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We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations., (© 2022. The Author(s).)

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (β = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (β = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural-geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a 2  = 0.43; 0.41-0.44), but also environmental variation shared by co-twins was substantial (c 2  = 0.31; 0.30-0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900-1949 (a 2  = 0.44; 0.41-0.46) than in the later cohorts born in 1950-1989 (a 2  = 0.38; 0.36-0.40), with a corresponding lower influence of common environmental factors (c 2  = 0.31; 0.29-0.33 and c 2  = 0.34; 0.32-0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.

Genetic factors explain a major proportion of human height variation, but differences in mean stature have also been found between socio-economic categories suggesting a possible effect of environment. By utilizing a classical twin design which allows decomposing the variation of height into genetic and environmental components, we tested the hypothesis that environmental variation in height is greater in offspring of lower educated parents. Twin data from 29 cohorts including 65,978 complete twin pairs with information on height at ages 1 to 69 years and on parental education were pooled allowing the analyses at different ages and in three geographic-cultural regions (Europe, North America and Australia, and East Asia). Parental education mostly showed a positive association with offspring height, with significant associations in mid-childhood and from adolescence onwards. In variance decomposition modeling, the genetic and environmental variance components of height did not show a consistent relation to parental education. A random-effects meta-regression analysis of the aggregate-level data showed a trend towards greater shared environmental variation of height in low parental education families. In conclusion, in our very large dataset from twin cohorts around the globe, these results provide only weak evidence for the study hypothesis.

The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.

Objective: The objective of this study was to analyze how parental education modifies the genetic and environmental variances of BMI from infancy to old age in three geographic-cultural regions., Methods: A pooled sample of 29 cohorts including 143,499 twin individuals with information on parental education and BMI from age 1 to 79 years (299,201 BMI measures) was analyzed by genetic twin modeling., Results: Until 4 years of age, parental education was not consistently associated with BMI. Thereafter, higher parental education level was associated with lower BMI in males and females. Total and additive genetic variances of BMI were smaller in the offspring of highly educated parents than in those whose parents had low education levels. Especially in North American and Australian children, environmental factors shared by co-twins also contributed to the higher BMI variation in the low education level category. In Europe and East Asia, the associations of parental education with mean BMI and BMI variance were weaker than in North America and Australia., Conclusions: Lower parental education level is associated with higher mean BMI and larger genetic variance of BMI after early childhood, especially in the obesogenic macro-environment. The interplay among genetic predisposition, childhood social environment, and macro-social context is important for socioeconomic differences in BMI., (© 2019 The Obesity Society.)

Background: There is evidence that birth weight is positively associated with education, but it remains unclear whether this association is explained by familial environmental factors, genetic factors or the intrauterine environment. We analysed the association between birth weight and educational years within twin pairs, which controls for genetic factors and the environment shared between co-twins., Methods: The data were derived from nine twin cohorts in eight countries including 6116 complete twin pairs. The association between birth weight and educational attainment was analysed both between individuals and within pairs using linear regression analyses., Results: In between-individual analyses, birth weight was not associated with educational years. Within-pairs analyses revealed positive but modest associations for some sex, zygosity and birth year groups. The greatest association was found in dizygotic (DZ) men (0.65 educational years/kg birth weight, p=0.006); smaller effects of 0.3 educational years/kg birth weight were found within monozygotic (MZ) twins of both sexes and opposite-sex DZ twins. The magnitude of the associations differed by birth year in MZ women and opposite-sex DZ twins, showing a positive association in the 1915-1959 birth cohort but no association in the 1960-1984 birth cohort., Conclusion: Although associations are weak and somewhat inconsistent, our results suggest that intrauterine environment may play a role when explaining the association between birth weight and educational attainment., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The genetic architecture of birth size may differ geographically and over time. We examined differences in the genetic and environmental contributions to birthweight, length and ponderal index (PI) across geographical-cultural regions (Europe, North America and Australia, and East Asia) and across birth cohorts, and how gestational age modifies these effects., Methods: Data from 26 twin cohorts in 16 countries including 57 613 monozygotic and dizygotic twin pairs were pooled. Genetic and environmental variations of birth size were estimated using genetic structural equation modelling., Results: The variance of birthweight and length was predominantly explained by shared environmental factors, whereas the variance of PI was explained both by shared and unique environmental factors. Genetic variance contributing to birth size was small. Adjusting for gestational age decreased the proportions of shared environmental variance and increased the propositions of unique environmental variance. Genetic variance was similar in the geographical-cultural regions, but shared environmental variance was smaller in East Asia than in Europe and North America and Australia. The total variance and shared environmental variance of birth length and PI were greater from the birth cohort 1990-99 onwards compared with the birth cohorts from 1970-79 to 1980-89., Conclusions: The contribution of genetic factors to birth size is smaller than that of shared environmental factors, which is partly explained by gestational age. Shared environmental variances of birth length and PI were greater in the latest birth cohorts and differed also across geographical-cultural regions. Shared environmental factors are important when explaining differences in the variation of birth size globally and over time.

