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Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Background and Aims: Plasma apolipoprotein C3 (ApoC3) is associated with higher plasma triglyceride and type 2 diabetes incidence. We evaluated whether body mass index (BMI) or glucose metabolism were associated with ApoC3 in healthy monozygotic (MZ) twins., Methods and Results: Forty-seven MZ twin-pairs (20 man, 27 women), aged 23-42 years, were divided in subgroups according to discordance or concordance for (a) BMI (within-pair difference (Δ) in BMI≥3.0 or<3.0 kg/m 2 ), or (b) 2-h glucose iAUC, during oral glucose tolerance test (ΔGlucose iAUC ≥97.5 or<97.5 mmol × 120 minutes). Within these discordant or concordant subgroups, we tested (Wilcoxon signed-rank test) co-twin differences in ApoC3, adiposity measures, insulin-resistance and beta-cell function indices, and plasma and lipoprotein lipids. In BMI-Discordant (p = 0.92) or BMI-Concordant (p = 0.99) subgroups, ApoC3 did not differ between leaner and heavier co-twins. In the Glucose-Discordant subgroup, ApoC3 was significantly higher in twins with higher Glucose iAUC than in their co-twins with the lower Glucose iAUC (10.03 ± 0.78 vs. 8.48 ± 0.52 mg/dl; M ± SE; p = 0.032). Co-twins with higher Glucose iAUC also had higher waist circumference, body fat percentage, liver fat content, worse insulin-sensitivity and beta-cell function and higher cholesterol and triglyceride in plasma VLDL, IDL, and LDL. In Glucose-Concordant twin-pairs, no significant differences were observed in the explored variables. In all twin-pairs, ΔApoC3 correlated with Δ in lipids and glucose metabolism variables, the closest relationship being between ΔApoC3 and ΔVLDL triglyceride (r = 0.74, p < 0.0001)., Conclusions: While ApoC3 was not related to acquired differences in BMI, it associated with early dysregulation of glucose metabolism independently of obesity and genetic background., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest associated with this manuscript., (Copyright © 2019. Published by Elsevier B.V.)

We aimed to investigate the associations of long-term leisure-time physical inactivity, body mass index (BMI) change, and education with sitting time in a 35-year follow-up based on self-reports in surveys. Influences of working status in 2011 and familial confounding on the associations were tested. Data were based on the population-based Finnish Twin Cohort of 5232 twins (53-67-year-old, 41% men) with four surveys in 1975-2011. Statistical analyses were performed using linear regression with several covariates. The effect of familial confounding (genetics and shared environment) was analyzed using a co-twin control design which should be interpreted as if familial confounding plays a role, an association should be seen among all individuals but not in discordant twin pairs. Compared to those not at work, those at work had a longer total sitting time/d. For those at work, higher education was associated with more total sitting but with less non-work sitting. Long-term leisure-time physical inactivity was associated with more non-work sitting among those at work, whereas long-term weight gain with more total and non-work sitting regardless of working status. Familial confounding attenuated the associations, except for the association of increasing BMI with total and non-work sitting among women at work. To conclude, total sitting time was longer among those still at work, but it was also influenced by long-term leisure-time physical inactivity, higher education, and an increase of BMI over the years. Public health efforts should be targeted to reduce sedentary behavior by promoting life-long leisure-time physical activity and weight control., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We aimed to study the eating behavioral traits that associate with body mass index (BMI) among BMI-discordant twin pairs. This cross-sectional study examined self-reported eating behaviors in 134 healthy young adult twin pairs (57 monozygotic [MZ] and 77 same-sex dizygotic [DZ]), of whom 29 MZ and 46 DZ pairs were BMI discordant (BMI difference ≥ 3 kg/m2). In both MZ and DZ BMI-discordant pairs, the heavier co-twins reported being less capable of regulating their food intake optimally than their leaner co-twins, mainly due to 'frequent overeating'. Furthermore, the heavier co-twins reported augmented 'disinhibited eating', 'binge-eating scores' and 'body dissatisfaction'. The twins agreed more frequently that the heavier co-twins (rather than the leaner co-twins) ate more food in general, and more fatty food, in particular. No significant behavioral differences emerged in BMI-concordant twin pairs. Overeating - measured by 'frequent overeating', 'disinhibited eating' and 'binge-eating score' - was the main behavioral trait associated with higher BMI, independent of genotype and shared environment.

