Changing genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts.

BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.

Etiological Overlap Between Sex Under the Influence and Number of Lifetime Sexual Partners.

Drug and alcohol use is associated with risky sexual behavior (RSB). It is unclear whether this association is due to correlated liabilities (e.g., third variables influencing both traits), or whether use of drugs and alcohol during sexual decision making increases RSB. This study addresses this question by fitting a series of biometrical models using over 800 twin pairs assessed in early adulthood (m = 25.21 years). Measures included an index of sex under the influence (e.g., frequency that drugs or alcohol affect sexual decision making), number of lifetime sexual partners, and a general measure of substance use. Analyses suggest the covariance among these measures is explained by both genetic and environmental correlated liabilities. The overlap was not specific to sex under the influence, but was shared with a measure of general substance use. Models testing necessary but not sufficient parameters for direction of causation suggest that sex under the influence is unlikely to cause an increase in RSB; more evidence for reverse causation was found.

Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts.

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 (ß = -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 (ß = 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.

Education, Smoking, and Cohort Change: Forwarding a Multidimensional Theory of the Environmental Moderation of Genetic Effects.

We introduce a genetic correlation by environment interaction model [(rG)xE] which allows for social environmental moderation of the genetic relationship between two traits. To empirically demonstrate the significance of the (rG)xE perspective, we use genome wide information from respondents of the Health and Retirement Study (HRS; n = 8,181; birth years 1920-1959) and the National Longitudinal Study of Adolescent to Adult Health (Add Health; n = 4,347; birth years 1974-1983) to examine whether the genetic correlation (rG) between education and smoking has increased over historical time. Genetic correlation estimates (rGHRS = -0.357; rGAdd Health = -0.729) support this hypothesis. Using polygenic scores for educational attainment, we show that this is not due to latent indicators of intellectual capacity, and we highlight the importance of education itself as an explanation of the increasing genetic correlation. Analyses based on contextual variation the milieus of the Add Health respondents corroborate key elements of the birth cohort analyses. We argue that the increasing overlap with respect to genes associated with educational attainment and smoking is a fundamentally social process involving complex process of selection based on observable behaviors that may be linked to genotype.

Genetic influences on the human oral microbiome.

BACKGROUND: The human oral microbiome is formed early in development. Its composition is influenced by environmental factors including diet, substance use, oral health, and overall health and disease. The influence of human genes on the composition and stability of the oral microbiome is still poorly understood. We studied both environmental and genetic characteristics on the oral microbiome in a large twin sample as well as in a large cohort of unrelated individuals. We identify several significantly heritable features of the oral microbiome. The heritability persists in twins even when their cohabitation changes. The heritability of these traits correlates with the cumulative genetic contributions of over half a million single nucleotide sequence variants measured in a different population of unrelated individuals. Comparison of same-sex and opposite sex cotwins showed no significant differences. We show that two new loci on chromosomes 7 and 12 are associated with the most heritable traits. RESULTS: An analysis of 752 twin pairs from the Colorado Twin Registry, shows that the beta-diversity of monozygotic twins is significantly lower than for dizygotic or unrelated individuals. This is independent of cohabitation status. Intraclass correlation coefficients of nearly all taxa examined were higher for MZ than DZ twin pairs. A comparison of individuals sampled over 2-7 years confirmed previous reports that the oral microbiome remains relatively more stable in individuals over that time than to unrelated people. Twin modeling shows that a number of microbiome phenotypes were more than 50% heritable consistent with the hypothesis that human genes influence microbial populations. To identify loci that could influence microbiome phenotypes, we carried out an unbiased GWAS analysis which identified one locus on chromosome 7 near the gene IMMPL2 that reached genome-wide significance after correcting for multiple testing. Another locus on chromosome 12 near the non-coding RNA gene INHBA-AS1 achieved genome-wide significance when analyzed using KGG4 that sums SNP significance across coding genes. DISCUSSION: Using multiple methods, we have demonstrated that some aspects of the human oral microbiome are heritable and that with a relatively small sample we were able to identify two previously unidentified loci that may be involved.