Background: Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background., Methods and Findings: The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m2 lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m2 lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m2 higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m2 higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ co-twins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m2, 95% CI 0.04, 0.23 among men; -0.04 kg/m2, 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade., Conclusions: Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m2., Competing Interests: TK reports personal consultation fees from Pfizer Finland, during the conduct of the study but outside of this study. JK reports grants from the Academy of Finland and the Sigrid Juselius Foundation, during the conduct of the study, and personal fees from Pfizer Inc., outside the submitted study. AB reports working in the HealthTwiSt GmbH but the company did not have any impact on this study. FI reports grants from JSPS KAKENHI JP (23593419,16K15978), during the conduct of the study. MG reports grants from the National Institutes of Health, during the conduct of the study, and other grants from National Institutes of Health, outside the submitted work period. All other authors have nothing to declare. None of the funders played a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials. None of the commercial affiliations affects our adherence to PLOS ONE policies on sharing data and materials. The specific roles of authors with commercial affiliations (AB, JK, TK) are articulated in the 'author contributions' section. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit the paper for publication.

Background: There is evidence that birth size is positively associated with height in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment., Aim: To analyze the associations of birth weight, length and ponderal index with height from infancy through adulthood within mono- and dizygotic twin pairs, which provides insights into the role of genetic and environmental individual-specific factors., Methods: This study is based on the data from 28 twin cohorts in 17 countries. The pooled data included 41,852 complete twin pairs (55% monozygotic and 45% same-sex dizygotic) with information on birth weight and a total of 112,409 paired height measurements at ages ranging from 1 to 69 years. Birth length was available for 19,881 complete twin pairs, with a total of 72,692 paired height measurements. The association between birth size and later height was analyzed at both the individual and within-pair level by linear regression analyses., Results: Within twin pairs, regression coefficients showed that a 1-kg increase in birth weight and a 1-cm increase in birth length were associated with 1.14-4.25 cm and 0.18-0.90 cm taller height, respectively. The magnitude of the associations was generally greater within dizygotic than within monozygotic twin pairs, and this difference between zygosities was more pronounced for birth length., Conclusion: Both genetic and individual-specific environmental factors play a role in the association between birth size and later height from infancy to adulthood, with a larger role for genetics in the association with birth length than with birth weight., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

It is well established that boys are born heavier and longer than girls, but it remains unclear whether birth size in twins is affected by the sex of their co-twin. We conducted an individual-based pooled analysis of 21 twin cohorts in 15 countries derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), including 67,850 dizygotic twin individuals. Linear regression analyses showed that boys having a co-twin sister were, on average, 31 g (95% CI 18 to 45) heavier and 0.16 cm (95% CI 0.045 to 0.274) longer than those with a co-twin brother. In girls, birth size was not associated (5 g birth weight; 95% CI -8 to -18 and -0.089 cm birth length; 95% CI -0.202 to 0.025) with the sex of the co-twin. Gestational age was slightly shorter in boy-boy pairs than in boy-girl and girl-girl pairs. When birth size was standardized by gestational age, the magnitude of the associations was attenuated in boys, particularly for birth weight. In conclusion, boys with a co-twin sister are heavier and longer at birth than those with a co-twin brother. However, these differences are modest and partly explained by a longer gestation in the presence of a co-twin sister.

Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990-1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.

Background: There is evidence that birthweight is positively associated with body mass index (BMI) in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. We analysed the association between birthweight and BMI from infancy to adulthood within twin pairs, which provides insights into the role of genetic and environmental individual-specific factors., Methods: This study is based on the data from 27 twin cohorts in 17 countries. The pooled data included 78 642 twin individuals (20 635 monozygotic and 18 686 same-sex dizygotic twin pairs) with information on birthweight and a total of 214 930 BMI measurements at ages ranging from 1 to 49 years. The association between birthweight and BMI was analysed at both the individual and within-pair levels using linear regression analyses., Results: At the individual level, a 1-kg increase in birthweight was linearly associated with up to 0.9 kg/m2 higher BMI (P < 0.001). Within twin pairs, regression coefficients were generally greater (up to 1.2 kg/m2 per kg birthweight, P < 0.001) than those from the individual-level analyses. Intra-pair associations between birthweight and later BMI were similar in both zygosity groups and sexes and were lower in adulthood., Conclusions: These findings indicate that environmental factors unique to each individual have an important role in the positive association between birthweight and later BMI, at least until young adulthood., (© The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association)

Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m 2 )], but factors modifying these variance components are poorly understood. Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity. Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs). Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI. Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population., (© 2017 American Society for Nutrition.)

Background: The comparison of traits in twins from opposite-sex (OS) and same-sex (SS) dizygotic twin pairs is considered a proxy measure of prenatal hormone exposure. To examine possible prenatal hormonal influences on anthropometric traits, we compared mean height, body mass index (BMI), and the prevalence of being overweight or obese between men and women from OS and SS dizygotic twin pairs., Methods: The data were derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) database, and included 68,494 SS and 53,808 OS dizygotic twin individuals above the age of 20 years from 31 twin cohorts representing 19 countries. Zygosity was determined by questionnaires or DNA genotyping depending on the study. Multiple regression and logistic regression models adjusted for cohort, age, and birth year with the twin type as a predictor were carried out to compare height and BMI in twins from OS pairs with those from SS pairs and to calculate the adjusted odds ratios and 95% confidence intervals for being overweight or obese., Results: OS females were, on average, 0.31 cm (95% confidence interval (CI) 0.20, 0.41) taller than SS females. OS males were also, on average, taller than SS males, but this difference was only 0.14 cm (95% CI 0.02, 0.27). Mean BMI and the prevalence of overweight or obesity did not differ between males and females from SS and OS twin pairs. The statistically significant differences between OS and SS twins for height were small and appeared to reflect our large sample size rather than meaningful differences of public health relevance., Conclusions: We found no evidence to support the hypothesis that prenatal hormonal exposure or postnatal socialization (i.e., having grown up with a twin of the opposite sex) has a major impact on height and BMI in adulthood.

Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve., Competing Interests: The authors declare that no competing interests exist.

Background: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking., Objectives: We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments., Design: Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling., Results: The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a(2) = 0.42) and girls (a(2) = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions., Conclusions: Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity., (© 2016 American Society for Nutrition.)

Height variation is known to be determined by both genetic and environmental factors, but a systematic description of how their influences differ by sex, age and global regions is lacking. We conducted an individual-based pooled analysis of 45 twin cohorts from 20 countries, including 180,520 paired measurements at ages 1-19 years. The proportion of height variation explained by shared environmental factors was greatest in early childhood, but these effects remained present until early adulthood. Accordingly, the relative genetic contribution increased with age and was greatest in adolescence (up to 0.83 in boys and 0.76 in girls). Comparing geographic-cultural regions (Europe, North-America and Australia, and East-Asia), genetic variance was greatest in North-America and Australia and lowest in East-Asia, but the relative proportion of genetic variation was roughly similar across these regions. Our findings provide further insights into height variation during childhood and adolescence in populations representing different ethnicities and exposed to different environments.