Purpose: The purpose of this study is to elucidate the effect of excess body weight and liver fat on the plasma proteome without interference from genetic variation., Experimental Design: The effect of excess body weight is assessed in young, healthy monozygotic twins from pairs discordant for body mass index (intrapair difference (Δ) in BMI > 3 kg m -2 , n = 26) with untargeted LC-MS proteomics quantification. The effect of liver fat is interrogated via subgroup analysis of the BMI-discordant twin cohort: liver fat discordant pairs (Δliver fat > 2%, n = 12) and liver fat concordant pairs (Δliver fat < 2%, n = 14), measured by magnetic resonance spectroscopy., Results: Seventy-five proteins are differentially expressed, with significant enrichment for complement and inflammatory response pathways in the heavier co-twins. The complement dysregulation is found in obesity in both the liver fat subgroups. The complement and inflammatory proteins are significantly associated with adiposity measures, insulin resistance and impaired lipids., Conclusions and Clinical Relevance: The early pathophysiological mechanisms in obesity are incompletely understood. It is shown that aberrant complement regulation in plasma is present in very early stages of clinically healthy obese persons, independently of liver fat and in the absence of genetic variation that typically confounds human studies., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes., Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span., Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity., Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed., Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.

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.

Introduction: Higher midlife body mass index (BMI) is suggested to increase the risk of dementia, but weight loss during the preclinical dementia phase may mask such effects., Methods: We examined this hypothesis in 1,349,857 dementia-free participants from 39 cohort studies. BMI was assessed at baseline. Dementia was ascertained at follow-up using linkage to electronic health records (N = 6894). We assumed BMI is little affected by preclinical dementia when assessed decades before dementia onset and much affected when assessed nearer diagnosis., Results: Hazard ratios per 5-kg/m 2 increase in BMI for dementia were 0.71 (95% confidence interval = 0.66-0.77), 0.94 (0.89-0.99), and 1.16 (1.05-1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis., Conclusions: The association between BMI and dementia is likely to be attributable to two different processes: a harmful effect of higher BMI, which is observable in long follow-up, and a reverse-causation effect that makes a higher BMI to appear protective when the follow-up is short., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

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 recent obesity epidemic in children also showed an increase in the prevalence of hypertension. As blood pressure (BP) is associated with (long-chain) polyunsaturated fatty acids (LC PUFA), genetic variation in desaturase enzymes being involved in the synthesis of LC PUFA may be associated with BP. This study aimed to investigate the direct effects (independent of mediating variables) and indirect effects (mediated through intermediate variables) of a common variant in the FADS1 gene, rs174546, known to affect delta-5 desaturase (D5D) activity on PUFA level, body mass index (BMI) and BP., Methods: A subsample of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) baseline survey including 520 children aged 2 to <10 years from six European countries was included. The association between rs174546 (T

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.

Binge eating disorder (BED) is associated with high levels of obesity and psychological suffering, but little is known about 1) the distribution of features of BED in the general population and 2) their consequences for weight development and psychological distress in young adulthood. We investigated the prevalence of features of BED and their association with body mass index (BMI) and psychological distress among men (n = 2423) and women (n = 2825) from the longitudinal community-based FinnTwin16 cohort (born 1975-1979). Seven eating-related cognitions and behaviors similar to the defining features of BED were extracted from the Eating Disorder Inventory-2 and were assessed at a mean age of 24. BMI and psychological distress, measured with the General Health Questionnaire, were assessed at ages 24 and 34. We assessed prevalence of the features and their association with BMI and psychological distress cross-sectionally and prospectively. More than half of our participants reported at least one feature of BED; clustering of several features in one individual was less common, particularly among men. The most frequently reported feature was 'stuffing oneself with food', whereas the least common was 'eating or drinking in secrecy'. All individual features of BED and their clustering particularly were associated with higher BMI and more psychological distress cross-sectionally. Prospectively, the clustering of features of BED predicted increase in psychological distress but not additional weight gain when baseline BMI was accounted for. In summary, although some features of BED were common, the clustering of several features in one individual was not. The features were cumulatively associated with BMI and psychological distress and predicted further increase in psychological distress over ten years of follow-up., (Copyright © 2016. Published by Elsevier Ltd.)