A Longitudinal Adoption Study of Substance Use Behavior in Adolescence.

Although cross-sectional twin studies have assessed the genetic and environmental etiologies of substance use during adolescence and early adulthood, comparisons of results across different samples, measures, and cohorts are problematic. While several longitudinal twin studies have investigated these issues, few corroborating adoption studies have been conducted. The current study is the first to estimate the magnitude of genetic, shared environmental, and non-shared environmental influences on substance use (cigarettes, alcohol, and marijuana) from ages 14 to 18 years, using a prospective longitudinal adoption design. Adoptive and control sibling correlations provided substantial evidence for early genetic effects on cigarette, alcohol, and marijuana use/no use. Shared environmental effects were relatively modest, except for alcohol use, which showed increases in late adolescence (age 17 to 18 years). Sibling similarity for quantity/frequency of use also support additive genetic influences across adolescence, with some shared environmental influences for all three substances. To test the stability of these influences across time, a series of independent pathway models were run to explore common and age-specific influences. For all substances, there were minimal age-specific additive genetic and shared environmental influences on quantity/frequency of use. Further, there was a trend toward increasing genetic influences on cigarette and alcohol use across ages. Genetic influences on marijuana were important early, but did not contribute substantially at age 17 and 18 years. Overall, the findings indicate that genetic influences make important contributions to the frequency/quantity of substance use in adolescence, and suggest that new genetic influences may emerge in late adolescence for cigarette and alcohol use.

Testing the role of adolescent sexual initiation in later-life sexual risk behavior: a longitudinal twin design.

The consistent association between adolescent sexual initiation (ASI) and risky adult sexual behavior (RASB) has generally been assumed to indicate that ASI has a causal effect on RASB; consequently, it is assumed that delaying ASI will reduce RASB. Yet the ASI-RASB association might be better accounted for by some third variable. We evaluated the causal role of ASI (initiation of oral, anal, or vaginal sex at or before age 16) in influencing RASB in a longitudinal sample of 2,173 twins (followed from ages 11 to 24 or from ages 17 to 29) using two methods: the discordant-twin design and the propensity-score design. The former controlled for unmeasured genetic and shared environmental factors, and the latter controlled for measured nonshared environmental factors. We replicated the link between ASI and RASB reported in previous research, but results from the discordant-twin and propensity-score analyses suggested that this association is better explained by common genetic or environmental risk factors than as a causal effect. These findings suggest that preventing ASI is unlikely to reduce RASB.

Mortality and Obesity Among U.S. Older Adults: The Role of Polygenic Risk.

OBJECTIVES: To examine the relationship between obesity and mortality as a function of polygenic risk for obesity among older U.S. adults. METHOD: Using data from the 1994-2014 Health and Retirement Study in conjunction with genome-wide data, we evaluated the risk of mortality as a function of obesity classification, an individual's polygenic risk score (PGS) for obesity, and their interaction, stratified by sex. We conducted our analyses using cox proportional hazard models. RESULTS: Among those with an average PGS for obesity (8,143 [68.8%]), obese I (hazard ratio [HR] = 0.79, p = .336) adults show no difference in their risk for mortality and obese II/III (HR = 3.17, p = .000) adults present higher risk of mortality relative to non-obese adults. The interaction of obesity classification and PGS suggests that obese II/III respondents with low PGS in the total sample (HR = 2.71, p = .006) and among women (HR = 3.02, p = .023) are at significantly higher risk of death when compared to obese II/III respondents with average or high PGS. DISCUSSION: We posit that these findings suggest that the pathway to obesity, in this case, more socio-behavioral rather than genetic, may influence subsequent risk of death in older adults. We suggest that practitioners and population researchers be mindful of these pathways as to better identify and understand mortality risk.

Genes Related to Education Predict Frailty Among Older Adults in the United States.