A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.

For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.

Adenovirus infection has been shown to increase adiposity in chickens, mice, and nonhuman primates. Adenovirus type 36 (Ad-36) DNA was detected in adipose tissues in these animal trials. In the United States, Ad-36 significantly correlates with obesity as illustrated by an Ad-36 seroprevalence of 30% in obese individuals and 11% in nonobese individuals. We investigated the possibility of a similar correlation of Ad-36 in Dutch and Belgian persons. In total, 509 serum samples were analyzed for Ad-36 antibodies using a serum neutralization assay. In addition, PCR was used to detect adenoviral DNA in visceral adipose tissue of 31 severely obese surgical patients. Our results indicated an overall Ad-36 seroprevalence of 5.5% increasing with age. BMI of Ad-36 seropositive humans was not significantly different from seronegative humans. No adenoviral DNA could be found using PCR on visceral adipose tissue. In conclusion, this first Ad-36 study in the Netherlands and in Belgium indicates that Ad-36 does not play a role as a direct cause of BMI increase and obesity in humans in Western Europe.

Objective: Evidence of a genetic basis of metabolic risk factors (MRFs) is growing. Studies examining the genetic and environmental basis of the clustering of MRFs, grouped together in the metabolic syndrome (MetS), are however sparse. The aim of this study therefore was to study the heritabilities of the MRFs and the genetic and environmental correlations between the MRFs., Methods: Study participants were 768 Caucasian twins coming from 418 pairs (18-34 years). MRFs were those included in the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS. Multivariate path analysis on the continuous MRFs of the MetS was implemented., Results: Heritabilities ranged between 47.0% and 80.2% (men) and 58.5% and 77.9% (women) for the individual MRFs. Evidence was found for overarching genetic (A) and environmental (E) sources of variance, both however loading mainly on waist circumference. Furthermore, the model included a 'lipids' and a 'blood pressure'-factor both in part attributable to A and E. The majority of the variance however was MRF-specific., Conclusion: Based on our sample of young adults with a low prevalence of the MetS, it can be concluded that both genes and environment contribute significantly to the clustering of the MRFs although the majority of the variation is MRF-specific. Therefore, future QTL searches in young adults may want to focus on MRF-specific loci, rather than 'cluster-phenotypes' such as the MetS.

To extract functional information on genes and processes from large expression datasets, analysis methods are required that can computationally deal with these amounts of data, are tunable to specific research questions, and construct classifiers that are not overspecific to the dataset at hand. To satisfy these requirements, a stepwise procedure that combines elements from principal component analysis and discriminant analysis, was developed to specifically retrieve genes involved in processes of interest and classify samples based upon those genes. In a global expression dataset of 300 gene knock-outs in Saccharomyces cerevisiae, the procedure successfully classified samples with similar 'cellular component' Gene Ontology annotations of the knock-out gene by expression signatures of limited numbers of genes. The genes discriminating 'mitochondrion' from the other subgroups were evaluated in more detail. The thiamine pathway turned out to be one of the processes involved and was successfully evaluated in a logistic model to predict whether yeast knock-outs were mitochondrial or not. Further, this pathway is biologically related to the mitochondrial system. Hence, this strongly indicates that our approach is effective and efficient in extracting meaningful information from large microarray experiments and assigning functions to yet uncharacterized genes.

