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Objective: This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin pairs with large intrapair BMI differences (within-pair ΔBMI ≥ 3 kg/m 2 )., Methods: Together, 3227 like-sexed twin pairs (34% monozygotic) were examined at age ~30 years in 1975 and followed up in 1981, 1990, and 2011. An individual's observed BMI in 1975 was considered within (±2.0), below (<-2.0), or above (>+2.0) genetically predicted BMI, measured by a polygenic risk score of 996,919 single nucleotide polymorphisms., Results: In monozygotic and dizygotic twin pairs with large intrapair BMI differences, the co-twin with a higher observed BMI in 1975 deviated above predicted BMI more frequently (~2/3) than the co-twin with a lower BMI deviated below prediction (~1/3). Individuals below, within, and above prediction in 1975 reached, respectively, normal weight, overweight, and obesity by 2011, with a mean BMI increase of 4.5 (95% CI: 4.3-4.8)., Conclusions: Categorizing BMI as below, within, or above polygenic risk score-predicted BMI helps identifying individuals who have been resistant or susceptible to weight gain. This may provide new insights into determinants and consequences of obesity., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins' preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset ( ~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions., (© 2023. The Author(s).)

Background: Anthropometric measures show high heritability, and genetic correlations have been found between obesity-related traits. However, we lack a comprehensive analysis of the genetic background of human body morphology using detailed anthropometric measures., Methods: Height, weight, 7 skinfold thicknesses, 7 body circumferences and 4 body diameters (skeletal breaths) were measured in 214 pairs of twin children aged 3-18 years (87 monozygotic pairs) in the Autonomous Region of Madeira, Portugal. Factor analysis (Varimax rotation) was used to analyze the underlying structure of body physique. Genetic twin modeling was used to estimate genetic and environmental contributions to the variation and co-variation of the anthropometric traits., Results: Together, two factors explained 80% of the variation of all 22 anthropometric traits in boys and 73% in girls. Obesity measures (body mass index, skinfold thickness measures, as well as waist and hip circumferences) and limb circumferences loaded most strongly on the first factor, whereas height and body diameters loaded especially on the second factor. These factors as well as all anthropometric measures showed high heritability (80% or more for most of the traits), whereas the rest of the variation was explained by environmental factors not shared by co-twins. Obesity measures showed high genetic correlations (0.75-0.98). Height showed the highest genetic correlations with body diameter measures (0.58-0.76). Correlations between environmental factors not shared by co-twins were weaker than the genetic correlations but still substantial. The correlation patterns were roughly similar in boys and girls., Conclusions: Our results show high genetic correlations underlying the human body physique, suggesting that there are sets of genes widely affecting anthropometric traits. Better knowledge of these genetic variants can help to understand the development of obesity and other features of the human physique., (© 2023. The Author(s).)

Background: Living in single parent and blended families or as an only child-compared to living in two-parent biological families or with siblings, respectively-is associated with a higher body mass index (BMI) in cross-sectional studies. However, longitudinal research addressing the children's BMI in this context is scarce. Further, little is known about the association between family structure and metabolic health., Objectives: This study aimed at investigating the association between both aspects of family structure with BMI and a metabolic score (MetS)., Methods: Cross-sectional data from 7804 children participating in the European multi-center I.Family study (2013/2014) and longitudinal data from 5621 children who also participated previously in the IDEFICS study (2007-2010) were used. Family structure was assessed by a detailed interview. BMI z-score and the MetS were based on measured anthropometry, blood pressure, high-density lipoprotein, blood glucose, and triglycerides. Linear regressions were performed to model associations between family structure with BMI and MetS., Results: Children from single-parent families had higher BMI z-scores in the cross-sectional (β = 0.09, 95% confidence interval [CI]: 0.001 to 0.18) and longitudinal analyses compared to those from two-parent families. Cross-sectionally, the number of siblings was associated with lower BMI z-scores (β = -0.07, 95% CI: -0.10 to -0.03) and lower MetS (β = -0.14, 95% CI: -0.26 to -0.01). Longitudinally, only children between baseline and follow-up had higher BMI z-scores at follow-up (β = 0.07, 95% CI: 0.01 to 0.14) compared to stable siblings., Conclusion: Obesity prevention measures should focus on single-parent households and families with an only child., (© 2022 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

We analyzed the contribution of genetic factors on the association between puberty timing and body mass index (BMI) using longitudinal data and two approaches: (i) genetic twin design and (ii) polygenic scores (PGS) of obesity indices. Our data were derived from Finnish cohorts: 9080 twins had information on puberty timing and BMI and 2468 twins also had genetic data. Early puberty timing was moderately associated with higher BMI in childhood in both boys and girls; in adulthood these correlations were weaker and largely disappeared after adjusting for childhood BMI. The largest proportion of these correlations was attributable to genetic factors. The higher PGSs of BMI and waist circumference were associated with earlier timing of puberty in girls, whereas weaker associations were found in boys. Early puberty is not an independent risk factor for adult obesity but rather reflects the association between puberty timing and childhood BMI contributed by genetic predisposition., (© 2022. The Author(s).)

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.)

