as this was observed only once in 10 000 permutations. The estimated frequency of 1 haplotype (TGC) was substantially greater in high (13.3%) than low (0.6%) systolic pressure subjects ( P =0.0001). Three other haplotypes (TGG, TAC, and GGC) showed associations with high or low systolic pressure consistent with the observed associations of their composite alleles. These findings identify relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population.

To examine the familial correlations, heritability (h(2)) and common environmental components (c(2)) of myopia and ocular biometric traits (all treated as continuous outcomes) in families collected through the Genes in Myopia (GEM) family study in Australia. A total of 132 pedigrees (723 participants) were recruited for this study. All individuals completed a risk factor questionnaire and underwent a detailed eye examination including spherical equivalent (SphE) and ocular biometric measurements of axial length (AL), anterior chamber depth (ACD) and corneal curvature (CC). Familial correlations were calculated and h(2) and c(2) were estimated using a variance component model that assumes a multivariate t distribution within each pedigree. Two definitions of common environments (c(2)) were considered: nuclear family (current) shared environment (Model 1) and sib-ship (childhood) shared environment (Model 2). Population ascertainment adjustment was performed using the Blue Mountains eye study dataset. The trends observed for familial correlations suggested that SphE is influenced by both environmental and genetic factors whereas AL, ACD and CC are predominantly genetically determined. This was largely confirmed by variance components modelling. Heritability estimates (adjusted for age, sex and years of education) from the best fitting ACE model (Model 2, childhood shared environment) were 0.50 +/- 0.05 for SphE, 0.73 +/- 0.04 for AL, 0.78 +/- 0.04 for ACD and 0.16 +/- 0.06 for CC. Childhood environmental effects were significant with c(2) estimated to be 0.33 +/- 0.04 for SphE, 0.06 +/- 0.03 for AL, 0.22 +/- 0.04 for ACD and 0.10 +/- 0.05 for CC. Age was associated with SphE, total years of education was associated with AL and sex was associated with all traits studied. We used a novel and conservative approach to account for and estimate common environmental effects by specifying either nuclear family or sib-ship environment when estimating heritability estimates and showed that all traits examined (SphE, AL, ACD and CC) are heritable, thus reflecting a genetic component. These traits therefore all represent candidates for quantitative trait linkage analyses.