Objective: To study the genetic and environmental determination of variation in Heath-Carter somatotype (ST) components (endomorphy, mesomorphy and ectomorphy)., Design: Multivariate path analysis on twin data., Subjects: Eight hundred and three members of 424 adult Flemish twin pairs (18-34 years of age)., Results: The results indicate the significance of sex differences and the significance of the covariation between the three ST components. After age-regression, variation of the population in ST components and their covariation is explained by additive genetic sources of variance (A), shared (familial) environment (C) and unique environment (E). In men, additive genetic sources of variance explain 28.0% (CI 8.7-50.8%), 86.3% (71.6-90.2%) and 66.5% (37.4-85.1%) for endomorphy, mesomorphy and ectomorphy, respectively. For women, corresponding values are 32.3% (8.9-55.6%), 82.0% (67.7-87.7%) and 70.1% (48.9-81.8%). For all components in men and women, more than 70% of the total variation was explained by sources of variance shared between the three components, emphasising the importance of analysing the ST in a multivariate way., Conclusions: The findings suggest that the high heritabilities for mesomorphy and ectomorphy reported in earlier twin studies in adolescence are maintained in adulthood. For endomorphy, which represents a relative measure of subcutaneous adipose tissue, however, the results suggest heritability may be considerably lower than most values reported in earlier studies on adolescent twins. The heritability is also lower than values reported for, for example, body mass index (BMI), which next to the weight of organs and adipose tissue also includes muscle and bone tissue. Considering the differences in heritability between musculoskeletal robustness (mesomorphy) and subcutaneous adipose tissue (endomorphy) it may be questioned whether studying the genetics of BMI will eventually lead to a better understanding of the genetics of fatness, obesity and overweight.

The East Flanders Prospective Twin Survey (EFPTS) is a prospective, population-based registry of multiple births in the province of East Flanders, Belgium. EFPTS has several unique features: it is population based and prospective, with the possibility of long-term follow-up; the twins (and higher order multiple births) are ascertained at birth; basic perinatal data recorded; chorion type and zygosity established; and since 1969 placental biopsies have been taken and frozen at -20 degrees C for later determination of genetic markers. The EFPTS is the only large register that includes placental data and allows differentiation of 3 subtypes of monozygotic (MZ) twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early, before the 4th day after fertilization), the monochorionic-diamnionic pairs (intermediate, between the 4th and the 7th day post fertilization), and the monochorionic-monoamnionic pairs (late, after the 8-day post fertilization). This added a new dimension to didymology (the science of twins; didymos is the Greek word for twin): the timing of MZ twinning. Studies can be initiated taking into account primary biases, those originating in utero. Such studies could throw new light on the controversy over the validity of the classic twin method, the consequences of early embryological events (before and just after implantation of the embryo), the origin of congenital malformations, the sex proportion of multiples, the gene-environment interactions as far as intrauterine environment is concerned, to name but a few.

Genetic polymorphisms in genes involved in processes that affect DNA damage may explain part of the large interindividual variation in DNA adduct levels in smokers. We investigated the effect of 19 polymorphisms in 12 genes involved in carcinogen metabolism, DNA repair, and oxidant metabolism on DNA adduct levels (determined by (32)P post-labeling) in lymphocytes of 63 healthy Caucasian smokers. The total number of alleles that were categorized as putatively high-risk alleles seemed associated with bulky DNA adduct levels (P = 0.001). Subsequently, to investigate which polymorphisms may have the highest contribution to DNA adduct levels in these smokers, discriminant analysis was done. In the investigated set of polymorphisms, GSTM1*0 (P < 0.001), mEH*2 (P = 0.001), and GPX1*1 (P < 0.001) in combination with the level of exposure (P < 0.001) were found to be key effectors. DNA adduct levels in subjects with a relatively high number of risk alleles of these three genes were >2-fold higher than in individuals not having these risk alleles. Noteworthy, all three genes are involved in deactivation of reactive carcinogenic metabolites. This study shows that analysis of multiple genetic polymorphisms may predict the interindividual variation in DNA adduct levels upon exposure to cigarette smoke. It is concluded that discriminant analysis presents an important statistical tool for analyzing the effect of multiple genotypes on molecular biomarkers.

Previous findings show strong evidence for the role of retinoblastoma (Rb) in myoblast proliferation and differentiation. However, it is not known whether variation in the retinoblastoma gene (RB1 ) is responsible for normal variation in human muscle strength. Therefore, a linkage analysis for quantitative traits was performed on 329 young male siblings from 146 families with muscle strength, using a polymorphic marker in RB1 (D13S153 on 13q14.2). Trunk strength, a general strength indicator that requires activation of large muscle groups, was measured on a Cybex TEF isokinetic dynamometer. We found evidence for linkage between locus D13S153 at 13q14.2 and several measurements of trunk flexion with LOD scores between 1.62 and 2.78 (.002< p <.0002). No evidence for linkage was found with trunk extension. This first exploration of the relationship between RB1 and human muscle strength through linkage analysis warrants efforts for further fine mapping of this region.