Objective: F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored., Methods: We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed., Results: F13A1 mRNA showed significant increase in adipose tissue (p < 0.0001) and an adipocyte-enriched fraction (p = 0.0012) of the heavier co-twin. F13A1 differential expression in adipose tissue (Heavy-Lean ΔF13A1) showed significant negative correlation with circulating adiponectin (p = 0.0195) and a positive correlation with ΔWeight (p = 0.034), ΔBodyFat (0.044) and ΔAdipocyte size (volume, p = 0.012;) in adipocyte-enriched fraction. A whole transcriptome-wide association study (TWAS) on ΔF13A1 vs weight-correlated ΔTranscriptome identified 182 F13A1-associated genes (r > 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation., Conclusions: F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.

As the number of obese people is globally increasing, reports about the putative protective effect of obesity in life-threatening diseases, such as subarachnoid hemorrhage (SAH), are gaining more interest. This theory-the obesity paradox-is challenging to study, and the impact of obesity has remained unclear in survival of several critical illnesses, including SAH. Thus, we performed a systematic review to clarify the relation of obesity and SAH mortality. Our study protocol included systematic literature search in PubMed, Scopus, and Cochrane library databases, whereas risk-of-bias estimation and quality of each selected study were evaluated by the Critical Appraisal Skills Program and Cochrane Collaboration guidelines. A directional power analysis was performed to estimate sufficient sample size for significant results. From 176 reviewed studies, six fulfilled our eligibility criteria for qualitative analysis. One study found paradoxical effect (odds ratio, OR = 0.83 (0.74-0.92)) between morbid obesity (body mass index (BMI) > 40) and in-hospital SAH mortality, and another study found the effect between continuously increasing BMI and both short-term (OR = 0.90 (0.82-0.99)) and long-term SAH mortalities (OR = 0.92 (0.85-0.98)). However, according to our quality assessment, methodological shortcomings expose all reviewed studies to a high-risk-of-bias. Even though two studies suggest that obesity may protect SAH patients from death in the acute phase, all reviewed studies suffered from methodological shortcomings that have been typical in the research field of obesity paradox. Therefore, no definite conclusions could be drawn.

Transglutaminases TG2 and FXIII-A have recently been linked to adipose tissue biology and obesity, however, human studies for TG family members in adipocytes have not been conducted. In this study, we investigated the association of TGM family members to acquired weight gain in a rare set of monozygotic (MZ) twins discordant for body weight, i.e., heavy-lean twin pairs. We report that F13A1 is the only TGM family member showing significantly altered, higher expression in adipose tissue of the heavier twin. Our previous work linked adipocyte F13A1 to increased weight, body fat mass, adipocyte size, and pro-inflammatory pathways. Here, we explored further the link of F13A1 to adipocyte size in the MZ twins via a previously conducted TWA study that was further mined for genes that specifically associate to hypertrophic adipocytes. We report that differential expression of F13A1 (ΔHeavy-Lean) associated with 47 genes which were linked via gene enrichment analysis to immune response, leucocyte and neutrophil activation, as well as cytokine response and signaling. Our work brings further support to the role of F13A1 in the human adipose tissue pathology, suggesting a role in the cascade that links hypertrophic adipocytes with inflammation.

Background: Obesity susceptibility genes are highly expressed in the brain suggesting that they might exert their influence on body weight through eating-related behaviors., Objectives: To examine whether the genetic susceptibility to obesity is mediated by eating behavior patterns., Methods: Participants were 3977 twins (33% monozygotic, 56% females), aged 31-37 y, from wave 5 of the FinnTwin16 study. They self-reported their height and weight, eating behaviors (15 items), diet quality, and self-measured their waist circumference (WC). For 1055 twins with genome-wide data, we constructed a polygenic risk score for BMI (PRSBMI) using almost 1 million single nucleotide polymorphisms. We used principal component analyses to identify eating behavior patterns, twin modeling to decompose correlations into genetic and environmental components, and structural equation modeling to test mediation models between the PRSBMI, eating behavior patterns, and obesity measures., Results: We identified 4 moderately heritable (h2 = 36-48%) eating behavior patterns labeled "snacking," "infrequent and unhealthy eating," "avoidant eating," and "emotional and external eating." The highest phenotypic correlation with obesity measures was found for the snacking behavior pattern (r = 0.35 for BMI and r = 0.32 for WC; P < 0.001 for both), largely due to genetic factors in common (bivariate h2 > 70%). The snacking behavior pattern partially mediated the association between the PRSBMI and obesity measures (βindirect = 0.06; 95% CI: 0.02, 0.09; P = 0.002 for BMI; and βindirect = 0.05; 95% CI: 0.02, 0.08; P = 0.003 for WC)., Conclusions: Eating behavior patterns share a common genetic liability with obesity measures and are moderately heritable. Genetic susceptibility to obesity can be partly mediated by an eating pattern characterized by frequent snacking. Obesity prevention efforts might therefore benefit from focusing on eating behavior change, particularly in genetically susceptible individuals., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

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.)