Background: We investigated the stability and change of leisure-time physical inactivity in adult men and women during a 35-year follow-up. We also analysed the impact of long-term physical inactivity on the development of body mass index (BMI)., Methods: : In this population-based cohort study, 5254 Finnish twin individuals (59% women) participated in four surveys in 1975, 1981, 1990 and 2011. Mean age at baseline was 23.9 years. Individual long-term leisure-time physical activity (LTPA) was categorized into seven classes varying from 'persistently inactive' to 'persistently active'. We used the multivariate multilevel mixed-effects linear regression model and paired-sample t-test in the analyses. Co-twin control design was used for examining within-pair associations., Results: : Of men 11%, and of women 8%, were persistently inactive. Among both sexes, the mean BMI slope trajectories were steeper among the persistently inactive and those who became inactive than among those who were persistently active. Overall, the inactive participants gained 1.4 kg/m 2 [95% confidence interval (CI) 1.2 to 1.7] more in weight than did the active participants from 1975 to 2011. Among twin pairs discordant for LTPA, the corresponding difference was 1.4 kg/m 2 (95% CI 0.83 to 2.0) in dizygotic pairs and 0.68 kg/m 2 (95% CI 0.05 to1.3) in monozygotic pairs., Conclusions: Over a 35-year time span from young adulthood, persistently inactive participants and those who had become inactive had greater weight increases than those who were persistently active. This association was also found in twin-pair analyses, although attenuated in monozygotic pairs. This may support the importance of LTPA in weight management, although further causal inference is required., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Studies have suggested both adverse and protective associations of obesity with depressive symptoms. We examined the contribution of environmental and heritable factors in this association. Participants were same-sex twin pairs from two population-based twin cohort studies, the Older Finnish Twin Cohort (n = 8,215; mean age = 44.1) and the US Midlife Development in the United States (MIDUS; n = 1,105; mean age = 45.1). Body mass index (BMI) was calculated from self-reported height and weight. Depressive symptoms were assessed using Beck's Depression Inventory (BDI; Finnish Twin Cohort), and by negative and positive affect scales (MIDUS). In the Finnish Twin Cohort, higher BMI was associated with higher depressive symptoms in monozygotic (MZ) twins (B = 2.01, 95% CI = 1.0, 3.0) and dizygotic (DZ) twins (B = 1.17, 0.5, 1.9) with BMI >22. This association was observed in within-pair analysis in DZ twins (B = 1.47, CI = 0.4, 2.6) but not in within-pair analysis of MZ twins (B = 0.03, CI = -1.9, 2.0). Consistent with the latter result, a bivariate genetic model indicated that the association between higher BMI and higher depressive symptoms was largely mediated by genetic factors. The results of twin-pair analysis and bivariate genetic model were replicated in the MIDUS sample. These findings suggest an association between obesity and higher depressive symptoms, which is largely explained by shared heritable biological mechanisms.

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.)

Aims: To investigate whether stability or change in body mass index (BMI) predict disability pension (DP) due to musculoskeletal diagnosis (MSD) when controlling for familial confounding., Methods: Our study cohort consisted of 17,169 Finnish twins born before 1958. Data on BMI and multiple covariates from questionnaires in 1975 and 1981 were included and DPs were collected from the national pension registers until the end of 2004. Cox proportional hazards regression models with Hazard Ratios (HR) and 95% Confidence Intervals (CI) were used for statistical analyses., Results: General DP was granted to 2853 individuals and DP due to MSD to 1143 individuals during the 23-year follow-up. A one-unit increase in BMI in both 1975 (HR 1.08, 95% CI 1.05, 1.10) and 1981 (HR 1.06, 95% CI 1.04, 1.07), as well as the stability of and change in BMI from 1975 to 1981 were all associated with an increased risk of DP. These associations held in the analyses controlling for multiple covariates (age, sex, socioeconomic status, education, marital status, leisure-time physical activity, and musculoskeletal pain), and mainly also familial confounding, that is, genetics and shared environment. HR for stable obesity was 2.28 (95% CI 1.69, 3.08) for DP due to MSD, and 1.91 (95% CI 1.56, 2.34) for general DP in the fully adjusted models. CONCLUSIONS BMI IS AN EARLY PREDICTOR OF GENERAL DP AND ALSO OF DP DUE TO MSD OWING TO THE INDEPENDENCY OF VARIOUS COVARIATES AND POTENTIALLY ALSO FAMILIAL CONFOUNDING, BMI MAY POSSIBLY HAVE A DIRECT EFFECT ON THE RISK OF DP., (© 2016 the Nordic Societies of Public Health.)

We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.

Objective: To quantify weight ideals of young adults and to examine whether the discrepancy between actual and ideal weight is associated with 10-year body mass index (BMI) change in the population., Methods: This study comprised 4,964 adults from the prospective population-based FinnTwin16 study. They reported their actual and ideal body weight at age 24 (range 22-27) and 10 years later (attrition 24.6%). The correlates of discrepancy between actual and ideal body weight and the impact on subsequent BMI change were examined., Results: The discrepancy between actual and ideal weight at 24 years was on average 3.9 kg (1.4 kg/m(2) ) among women and 1.2 kg (0.4 kg/m(2) ) among men. On average, participants gained weight during follow-up irrespective of baseline ideal weight: women ¯x = +4.8 kg (1.7 kg/m(2) , 95% CI 1.6-1.9 kg/m(2) ), men ¯x = +6.3 kg (2.0 kg/m(2) , 95% CI 1.8-2.1 kg/m(2) ). Weight ideals at 24 years were not correlated with 10-year weight change. At 34 years, just 13.2% of women and 18.9% of men were at or below the weight they had specified as their ideal weight at 24 years. Women and men adjusted their ideal weight upward over time., Conclusions: Irrespective of ideal weight at baseline, weight gain was nearly universal. Weight ideals were shifted upward over time., (© 2016 The Obesity Society.)