OBJECTIVE: This article expands on research that links education and frailty among older adults by considering the role of genes associated with education. METHOD: Data come from a sample of 7,064 non-Hispanic, white adults participating in the 2004-2012 waves of the Health and Retirement Study. Frailty was measured with two indices: (a) The Frailty Index which corresponds to a deficit accumulation model; and (b) The Paulson-Lichtenberg Frailty Index which corresponds to the biological syndrome/phenotype model. Genes associated with education were quantified using an additive polygenic score. Associations between the polygenic score and frailty indices were tested using a series of multilevel models, controlling for multiple observations for participants across waves. RESULTS: Results showed a strong and negative association between genes for education and frailty symptoms in later life. This association exists above and beyond years of completed education and we demonstrate that this association becomes weaker as older adults approach their 80s. DISCUSSION: The results contribute to the education-health literature by highlighting new and important pathways through which education might be linked to successful aging.

A mutation associated with stress resistance in mice is associated with human grip strength and mortality.

Hand grip strength (GS) is a valid and reliable predictor of future morbidity and mortality and is considered a useful indicator of aging. In this paper, we use results from the genetic analysis in animal studies to evaluate associations for GS, frailty, and subsequent mortality among humans. Specifically, we use data from the Health and Retirement Survey (HRS) to investigate the association between three polymorphisms in a candidate frailty gene (Tiam1) and GS. Results suggest that the A allele in rs724561 significantly reduces GS among older adults in the US (b = -0.340; p < .006) and is significantly associated with self-reported weakness (b = 0.221; p = .036). This same polymorphism was weakly associated (one-tailed) with an increased risk of mortality (b = 1.091; p < .093) and adjustments for GS rendered this association statistically non-significant (b = 1.048; p < .361). Overall, our results provide tentative evidence that the Tiam1 gene may be associated with frailty development, but we encourage further studies.

Genetic and environmental influences on human height from infancy through adulthood at different levels of parental education.

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.

Childhood language development and later alcohol use behaviors.

BACKGROUND: Studies have shown a correlation between language abilities and alcohol use; however, results are inconsistent. A recent study using a discordant twin design showed an association between early child language development and later alcohol use behaviors; i.e., the twin with more advanced language abilities was more likely to try alcohol earlier in adolescence (Latvala et al., 2014). The authors suggested that this could result from better socialization of individuals with greater language abilities, which could lead to more opportunities for alcohol experimentation. The findings by Latvala et al. raise interesting questions, but the study has limitations, and replication is needed. METHOD: We aimed to replicate and build upon these results utilizing 488 same sex twin pairs from the Colorado Longitudinal Twin Study, a longitudinal sample with quantitative measures of language abilities starting when the twins were 14 months old. RESULTS: We found no significant correlations between a latent measure of child language abilities or measures of general cognitive ability at ages 14, 20, and 24 months and a latent alcohol use variable at ages 17 and 22 years. CONCLUSION: Our results did not replicate the association between early language ability and later alcohol use reported by Latvala et al. Possible reasons for differing results across samples, including varying cultural norms as well as differences in educational attainment, peer influences, and novelty seeking, were discussed.

Parental Education and Genetics of BMI from Infancy to Old Age: A Pooled Analysis of 29 Twin Cohorts.

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.

Association of current and former smoking with body mass index: A study of smoking discordant twin pairs from 21 twin cohorts.

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.

Genetic and environmental factors affecting birth size variation: a pooled individual-based analysis of secular trends and global geographical differences using 26 twin cohorts.

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.

Associations between birth size and later height from infancy through adulthood: An individual based pooled analysis of 28 twin cohorts participating in the CODATwins project.

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.

Does the sex of one's co-twin affect height and BMI in adulthood? A study of dizygotic adult twins from 31 cohorts.

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.

Association between birthweight and later body mass index: an individual-based pooled analysis of 27 twin cohorts participating in the CODATwins project.

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.

Genetic and environmental effects on body mass index from infancy to the onset of adulthood: an individual-based pooled analysis of 45 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) study.

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.

Genetic and environmental influences on height from infancy to early adulthood: An individual-based pooled analysis of 45 twin cohorts.

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.