Background: There has been an increase in children growing up in non-traditional families, such as single-parent and blended families. Children from such families have a higher prevalence of obesity and poorer health outcomes, but research on the relationship with obesogenic behaviours is limited., Objectives: Therefore, the aim of this study was to investigate whether there are associations between family structures and obesogenic behaviours and related family rules in European children and adolescents., Methods: The sample included 7664 children (mean age ± SD: 10.9 ± 2.9) from 4923 families who were participants of the multi-centre I.Family study (2013/2014) conducted in 8 European countries. Family structure was assessed by a detailed interview on kinship and household. Obesogenic behaviours (screen time, sleep duration, consumption of sugar-sweetened beverages (SSBs)) and family rules (rules for computer and television, bedtime routine, availability of SSBs during meals) were determined by standardized questionnaires. Multilevel mixed-effects linear and logistic regression models were used to model the associations of family structure with obesogenic behaviours and family rules. Sex, age, parental education level, number of children and adults in the household and BMI z-score were covariates in the models. Two-parent biological families were set as the reference category., Results: Children from single-parent families were less likely to have family rules regarding screen time (OR: 0.62, 95% CI: 0.40-0.94, p = 0.026) with higher reported hours of screen time per week (β = 2.70 h/week, 95% CI: 1.39-4.00, p < 0.001). The frequency of weekly SSB consumption differed by family structure in a sex-specific manner: girls from single-parent (β = 3.19 frequency/week, 95% CI: 0.91-5.47, p = 0.006) and boys from blended/adoptive families (β = 3.01 frequency/week, 95% CI: 0.99-5.03, p = 0.004) consumed more SSBs. Sleep duration, bedtime routines and availability of SSBs during meals did not differ between children from these family structures. Parental education did not modify any of these associations., Conclusions: Parents in non-traditional family structures appear to experience more difficulties in restricting screen time and the intake of SSBs in their children than parents in traditional two-parent family structures. Our findings therefore suggest that additional support and effective strategies for parents in non-traditional families may help to reduce obesogenic behaviours in children from such family types.

We constructed a food-based diet quality score (DQS) and examined its association with obesity measures, eating styles and nutrient intakes. Participants were 3592 individuals (764 dizygotic [DZ] and 430 monozygotic [MZ] twin pairs) from the FinnTwin16 study. The DQS (0-12 points) was constructed from a short 14 item food frequency questionnaire. Anthropometric measures and eating styles were self-reported. Nutrient intakes were calculated from food diaries completed in a subsample of 249 individuals (45 same-sex DZ and 60 MZ twin pairs). Twins were analyzed both as individuals and as twin pairs. The DQS was inversely associated with body mass index (β = -0.12, per one-unit increase in DQS, p < 0.001), waist circumference (β = -0.34, p < 0.001), obesity (odds ratio [OR]: 0.95, p = 0.004) and abdominal obesity (OR: 0.88, p < 0.001), independent of sex, age, physical activity and education. A higher DQS was associated with health-conscious eating, having breakfast, less snacking, fewer evening meals, and a higher frequency and regularity of eating. The DQS was positively correlated with the intakes of protein, fiber and magnesium and negatively correlated with the intakes of total fat, saturated fat and sucrose. Within twin pairs, most of the associations between the DQS with eating styles and some nutrients remained, but the DQS was not associated with obesity measures within twin pairs. The DQS is an easy-to-use tool for ranking adults according to diet quality and shows an association with obesity measures, eating styles and key nutrients in the expected direction., Competing Interests: The authors declare no conflict of interest.

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.)

Background: Obesity is related to a myriad of cardiometabolic outcomes, each of which may have a specific metabolomic signature and a genetic basis. We identified plasma metabolites associating with different cardiometabolic risk factors (adiposity, cholesterol, insulin resistance, and inflammation) in monozygotic (MZ) twins. Additionally, we assessed if metabolite profiling can identify subgroups differing by cardiometabolic risk factors., Methods: We quantified 111 plasma metabolites (Acquity UPLC-triple quadrupole mass spectrometry), and measured blood lipids, HOMA index, CRP, and adiposity (BMI, %bodyfat by DEXA, fat distribution by MRI) in 40 MZ twin pairs (mean BMI 27.9 kg/m 2 , age 30.7). We determined associations among individuals (via linear regression) between metabolites and clinical phenotypes, and assessed, with within-twin pair analysis, if these associations were free from genetic confounding. We also performed cluster analysis to identify distinct subgroups based on subjects' metabolite profiles., Results: We identified 42 metabolite-phenotype associations (FDR < 0.05), 19 remained significant after controlling for shared factors within the twin pairs. Aspartate, propionylcarnitine, tyrosine hexanoylcarnitine, and deoxycytidine associated positively with two or more adiposity measures. HDL cholesterol (HDL-C) associated negatively and BMI positively with the most numbers of metabolites; 12 were unique for HDL-C and 3 for BMI. Metabolites associating with HDL-C had the strongest effect size. Metabolite profiling revealed two distinct subgroups of individuals, differing by 32 metabolites (p < 0.05), and by total and LDL cholesterol (LDL-C). Forty-two metabolites predicted subgroup membership in correlation with total cholesterol and 45 metabolites predicted subgroup membership in correlation with LDL-C., Conclusions: Different fat depots share metabolites associating with general adiposity. BMI and HDL-C associated with the most pronounced and specific metabolomic signature. Metabolomics profiling can be used to identify distinct subgroups of individuals that differ by cholesterol measures. Most of the observed metabolite-phenotype associations are free of confounding by genetics and environmental factors shared by the co-twins.

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.)