There is a lack of evidence pointing to specific dietary elements related to weight gain and obesity prevention in childhood and adulthood. Dietary intake and obesity are both inherited and culturally transmitted, but most prospective studies on the association between diet and weight status do not take genetics into consideration. The objective of this study was to document the association between dietary intake at 9 years and subsequent Body Mass Index (BMI) in adolescent monozygotic boy and girl twin pairs. This research used data from 152 twin pairs. Dietary data were collected from two 24-hour-recall interviews with a parent and the child aged 9 years. Height and weight were obtained when the twins were aged 9, 12, 13, and 14 years. Intrapair variability analysis was performed to identify dietary elements related to BMI changes in subsequent years. BMI-discordant monozygotic twin pairs were also identified to analyze the dietary constituents that may have generated the discordance. After eliminating potential confounding genetic factors, pre-adolescent boys who ate fewer grain products and fruit and consumed more high-fat meat and milk had higher BMIs during adolescence; pre-adolescent girls who consumed more grain products and high-fat meat and milk had higher BMIs during adolescence. Energy intake (EI) at 9 years was not related to BMI in subsequent years. Our study suggests that messages and interventions directed at obesity prevention could take advantage of sex-specific designs and' eventually' genetic information.

The loss of estrogen during menopause causes changes in the female body, with wide-ranging effects on health. Estrogen-containing hormone replacement therapy (HRT) leads to a relief of typical menopausal symptoms, benefits bone and muscle health, and is associated with tissue-specific gene expression profiles. As gene expression is controlled by epigenetic factors (including DNA methylation), many of which are environmentally sensitive, it is plausible that at least part of the HRT-associated gene expression is due to changes in DNA methylation profile. We investigated genome-wide DNA methylation and gene expression patterns of white blood cells (WBCs) and their associations with body composition, including muscle and bone measures of monozygotic (MZ) female twin pairs discordant for HRT. We identified 7,855 nominally significant differentially methylated regions (DMRs) associated with 4,044 genes. Of the genes with DMRs, five (ACBA1, CCL5, FASLG, PPP2R2B, and UHRF1) were also differentially expressed. All have been previously associated with HRT or estrogenic regulation, but not with HRT-associated DNA methylation. All five genes were associated with bone mineral content (BMC), and ABCA1, FASLG, and UHRF1 were also associated with body adiposity. Our study is the first to show that HRT associates with genome-wide DNA methylation alterations in WBCs. Moreover, we show that five differentially expressed genes with DMRs associate with clinical measures, including body fat percentage, lean body mass, bone mass, and blood lipids. Our results indicate that at least part of the known beneficial HRT effects on body composition and bone mass may be regulated by DNA methylation associated alterations in gene expression in circulating WBCs.

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.

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

We aimed to analyze the characteristics of development of relative weight in Japanese triplets from birth until 12 years of age. Data were collected through a mailed questionnaire sent to mothers of triplets asking for information recorded in medical records. Altogether we had information on 1,061 triplet children of 354 mothers born between 1978 and 2006. For these births, data on triplets' height and weight growth, gestational age, sex, parity, and maternal age at delivery were obtained from records in the maternal and child health handbooks and records from the schools where children receive health check-ups. In addition, information on maternal height and weight was obtained. Triplets have a lower ponderal index at birth and lower body mass index (BMI) compared with the general population until 12 years of age, except for the period during 1 and 3 years of age. Moreover, birth weight had the strongest contribution to BMI of triplets until 6 years of age. After 9 years of age, maternal BMI was a significant factor affecting BMI of triplets.