This study was the first to explore the potential role of the myostatin (GDF8) pathway in relation to muscle strength and estimated muscle cross-sectional area in humans using linkage analysis with a candidate gene approach. In young male sibs (n = 329) 11 polymorphic markers in or near 10 candidate genes from the myostatin pathway were genotyped. Muscle mass was estimated by anthropometric measurements, and maximal knee strength was evaluated using isokinetic dynamometers (Cybex NORM). Single-point nonparametric variance components and linear quantitative trait locus regression linkage analysis methods were used. Linkage patterns were observed between knee extension and flexion peak torque with markers D2S118 (GDF8), D6S1051 (CDKN1A), and D11S4138 (MYOD1), and a maximum LOD score of 2.63 (P = 0.0002) was observed with D2S118. The ratios of peak torque over muscle and bone area of the midthigh of the lower contraction velocity (60 degrees/s) showed more frequently significant LOD scores than the torques at high velocity (240 degrees/s). Although myostatin is physiologically more related to muscle mass through possible effects of hyperplasia and hypertrophy than it is to strength, only two estimated muscle cross-sectional areas were marginally linked (LOD 1.06 and 1.07, P = 0.01) with marker D2S118 near GDF8 (2q32.2). The present results gave suggestive evidence that the myostatin pathway might be important for strength phenotypes, and GDF8, CDKN1A, and MYOD1 are potential candidate regions for a further and denser mapping with respect to these phenotypes.

The purpose of this study was to estimate the genetic and environmental contribution to variation in skeletal muscle mass and strength. In addition, important determinants were analyzed by stepwise multiple regression. In a large (N = 748) sibling pair sample of young brothers, ages 24.3 +/- 4.5 years, upper-limit heritabilities (t2) were estimated as a proportion of genetic and shared environmental variability over total phenotypic variability by the variance components method in QTDT. Maximal isometric strength measures of knee, trunk, and elbow had higher t2 (82 to 96%) than concentric strength (63 to 87%) on Cybex isokinetic dynamometers. Indicators of muscle mass revealed very high transmissions (>90%) whereas t2 was lower for adiposity (<70%). Stepwise regression showed that fat-free mass was the primary determinant in knee and trunk strength (partial explained variance, R2 = 33-45%), but a local muscularity estimate (forearm circumference) was the main covariable for elbow strength (partial R2 = 18-39%). In this sample neither age nor physical activity, measured by the sport index of Baecke, appeared to be an important determinant of muscle mass or strength. These results show that maximal muscle strength and mass are highly transmissible and that muscle mass is the primary determinant of muscle strength.

Background: Several studies have assessed the relationship between the angiotensin-converting enzyme (ACE) I/D or angiotensin II type 1 receptor (AT(1)R)-A C polymorphisms and blood pressure (BP). Since most data have been obtained in selected populations, the present study was performed in a healthy normotensive primary care population., Objective: To investigate the individual effects of the aforementioned polymorphisms and their interaction on BP., Methods: This cross-sectional study included 198 healthy subjects. Office BP was measured and polymorphisms were genotyped (polymerase chain reaction). Polymorphism interaction was tested using the following model: systolic blood pressure (SBP) (or diastolic blood pressure, DBP) = b(0)+ b(1)X + b(2)Y + b(3)XY, in which X and Y represent the polymorphisms' risk alleles., Results: The ACE I/D polymorphism was associated with SBP (P = 0.002) and DBP (P = 0.004); highest pressures tracked with the DD genotype. Furthermore, in multiple linear regression analysis the ACE D allele was associated with SBP (P = 0.005) and DBP (P = 0.001), when adjusted for body mass index (BMI) and age. With respect to the AT(1)R-A C polymorphism, SBP was highest in the CC genotype (P = 0.025). In linear regression analysis the C allele was not associated with SBP. No synergistic effect of ACE D and AT(1)R C alleles on BP was found. Nevertheless, highest DBP tracked with the DDCC combination in comparison with other homozygous allele combinations (P = 0.030)., Conclusions: This study confirmed an association of ACE I/D and AT(1)R-A C polymorphisms with BP in a healthy normotensive primary care population. Although synergistic effect of both polymorphisms on BP does not seem to be present, an additive effect on DBP is likely.