Objectives: There is no consensus on whether cognitive control over food intake (that is, restrained eating) is helpful, merely ineffective or actually harmful in weight management. We examined the interplay between genetic risk of obesity, restrained eating and changes in body weight and size., Methods: Participants were Finnish aged 25-74 years who attended the DIetary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome study at baseline in 2007 and follow-up in 2014. At baseline (n=5024), height, weight and waist circumference (WC) were measured in a health examination and participants self-reported their weight at age 20 years. At follow-up (n=3735), height, weight and WC were based on measured or self-reported information. We calculated 7-year change in body mass index (BMI) and WC and annual weight change from age 20 years to baseline. Three-Factor Eating Questionnaire-R18 was used to assess restrained eating. Genetic risk of obesity was assessed by calculating a polygenic risk score of 97 known BMI-related loci., Results: Cross-lagged autoregressive models indicated that baseline restrained eating was unrelated to 7-year change in BMI (β=0.00; 95% confidence interval (CI)=-0.01, 0.02). Instead, higher baseline BMI predicted greater 7-year increases in restrained eating (β=0.08; 95% CI=0.05, 0.11). Similar results were obtained with WC. Polygenic risk score correlated positively with restrained eating and obesity indicators in both study phases, but it did not predict 7-year change in BMI or WC. However, individuals with higher genetic risk of obesity tended to gain more weight from age 20 years to baseline, and this association was more pronounced in unrestrained eaters than in restrained eaters (P=0.038 for interaction)., Conclusions: Our results suggest that restrained eating is a marker for previous weight gain rather than a factor that leads to future weight gain in middle-aged adults. Genetic influences on weight gain from early to middle adulthood may vary according to restrained eating, but this finding needs to be replicated in future studies.

Background: Few studies have examined both gene expression and DNA methylation profiles in subcutaneous adipose tissue (SAT) during long-term weight loss. Thus, molecular mechanisms in weight loss and regain remain elusive., Participants/methods: We performed a 1-year weight loss intervention on 19 healthy obese participants (mean body mass index (BMI) 34.6 kg m -2 ) and studied longitudinal gene expression (Affymetrix Human Genome U133 Plus 2.0) and DNA methylation (Infinium HumanMethylation450 BeadChip) in SAT at 0, 5 and 12 months. To examine whether weight loss and acquired obesity produce reciprocal profiles, we verified our findings in 26 BMI-discordant monozygotic twin pairs., Results: We found altered expression of 69 genes from 0 to 5' months (short-term) weight loss. Sixty of these genes showed reversed expression in acquired obesity (twins). Altogether 21/69 genes showed significant expression-DNA methylation correlations. Pathway analyses revealed increased high-density lipoprotein-mediated lipid transport characteristic to short-term weight loss. After the fifth month, two groups of participants evolved: weight losers (WLs) and weight regainers (WRs). In WLs five genes were differentially expressed in 5 vs 12 months, three of which significantly correlated with methylation. Signaling by insulin receptor pathway showed increased expression. We further identified 35 genes with differential expression in WLs from 0 to 12 months (long-term) weight loss, with 20 showing opposite expression patterns in acquired obesity, and 16/35 genes with significant expression-DNA methylation correlations. Pathway analyses demonstrated changes in signal transduction, metabolism, immune system and cell cycle. Notably, seven genes (UCHL1, BAG3, TNMD, LEP, BHMT2, EPDR1 and OSTM1) were found to be downregulated during both short- and long-term weight loss., Conclusions: Our study indicates short- and long-term weight loss influences in transcription and DNA methylation in SAT of healthy participants. Moreover, we demonstrate that same genes react in an opposite manner in weight loss and acquired obesity.

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.