Background: Body mass index (BMI) is associated with subjective well-being. Higher BMI is believed to be related with lower well-being. However, the association may not be linear. Therefore, we investigated whether a nonlinear (U-shaped) trend would better describe this relationship, and whether eating disorders might account for the association in young adults., Methods: FinnTwin16 study evaluated multiple measures of subjective well-being, including life satisfaction, General Health Questionnaire (GHQ-20), satisfaction with leisure time, work, and family relationships, and satisfaction with sex life in young adulthood in the 1975-79 birth cohorts of Finnish twins (n=5240). We studied the relationship between indicators of subjective well-being and BMI both in full birth cohorts and in subgroups stratified by lifetime DSM-IV eating disorders., Results: We found an inverse U-shaped relationship between all indicators of subjective well-being and BMI in men. There was no overall association between BMI and subjective well-being in women. However, there was an inverse U-shaped relationship between BMI and indicators of subjective well-being in women with a lifetime eating disorder and their healthy female co-twins. Subjective well-being was optimal in the overweight category., Conclusions: Both underweight and obesity are associated with impaired subjective well-being in young men. The BMI reflecting optimal subjective well-being of young men may be higher than currently recognized. Categorization of body weight in terms of BMI may need to be reassessed in young men. BMI and subjective well-being are related in women with a lifetime eating disorder, but not in the general population of young women.

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

To investigate how parental education modifies genetic and environmental influences on variation in BMI during adolescence, self-reported BMI at 11-12, 14, and 17 years of age was collected from a population sample of 2,432 complete Finnish twin pairs born in 1983-1987. Based on parental report, twins were divided to those with high (both parents high school graduates), mixed level (one parent a graduate, the other not), and limited (neither parent a graduate) parental education. Genetic and environmental influences on variation in BMI in different education classes were modeled using twin analysis. Heritability of BMI among 11-12-year-olds with high parental education was 85-87% whereas it was 61-68% if parental education was limited or mixed level. Common environmental effect, i.e., effect of environmental factors shared by family members, was found (17-22%) if parental education was limited or mixed level but not if it was high. With increasing parental education, common environmental variance in BMI decreased at age 14 among boys (from 22 to 3%) and girls (from 17 to 10%); heritability increased among boys from 63 to 78%, but did not change among girls. The common environmental component disappeared and heritability of BMI was larger at the age of 17 in all parental education classes. To conclude, common environment did not affect variation of adolescent BMI in high-educated families but did so in families with limited parental education. This suggests that intervention and prevention campaigns could effectively target families identified by limited parental education.

BMI increases progressively from adolescence to young adulthood. The aims of the present study were firstly, to investigate the extent to which genetic and environmental influences account for differences in BMI trajectories during this period, and secondly to examine whether boys and girls show divergences in these influences, as their BMI normally start differing across adolescence. The study sample consisted of 4,915 monozygotic and like- and unlike-sex dizygotic twins, born between 1975 and 1979. Data on BMI was gathered when twins were on average 16.1, 17.1, 18.6 and 24.4 years old. Genetic and environmental influences on the BMI trajectories were modeled using a latent growth curve approach. The results showed that the heritability of BMI decreased slightly after the adolescence period, from ≈ 80 to 70%. BMI transition from adolescence to young adulthood was best described by a quadratic trajectory that was highly accounted (61.7-86.5%) for by additive genetic influences. Genetic influences on BMI level showed a low correlation with those on the trend in BMI with age indicating that different sets of genes underlie the change of BMI during this period. Importantly, the analyses also evidenced that different genetic and environmental influences may underlie boys and girls evolution. In conclusion, our results suggested specific genetic influences accounting for the BMI rate-of-change from adolescence to young adulthood. This indicates that the specific genes behind BMI level may not be the same as the genes affecting BMI change which should be taken into account in further efforts to identify these genes.

We analyzed the genetic architecture of prepubertal development of relative weight to height in 216 monozygotic and 159 dizygotic complete Japanese twin pairs (52% girls). Ponderal index at birth (kg/m(3)) and body mass index (BMI, kg/m(2)) from 1 to 11 years of age were used. Additive genetic factors explained the major proportion (52-74%) of the variation of BMI from 1 to 11 years of age. Environmental factors common to both co-twins also showed some effect (7-28%), but at most ages this was not statistically significant. Strong genetic tracking was found for BMI from 1 to 11 years of age, but there was also evidence for a persistent effect of common environmental factors. Our results suggest that the genetic architecture of BMI development in the Japanese population is generally similar to that found in previous twin studies in Caucasian populations.

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Weight gain through middle age is a common phenomenon that increases the risk for different types of metabolic diseases and functional limitations later in life. This study examined genetic and environmental influences on the evolution of body mass index (BMI) in women from middle to old age. BMI was evaluated in 102 monozygotic and 114 dizygotic pairs of twin sisters from the year 1975, when they were 42.6 +/- 3.4 years-old, and thereafter in 1981, 1990, 2001 and 2004, in a total 29-year follow-up period. We examined genetic and environmental influences explaining BMI overall level and its rate of change using a latent growth modeling approach. The results showed that mean (+/-SD) BMI increased from 24.1 +/- 3.1 to 28.2 +/- 5.1 kg/m(2) during the 29-year period. The heritability of BMI showed a consistent increment across occasions, from 54% in 1975, to 72% in 2004. Genetic influences accounted for both overall BMI level (60%) and BMI rate of change (64%). Genetic and environmental correlations between BMI level and rate of change were: r(g) = 0.40 and r(e) = -0.24, respectively. We conclude that in relatively healthy women, genes affecting level of BMI may differ from those affecting change in BMI with age. These results provide a basis for identifying genetic variants for change in BMI.