This study explores the use of an individual's genetic (IGFS) and environmental factor score (IEFS), constructed using genetic model fitting of a multivariate strength phenotype. Maximal isometric and dynamic strength measures, one maximal repetition load (1RM) and muscle cross-sectional area (MCSA) were measured in 25 monozygotic and 16 dizygotic twin pairs. The use of IGFS and IEFS in predicting the sensitivity to environmental stress was evaluated by the association of the scores with strength training gains after a 10-week high resistance strength training programme. Results show a high contribution of genetic factors to the covariation between maximal strength and muscle cross-sectional area (84-97%) at pre-training evaluation. Individual factor scores explained the largest part of the variation in IRM and other strength measures at pre-training and post-training evaluation respectively. Genes that are switched on due to training stress (gene-environment interaction) could explain the decrease in explained variation over time. A negative correlation was found between IGFS and strength training gains (-0.24 to -0.51, P < 0.05); individuals with a high IGFS tend to gain less strength than individuals with low IGFS. Individual environmental factor scores have lower differential power. The predictive value of the IGFS has potential utility in identifying an individual's susceptibility to environmental stress in a variety of multifactorial characteristics, eg diseases and impairments, and for selection of sib pairs for QTL analyses.

Maximal static, eccentric and concentric torques and arm components estimated by anthropometry and measured by computed tomography were evaluated in 25 male monozygotic twins and 16 dizygotic twins (22.4 +/- 3.7 years). The importance of genetic and environmental factors in the observed variation in these measurements was estimated by genetic model-fitting techniques. In this sample of young adult male twins, genetic factors were significant in most of the strength measurements, arm muscle components and muscle activation variables. The contribution of genetic factors in strength measures depended on the angle, contraction type and to some extent on contraction velocity. For isometric strength, angle-specificity in genetic and environmental variation could be attributed to the degree of variability in muscle activation and performance discomfort at each specific angle, with the highest unique environmental impact at extreme angles. The high genetic contribution at 170 degrees, but not at 50 degrees, possibly expressed different contributions of genetic factors in the muscle-length factor and moment arm in torques at both angles. The importance of genetic factors in eccentric arm flexor strength (62-82%) was larger than for concentric flexion (29-65%), as the pattern of genetic determination followed the torque-velocity curve. Genetic variations in contractile and elastic components, contributing differently to eccentric and concentric torques, together with velocity-dependent actin-myosin binding factors, could account for the observed differences. The broad heritability was very high for all anthropometric and arm cross-sectional area measurements (> 85%) and common environmental factors were only significant for anthropometrically estimated mid-arm muscle tissue are (48%). Heritability estimates of different arm muscularity measurements were comparable.

The maximal isometric moment at five different elbow joint angles was measured in 25 monozygotic and 16 dizygotic male adult twin pairs (22.4 +/- 3.7 yr). Genetic model fitting was used to quantify the genetic and environmental contributions to individual differences in isometric strength. Additive genetic factors explained 66-78% of the variance in maximal torque at 170-140-110 and 80 degrees flexion (extension = 180 degrees). At 50 degrees flexion, common and subject-specific environmental factors contributed equally to the variation. The contribution of unique environmental factors concurs with the level of variability in muscle activation and (dis)-comfort of torque production in the specific angle. The relative contribution of lever arm and force-length relationship in torque varies according to the angle. Because these factors might be genetic, this variability is reflected in the genetic contribution at the extreme angles of 170 and 50 degrees. Multivariate analyses suggested a general set of genes that control muscle area and isometric strength, together with a more specific strength factor. Genetic correlations were high (0.82-0.99). Genes responsible for arm-segment lengths did not contribute to muscle area nor to isometric strength.