Obesity and ageing are associated with lower serum testosterone levels in men. How fat distribution or adipose tissue metabolism, independent of genetic factors and age, are related to sex steroid metabolism is less clear. We studied the associations between adiposity and serum sex hormone concentrations, and mRNA expression of genes regulating sex hormone metabolism in adipose tissue in young adult male monozygotic (MZ) twin pairs. The subjects [n=18 pairs; mean age, 32 years; individual body mass indexes (BMIs) 22-36kg/m 2 ] included 9 male MZ twin pairs discordant for BMI [intra-pair difference (Δ) in BMI ≥3kg/m 2 ]. Sex steroid concentrations were determined by liquid chromatography-tandem mass spectrometry, body composition by dual-energy X-ray absorptiometry and magnetic resonance imaging, and mRNA expressions from subcutaneous adipose tissue by Affymetrix. In BMI-discordant pairs (mean ΔBMI=5.9kg/m 2 ), serum dihydrotestosterone (DHT) was lower [mean 1.9 (SD 0.7) vs. 2.4 (1.0) nmol/l, P=0.040] and mRNA expressions of DHT-inactivating AKR1C2 (P=0.021) and cortisol-producing HSD11B1 (P=0.008) higher in the heavier compared to the leaner co-twins. Serum free 17β-estradiol (E2) was higher [2.3 (0.5) vs. 1.9 (0.5) pmol/l, P=0.028], and in all twin pairs, serum E2 and estrone concentrations were higher in the heavier than in the leaner co-twins [107 (28) vs. 90 (22) pmol/l, P=0.006; and 123 (43) vs. 105 (27) pmol/l, P=0.025]. Within all twin pairs, i.e. independent of genetic effects and age, 1) the amount of subcutaneous fat inversely correlated with serum total and free testosterone, DHT, and sex hormone-binding globulin (SHBG) concentrations (P<0.01 for all), 2) intra-abdominal fat with total testosterone and SHBG (P<0.05), and 3) liver fat with SHBG (P=0.006). Also, 4) general and intra-abdominal adiposity correlated positively with mRNA expressions of AKR1C2, HSD11B1, and aromatase in adipose tissue (P<0.05). In conclusion, acquired adiposity was associated with decreased serum DHT and increased estrogen concentrations, independent of genetic factors and age. The reduction of DHT could be linked to its increased degradation (by AKR1C2 and HSD11B1) and increased estrogen levels to increased adiposity-related expression of aromatase in adipose tissue., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Subcutaneous adipose tissue (SAT) undergoes major changes in obesity, but little is known about the whole-genome scale patterns of these changes or about their variation between different obesity sub-groups. We sought to compare how transcriptomics profiles in SAT differ between monozygotic (MZ) co-twins who are discordant for body mass index (BMI), whether the profiles vary between twin pairs and whether the variation can be linked to clinical characteristics., Methods: We analysed the transcriptomics (Affymetrix U133 Plus 2.0) patterns of SAT in young MZ twin pairs (n=26, intra-pair difference in BMI >3 kg m -2 , aged 23-36), from 10 birth cohorts of adult Finnish twins. The clinical data included measurements of body composition, insulin resistance, lipids and adipokines., Results: We found 2108 genes differentially expressed (false discovery rate (FDR)<0.05) in SAT of the BMI-discordant pairs. Pathway analyses of these genes revealed a significant downregulation of mitochondrial oxidative pathways (P<0.05) and upregulation of inflammation pathways (P<0.05). Hierarchical clustering of heavy/lean twin ratios, representing effects of acquired obesity in the transcriptomics data, revealed three sub-groups with different molecular profiles (FDR<0.05). Analyses comparing these sub-groups showed that, in the heavy co-twins, downregulation of the mitochondrial pathways, especially that of branched chain amino acid degradation was more evident in two clusters while and upregulation of the inflammatory response was most evident in the last, presumably the unhealthiest cluster. High-fasting insulin levels and large adipocyte diameter were the predominant clinical characteristic of the heavy co-twins in this cluster (Bonferroni-adjusted P<0.05)., Conclusions: This is the first study in BMI-discordant MZ twin pairs reporting sub-types of obesity based on both SAT gene expression profiles and clinical traits. We conclude that a decrease in mitochondrial BCAA degradation and an increase in inflammation in SAT co-occur and associate with hyperinsulinemia and large adipocyte size in unhealthy obesity.

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.)

Aims/hypothesis: Low mitochondrial activity in adipose tissue is suggested to be an underlying factor in obesity and its metabolic complications. We aimed to find out whether mitochondrial measures are downregulated in obesity also in isolated adipocytes., Methods: We studied young adult monozygotic (MZ) twin pairs discordant (n = 14, intrapair difference ΔBMI ≥ 3 kg/m 2 ) and concordant (n = 5, ΔBMI < 3 kg/m 2 ) for BMI, identified from ten birth cohorts of 22- to 36-year-old Finnish twins. Abdominal body fat distribution (MRI), liver fat content (magnetic resonance spectroscopy), insulin sensitivity (OGTT), high-sensitivity C-reactive protein, serum lipids and adipokines were measured. Subcutaneous abdominal adipose tissue biopsies were obtained to analyse the transcriptomics patterns of the isolated adipocytes as well as of the whole adipose tissue. Mitochondrial DNA transcript levels in adipocytes were measured by quantitative real-time PCR. Western blots of oxidative phosphorylation (OXPHOS) protein levels in adipocytes were performed in obese and lean unrelated individuals., Results: The heavier (BMI 29.9 ± 1.0 kg/m 2 ) co-twins of the discordant twin pairs had more subcutaneous, intra-abdominal and liver fat and were more insulin resistant (p < 0.01 for all measures) than the lighter (24.1 ± 0.9 kg/m 2 ) co-twins. Altogether, 2538 genes in adipocytes and 2135 in adipose tissue were significantly differentially expressed (nominal p < 0.05) between the co-twins. Pathway analysis of these transcripts in both isolated adipocytes and adipose tissue revealed that the heavier co-twins displayed reduced expression of genes relating to mitochondrial pathways, a result that was replicated when analysing the pathways behind the most consistently downregulated genes in the heavier co-twins (in at least 12 out of 14 pairs). Consistently upregulated genes in adipocytes were related to inflammation. We confirmed that mitochondrial DNA transcript levels (12S RNA, 16S RNA, COX1, ND5, CYTB), expression of mitochondrial ribosomal protein transcripts and a major mitochondrial regulator PGC-1α (also known as PPARGC1A) were reduced in the heavier co-twins' adipocytes (p < 0.05). OXPHOS protein levels of complexes I and III in adipocytes were lower in obese than in lean individuals., Conclusions/interpretation: Subcutaneous abdominal adipocytes in obesity show global expressional downregulation of oxidative pathways, mitochondrial transcripts and OXPHOS protein levels and upregulation of inflammatory pathways., Data Availability: The datasets analysed and generated during the current study are available in the figshare repository, https://dx.doi.org/10.6084/m9.figshare.3806286.v1.