Aim and Method: Cause-specific mortality was studied in relation to body mass index (BMI) and weight stability (defined as less than 1 BMI unit change during a 6-year period) in 15,424 initially healthy twin subjects from the Finnish Twin Cohort, first examined in 1975, re-examined in 1981, and then followed over 22 years (1982-2003). Additionally, death discordant twin pairs were studied to assess whether body weight differences are associated with mortality independent of childhood factors and genetic background. Deaths and cause of death were ascertained from national registries. Associations with mortality were estimated by Cox proportional hazards model for all individuals and conditional logistic regression analysis for pairwise analyses., Results: Mortality increased with increasing BMI for all causes and coronary heart disease (CHD) in men, and there were no associations for all natural causes, cerebrovascular disease, and violent deaths. After adjustment for multiple co-variates and changes in co-variates between 1975 and 1981, BMI was associated with CHD mortality in all men (hazard ratio (HR) = 1.22, 95% CI 1.06-1.41) and in men with stable weight between 1975 and 1981 (HR = 1.26, 95% CI 1.03-1.55). Overall risk of death and cause-specific mortality was not associated with BMI in women., Conclusion: Among clinically healthy subjects at low risk of death, BMI appears to be associated with CHD risk in men., (Copyright 2009 S. Karger AG, Basel.)

The persistence of obesity from early childhood to late middle age is well known. We reviewed the results from existing genetic studies on tracking of BMI to discover how much genetic and environmental factors contribute to this tracking of obesity. In total, we found 5 genetic longitudinal studies on childhood obesity and 8 on obesity in adulthood. One was an adoption study, 3 were family studies, and 9 were twin studies. All were based on Caucasian populations, and one included genetic level information (the FTO gene). Strong genetic continuity in BMI was found from early childhood to onset of adulthood. Although new genetic factors started to affect BMI during the growth period, genetic correlations remained high. Evidence of the effect of common environment on the tracking of BMI during childhood was also found. The heritability estimates reported in twin studies ranged from 0.57 to 0.86 for the trend of BMI from early adulthood to late middle age. The three family studies gave lower estimates. Important unresolved questions are the genetics of BMI change in old age, the genetics of body composition change, the genetic architecture of tracking of obesity in ethnic groups other than Caucasians, and the interplay between genes and environment underlying the development and tracking of obesity., (Copyright 2009 S. Karger AG, Basel.)

Objective: To investigate the interplay between genetic factors influencing baseline level and changes in BMI in adulthood., Methods and Procedures: A longitudinal twin study of the cohort of Finnish twins (N = 10,556 twin individuals) aged 20-46 years at baseline was conducted and followed up 15 years. Data on weight and height were obtained from mailed surveys in 1975, 1981, and 1990., Results: Latent growth models revealed a substantial genetic influence on BMI level at baseline in males and females (heritability (h(2)) 80% (95% confidence interval 0.79-0.80) for males and h(2) = 82% (0.81, 0.84) for females) and a moderate-to-high influence on rate of change in BMI (h(2) = 58% (0.50, 0.69) for males and h(2) = 64% (0.58, 0.69) for females). Only very weak evidence for genetic pleiotropy was observed; the genetic correlation between baseline and rate of change in BMI was very modest (-0.070 (-0.13, -0.068) for males and 0.04 (0.00, 0.08) for females., Discussion: Our population-based results provide a basis for identifying genetic variants for change in BMI, in particular weight gain. Furthermore, they demonstrate for the first time that such genetic variants for change in BMI are likely to be different from those affecting level of BMI.

Background: The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background., Methods and Findings: We used a special study design of "clonal controls," rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean +/- standard deviation (SD) age 25.8 +/- 1.4 y and a body mass index (BMI) difference 5.2 +/- 1.8 kg/m(2). Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults., Conclusions: Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.