Background: Obesity has been recognized as a state of subclinical inflammation resulting in a loss of insulin receptors and decreased insulin sensitivity. We here studied in vivo the role of circulating matrix metalloproteinase-8 (MMP-8) among young healthy twin adults. Also, in vitro analysis of the cleavage of human insulin receptor (INSR) by MMP-8 was investigated as well its inhibition by doxycycline and other MMP-8 inhibitor, Ilomastat/GM6001, which are broad-spectrum MMP inhibitors., Materials and Methods: We analysed serum MMP-8 levels by a time-resolved immunofluorometric assay in obese (n = 34), overweight (n = 76) and normal weight (n = 130) twin individuals. The effect of MMP-8 on INSR and the effects of synthetic MMP-8 inhibitors, doxycycline and Ilomastat/GM6001, were studied by SDS-PAGE., Results: We found that in obese individuals relative to normal weight individuals, the serum MMP-8 levels and MMP-8/TIMP-1 ratio were significantly increased (P = 0·0031 and P = 0·031, respectively). Among normal weight and obese individuals, also smoking significantly increases serum MMP-8 and MMP-8/TIMP-1 ratio. In vitro, we found that INSR was degraded by MMP-8 and this was inhibited by doxycycline and Ilomastat/GM6001., Conclusions: Obesity associated with elevated circulating MMP-8 found among young adults may contribute to progression of insulin resistance by cleaving INSR. This INSR cleavage by MMP-8 can be inhibited by synthetic MMP-8 inhibitors such as doxycycline. In addition to obesity, also smoking independently explained increased MMP-8 levels. Our results suggest that MMP-8 is an essential mediator in systemic subclinical inflammatory response in obesity, and a potential drug target., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.)

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.)

Background: Little is known about epigenetic alterations associated with subcutaneous adipose tissue (SAT) in obesity. Our aim was to study genome-wide DNA methylation and gene expression differences in SAT in monozygotic (MZ) twin pairs who are discordant for body mass index (BMI). This design completely matches lean and obese groups for genetic background, age, gender and shared environment., Methods: 14We analyzed DNA methylome and gene expression from SAT, together with body composition (magnetic resonance imaging/spectroscopy) and glucose tolerance test, lipids and C-reactive protein from 26 rare BMI-discordant (intrapair difference in BMI ⩾3 kg m(-2)) MZ twin pairs identified from 10 birth cohorts of young adult Finnish twins., Results: We found 17 novel obesity-associated genes that were differentially methylated across the genome between heavy and lean co-twins. Nine of them were also differentially expressed. Pathway analyses indicated that dysregulation of SAT in obesity includes a paradoxical downregulation of lipo/adipogenesis and upregulation of inflammation and extracellular matrix remodeling. Furthermore, CpG sites whose methylation correlated with metabolically harmful fat depots (intra-abdominal and liver fat) also correlated with measures of insulin resistance, dyslipidemia and low-grade inflammation, thus suggesting that epigenetic alterations in SAT are associated with the development of unhealthy obesity., Conclusion: This is the first study in BMI-discordant MZ twin pairs reporting genome-wide DNA methylation and expression profiles in SAT. We found a number of novel genes and pathways whose methylation and expression patterns differ within the twin pairs, suggesting that the pathological adaptation of SAT to obesity is, at least in part, epigenetically regulated.

Context: Sirtuins (SIRTs) regulate cellular metabolism and mitochondrial function according to the energy state of the cell reflected by NAD(+) levels., Objective: Our aim was to determine whether expressions of SIRTs and NAD(+) biosynthesis genes are affected by acquired obesity and how possible alterations are connected with metabolic dysfunction while controlling for genetic and familial factors., Design and Participants: We studied a cross-sectional sample of 40 healthy pairs of monozygotic twins, including 26 pairs who were discordant for body mass index (within-pair difference > 3 kg/m(2)), from the FinnTwin12 and FinnTwin16 cohorts., Main Outcome Measures: Subcutaneous adipose tissue (SAT) transcriptomics was analyzed by using Affymetrix U133 Plus 2.0 chips, total SAT (poly-ADP) ribose polymerase (PARP) activity by an ELISA kit, body composition by dual-energy x-ray absorptiometry and magnetic resonance imaging/spectroscopy, and insulin sensitivity by an oral glucose tolerance test., Results: SIRT1, SIRT3, SIRT5, NAMPT, NMNAT2, NMNAT3, and NRK1 expressions were significantly down-regulated and the activity of main cellular NAD(+) consumers, PARPs, trended to be higher in the SAT of heavier co-twins of body mass index-discordant pairs. Controlling for twin-shared factors, SIRT1, SIRT3, NAMPT, NMNAT3, and NRK1 were significantly negatively correlated with adiposity, SIRT1, SIRT5, NMNAT2, NMNAT3, and NRK1 were negatively correlated with inflammation, and SIRT1 and SIRT5 were positively correlated with insulin sensitivity. Expressions of genes involved in mitochondrial unfolded protein response were also significantly down-regulated in the heavier co-twins., Conclusions: Our data highlight a strong relationship of reduced NAD(+)/SIRT pathway expression with acquired obesity, inflammation, insulin resistance, and impaired mitochondrial protein homeostasis in SAT.