Associations between anthropometric measures and cancer have been studied previously, but relatively few studies have had the opportunity to control for genetic and early shared environmental factors. In this study, we analyzed 2 twin cohorts from Sweden born 1886-1925 (n = 21,870) and 1926-1958 (n = 30,279) and 1 from Finland born 1880-1958 (n = 25,882) including in total 78,031 twins, and studied the association between BMI and height and risk of prostate, breast, ovarian, corpus uteri, colon and rectal cancer. The cohorts were both analyzed through a co-twin control method and as traditional cohorts. In co-twin control analyses, older obese (BMI > or = 30 kg/m(2)) subjects (median age 56 years at baseline) were at higher risk of cancer of the corpus uteri (OR = 3.0; 95% CI 0.9-10.6), colon (OR = 1.9; 95% CI 0.8-4.5) and breast (OR = 2.5; 95% CI 1.3-4.2). For younger obese women (median age 30 years at baseline), an inverse tendency was observed for breast cancer (OR = 0.6; 95% CI 0.3-1.5, p for trend = 0.05). The tallest women had an increased risk of breast (OR = 1.8; 95% CI 1.3-2.7) and ovarian cancer (OR = 1.7; 95% CI 0.8-3.5). No consistent associations were found for prostate cancer either for BMI or height. There are some suggestions in our study that uncontrolled genetic or early shared environmental factors may affect risk estimates in studies of anthropometric measures and cancer risk, but do not explain observations of increased cancer risks related to BMI or height.

Background: Overweight in children and adolescents has reached dimensions of a global epidemic during recent years. Simultaneously, information and communication technology use has rapidly increased., Methods: A population-based sample of Finnish twins born in 1983-1987 (N = 4098) was assessed by self-report questionnaires at 17 y during 2000-2005. The association of overweight (defined by Cole's BMI-for-age cut-offs) with computer and cell phone use and ownership was analyzed by logistic regression and their association with BMI by linear regression models. The effect of twinship was taken into account by correcting for clustered sampling of families. All models were adjusted for gender, physical exercise, and parents' education and occupational class., Results: The proportion of adolescents who did not have a computer at home decreased from 18% to 8% from 2000 to 2005. Compared to them, having a home computer (without an Internet connection) was associated with a higher risk of overweight (odds ratio 2.3, 95% CI 1.4 to 3.8) and BMI (beta coefficient 0.57, 95% CI 0.15 to 0.98). However, having a computer with an Internet connection was not associated with weight status. Belonging to the highest quintile (OR 1.8 95% CI 1.2 to 2.8) and second-highest quintile (OR 1.6 95% CI 1.1 to 2.4) of weekly computer use was positively associated with overweight. The proportion of adolescents without a personal cell phone decreased from 12% to 1% across 2000 to 2005. There was a positive linear trend of increasing monthly phone bill with BMI (beta 0.18, 95% CI 0.06 to 0.30), but the association of a cell phone bill with overweight was very weak., Conclusion: Time spent using a home computer was associated with an increased risk of overweight. Cell phone use correlated weakly with BMI. Increasing use of information and communication technology may be related to the obesity epidemic among adolescents.

Objective: To explore eating styles associated with intentional weight loss (IWL) and to determine whether the genetic liability in IWL is entirely shared with genetic liability affecting BMI., Research Methods and Procedures: As part of a longitudinal assessment of various health-related behaviors in a large population-based sample of twins, eating styles, BMI, and the number of times the study participants had intentionally lost > or = 5 kg were assessed by questionnaire from 4667 male and female twins (22 to 27 years of age). Associations of eating styles and IWL were explored using polytomous logistic regression models adjusted for BMI. Sex-specific bivariate structural equation modeling was used to explore genetic and environmental correlations of BMI and IWL., Results: Individuals who had engaged in IWL exhibited markedly more restricting, overeating, and alternating restricting/overeating than those in the no-IWL group. Snacking and eating in the evening were characteristic of women with at least two IWL attempts. Eating in response to visual and emotional cues was very pronounced in women who had engaged in IWL but much less so in men. IWL was estimated to have a heritability of 38% [95% confidence interval (CI), 19% to 55%] in men and 66% (95% CI, 55% to 75%) in women. The genetic covariance of BMI and IWL was 0.38 (95% CI, 0.28 to 0.47) for men and 0.45 (95% CI, 0.41 to 0.52) for women., Discussion: Distinct sex differences exist in eating styles associated with IWL and in the heritability of IWL. Most genetic factors affecting BMI are different from those affecting IWL.

Background: Disparities in body mass index (BMI) between persons with different educational levels in Western countries are well documented, but the background of these education-associated disparities remains poorly understood., Objective: The objective was to examine the influence of environmental and genetic factors on education-associated disparities in self-reported BMI and weight change., Design: Longitudinal postal surveys were performed in 1975, 1981, and 1990. The data were analyzed by using multivariate genetic models for twin data. The data derived from the Finnish Twin Cohort included 2482 monozygotic and 5113 dizygotic same-sex male and female twin pairs born between 1915 and 1957., Results: Education-associated differences in BMI and in weight change were clear in 1975 and 1981, respectively, whereas no differences were seen in weight change between 1981 and 1990 when age and baseline BMI were adjusted for. The trait correlation between baseline BMI and educational attainment (-0.15 in men and women) was mainly due to correlations between additive genetic factors that contributed to BMI and education in men (-0.20; 95% CI: -0.25, -0.14) and women (-0.32; 95% CI: -0.40, -0.25) when adjusted for age. Among women, a weaker positive correlation was found for the unshared environmental effects contributing to the 2 traits (0.06; 95% CI: 0.02, 0.12). The same factors that affected the association between education and BMI in 1975 largely explained the association between education and weight change in 1981., Conclusion: The results suggest the possibility that common genetic factors affect educational attainment and body weight, which contribute to education-associated disparities in BMI in adulthood.

Body mass index (BMI), a simple anthropometric measure, is the most frequently used measure of adiposity and has been instrumental in documenting the worldwide increase in the prevalence of obesity witnessed during the last decades. Although this increase in overweight and obesity is thought to be mainly due to environmental changes, i.e., sedentary lifestyles and high caloric diets, consistent evidence from twin studies demonstrates high heritability and the importance of genetic differences for normal variation in BMI. We analysed self-reported data on BMI from approximately 37,000 complete twin pairs (including opposite sex pairs) aged 20-29 and 30-39 from eight different twin registries participating in the GenomEUtwin project. Quantitative genetic analyses were conducted and sex differences were explored. Variation in BMI was greater for women than for men, and in both sexes was primarily explained by additive genetic variance in all countries. Sex differences in the variance components were consistently significant. Results from analyses of opposite sex pairs also showed evidence of sex-specific genetic effects suggesting there may be some differences between men and women in the genetic factors that influence variation in BMI. These results encourage the continued search for genes of importance to the body composition and the development of obesity. Furthermore, they suggest that strategies to identify predisposing genes may benefit from taking into account potential sex specific effects.

Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m2 ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m2 ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Background: Personalized interventions aiming to increase physical activity in individuals are effective. However, from a public health perspective, it would be important to stimulate physical activity in larger groups of people who share the vulnerability to be physically inactive throughout adulthood. To find these high-risk groups, we identified 36-year leisure-time physical activity profiles from young adulthood to late midlife in females and males. Moreover, we uncovered which anthropometric-, demographic-, lifestyle-, and health-related characteristics were associated with these physical activity profiles. Methods: We included 2,778 females and 1,938 males from the population-based older Finnish Twin Cohort Study, who responded to health and behavior surveys at the mean ages of 24, 30, 40 and 60. Latent profile analysis was used to identify longitudinal leisure-time physical activity profiles. Results: We found five longitudinal leisure-time physical activity profiles for both females and males. Females' profiles were: 1) Low increasing moderate (29%), 2) Moderate stable (23%), 3) Very low increasing low (20%), 4) Low stable (20%) and 5) High increasing high (9%). Males' profiles were: 1) Low increasing moderate (29%), 2) Low stable very low (26%), 3) Moderate decreasing low (21%), 4) High fluctuating high (17%) and 5) Very low stable (8%). In both females and males, lower leisure-time physical activity profiles were associated with lower education, higher body mass index, smoking, poorer perceived health, higher sedentary time, high blood pressure, and a higher risk for type 2 diabetes. Furthermore, lower leisure-time physical activity was linked to a higher risk of depression in females. Conclusions: We found several longitudinal leisure-time physical activity profiles with unique changes in both sexes. Fewer profiles in females than in males remained or became low physically active during the 36-year follow-up. We observed that lower education, higher body mass index, and more smoking already in young adulthood were associated with low leisure-time physical activity profiles. However, the fact that several longitudinal profiles demonstrated a change in their physical activity behavior over time implies the potential for public health interventions to improve leisure-time physical activity levels. [ABSTRACT FROM AUTHOR]

Despite emerging interest in gene-environment interaction (GxE) effects, there is a dearth of studies evaluating its potential relevance apart from specific hypothesized environments and biometrical variance trends. Using a monozygotic within-pair approach, we evaluated evidence of G×E for body mass index (BMI), depressive symptoms, and cognition (verbal, spatial, attention, working memory, perceptual speed) in twin studies from four countries. We also evaluated whether APOE is a 'variability gene' across these measures and whether it partly represents the 'G' in G×E effects. In all three domains, G×E effects were pervasive across country and gender, with small-to-moderate effects. Age-cohort trends were generally stable for BMI and depressive symptoms; however, they were variable-with both increasing and decreasing age-cohort trends-for different cognitive measures. Results also suggested that APOE may represent a 'variability gene' for depressive symptoms and spatial reasoning, but not for BMI or other cognitive measures. Hence, additional genes are salient beyond APOE.

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.