Objective: Some studies indicate an association between napping and increased risk of type 2 diabetes. We studied this prospectively in a sample representative of general population., Methods: A questionnaire was administered to the Finnish Twin Cohort in 1990 (response rate 77%, age 33-60 years). The study population included 12,244 subjects who replied to the question "Do you sleep during the daytime (take naps)?" with five response alternatives ranging from "no need" to "every or almost every day." Information on incident cases of diabetes was obtained by linkage to nationwide registers. Logistic regression models were used to obtain odds ratios (ORs) (95% confidence intervals) for incident type 2 diabetes risk in 1991-2004 by napping category. Adjustments were made for 11 socio-demographic and lifestyle covariates. For subjects aged 33-45 years at baseline, a questionnaire in 2011 provided information on prevalent diabetes., Results: Thirty-four per cent had no need for napping, and 15% did so on ≥3 days weekly. There were 356 incident type 2 diabetes cases during the follow-up. Using the 'no need' category as the reference, the risk of type 2 diabetes was significantly increased only among those napping most frequently [OR 1.86 (1.29-2.67), age- and sex-adjusted]. After adjusting for other covariates, the results were essentially the same, but when adjusted for body mass index, the association decreased (to about 1.3) and was statistically non-significant. Analysis of 2011 self-reported type 2 diabetes was in line with the register data., Conclusions: Frequent napping is associated with future risk of type 2 diabetes. This association is largely explained by obesity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The mechanisms through which genes influence body weight are not well understood, but appetite has been implicated as one mediating pathway. Here we use data from two independent population-based Finnish cohorts (4632 adults aged 25-74 years from the DILGOM study and 1231 twin individuals aged 21-26 years from the FinnTwin12 study) to investigate whether two appetitive traits mediate the associations between known obesity-related genetic variants and adiposity. The results from structural equation modelling indicate that the effects of a polygenic risk score (90 obesity-related loci) on measured body mass index and waist circumference are partly mediated through higher levels of uncontrolled eating (βindirect = 0.030-0.032, P < 0.001 in DILGOM) and emotional eating (βindirect = 0.020-0.022, P < 0.001 in DILGOM and βindirect = 0.013-0.015, P = 0.043-0.044 in FinnTwin12). Our findings suggest that genetic predispositions to obesity may partly exert their effects through appetitive traits reflecting lack of control over eating or eating in response to negative emotions. Obesity prevention and treatment studies should examine the impact of targeting these eating behaviours, especially among individuals having a high genetic predisposition to obesity.

Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8-36.2 years of age, who were discordant (ΔBMI >3 kg/m(2), mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (ΔBMI <3 kg/m(2), n = 14) for body weight, and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways with concomitant downregulation of mtDNA amount, mtDNA-dependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways, and OXPHOS proteins in SAT are downregulated in acquired obesity, and are associated with metabolic disturbances already at the preclinical stage., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

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.

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.

Background: Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain unclear., Methods: We studied this question in rare-weight discordant (intra-pair difference (Δ) body mass index (BMI) 3-10 kg m(-2), n=15) and concordant (ΔBMI 0-2 kg m(-)(2), n=5) young adult (22-35 years) monozygotic twin pairs identified from 10 birth cohorts of Finnish twins (n=5 500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (D × A)., Results: The concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91-0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs, the obese co-twins (BMI 30.6 ± 0.9 kg m(-2)) had significantly larger adipocytes (volume 547 ± 59 pl), than the lean co-twins (24.9 ± 0.9 kg m(-)(2); 356 ± 34 pl, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), homeostatic model assessment-index, C-reactive protein and low-density lipoprotein cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, Δadipocyte volume correlated positively and Δcell number correlated negatively with Δhomeostatic model assessment-index and Δlow-density lipoprotein, independent of Δbody fat. Transcripts most significantly correlating with Δadipocyte volume were related to a reduced mitochondrial function, membrane modifications, to DNA damage and cell death., Conclusions: Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.

Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m(2)). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P<0.05). We found that within-pair similarity is a dominant factor in the metabolic postprandial response, independent of acquired obesity. Branched chain amino acids were increased in heavier as compared with leaner co-twins in the fasting state, but their levels converged postprandially (paired t tests, FDR q<0.05). We also found that specific bacterial groups were associated with postprandial changes of specific metabolites. Our findings underline important roles of genetic and early life factors in the regulation of postprandial metabolite levels., (© FASEB.)

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.

Aims/hypothesis: Not all obese individuals display the metabolic disturbances commonly associated with excess fat accumulation. Mechanisms maintaining this 'metabolically healthy obesity' (MHO) are as yet unknown. We aimed to study different fat depots and transcriptional pathways in subcutaneous adipose tissue (SAT) as related to the MHO phenomenon., Methods: Sixteen rare young adult obesity-discordant monozygotic (MZ) twin pairs (intra-pair difference (∆) in BMI ≥ 3 kg/m(2)), aged 22.8-35.8 years, were examined for detailed characteristics of metabolic health (subcutaneous, intra-abdominal and liver fat [magnetic resonance imaging/spectroscopy]), OGTT, lipids, adipokines and C-reactive protein (CRP). Affymetrix U133 Plus 2.0 chips were used to analyse transcriptomics pathways related to mitochondrial function and inflammation in SAT., Results: Based on liver fat accumulation, two metabolically different subgroups emerged. In half (8/16) of the pairs (∆weight 17.1 ± 2.0 kg), the obese co-twin had significantly higher liver fat (∆718%), 78% increase in AUC insulin during OGTT and CRP, significantly more disturbance in the lipid profile and greater tendency for hypertension compared with the lean co-twin. In these obese co-twins, SAT expression of mitochondrial oxidative phosphorylation, branched-chain amino acid catabolism, fatty acid oxidation and adipocyte differentiation pathways were downregulated and chronic inflammation upregulated. In the other eight pairs (∆weight 17.4 ± 2.8 kg), the obese co-twin did not differ from the non-obese co-twin in liver fat (∆8%), insulin sensitivity, CRP, lipids, blood pressure or SAT transcriptomics., Conclusions/interpretation: Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.

OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for obesity) to determine the heritability of glucagon-like peptide 1 (GLP-1) responses to an oral glucose tolerance test (OGTT) and the influence of acquired obesity to GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) during OGTT or meal test. RESULTS The heritability of GLP-1 area under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults.

Objective: The effects of acquired obesity on lipid profile and lipoprotein composition in rare BMI-discordant monozygotic (MZ) twin pairs were studied., Design and Methods: Abdominal fat distribution, liver fat (magnetic resonance imaging and spectroscopy), fasting serum lipid profile (ultracentrifugation, gradient gel-electrophoresis, and colorimetric enzymatic methods), and lifestyle factors (questionnaires and diaries) were assessed in 15 BMI-discordant (within-pair difference [Δ] in BMI >3 kg/m2) and nin concordant (ΔBMI <3 kg/m2) MZ twin pairs, identified from two nationwide cohorts of Finnish twins., Results: Despite a strong similarity of MZ twins in lipid parameters (intra-class correlations 0.42-0.90, P < 0.05), concentrations of apolipoprotein B (ApoB), intermediate-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein 3a% (HDL3a%), and HDL3c% were higher (P < 0.05) and those of HDL cholesterol, HDL2-C, and HDL2b% were lower (P < 0.01) in the heavier co-twins of BMI-discordant pairs. The composition of lipoprotein particles was similar in the co-twins. When BMI-discordant pairs were further divided into liver fat-discordant and concordant (based on median for Δliver fat, 2.6%), the adverse lipid profile was only seen in those heavy co-twins who also had high liver fat. Conversely, BMI-discordant pairs concordant for liver fat did not differ significantly in lipid parameters. In multivariate analyses controlling for Δsubcutaneous, Δintra-abdominal fat, sex, Δsmoking and Δphysical activity, Δliver fat was the only independent variable explaining the variation in ΔApoB, Δtotal cholesterol, and ΔLDL-C concentration., Conclusions: Several pro-atherogenic changes in the amounts of lipids but not in the composition of lipoprotein particles were observed in acquired obesity. In particular, accumulation of liver fat was associated with lipid disturbances, independent of genetic effects., (Copyright © 2013 The Obesity Society.)

Obesity is a genetically complex disorder that produces a myriad of health problems. Most of the recognized complications of obesity are not only strongly influenced by lifestyle factors, but also present with independent genetic predispositions that are notoriously difficult to disentangle in humans. Most studies on the causes and consequences of acquired obesity are encumbered by the incomplete ability to control for genetic influences. However, utilizing a unique experiment of nature, namely monozygotic twins (MZ) discordant for obesity as 'clonal controls' of obese and non-obese individuals has enabled the fine characterization of the effects and possible antecedents of acquired obesity while controlling for the genetic background, as well as pointed to novel obesity predisposing candidate genes. This review is a distillation of the findings from more than 10 years of research done in an exceptionally well-characterized collection of MZ and dizygotic (DZ) twins, based on the Finnish Twin Cohorts. Topics covered include the nature of development of obesity from the childhood onwards, the role of exercise in modifying the genetic susceptibility, the resulting inflammatory, prediabetic and preatherosclerotic changes in whole body and adipose tissue physiology, as well as the newest insights provided by the omics revolution.

Epicardial fat with its close proximity to coronary arteries has been suggested to be a significant predictor of cardiovascular disease. We studied the relations among acquired obesity, low-grade inflammation, and genetic factors in the accumulation of epicardial fat. A rare sample (n = 15) of healthy monozygotic (MZ) twin pairs discordant for obesity (intrapair difference in body mass index ≥3 kg/m(2)) and 9 concordant MZ pairs 23 to 33 years old were examined for cardiac structure, function, epicardial fat thickness (echocardiography), abdominal subcutaneous tissue, and visceral adipose tissue (VAT), liver fat (magnetic resonance imaging/spectroscopy), and serum high-sensitivity C-reactive protein. In the entire sample, MZ cotwins were remarkably similar in most echocardiographic measurements including epicardial fat (intraclass correlation 0.63, p = 0.0004). However, in the discordant pairs, the obese cotwins (16.5 kg, 23% heavier) had 26% more epicardial fat (p = 0.0029) than nonobese cotwins. They also had significantly larger atrial and left ventricular dimensions. Epicardial fat correlated with VAT (r = 0.49, p = 0.02) in individual twins and when using intrapair differences of measurements within pairs (r = 0.39, p = 0.06). In multiple regression analyses including abdominal subcutaneous tissue, VAT, and liver fat, high-sensitivity C-reactive protein was the only factor that remained significantly associated with epicardial fat in individual twins and within pairs. In conclusion, subjects who share the same genes seem to have similar cardiac dimensions. However, acquired obesity increases epicardial fat independent of genetic factors. The close relation between epicardial fat and low-grade inflammation is likely to contribute to the development of cardiovascular disease in obesity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To investigate whether the paradoxical weight gain associated with dieting is better related to genetic propensity to weight gain than to the weight loss episodes themselves., Subjects: Subjects included 4129 individual twins from the population-based FinnTwin16 study (90% of twins born in Finland 1975-1979). Weight and height were obtained from longitudinal surveys at 16, 17, 18 and 25 years, and number of lifetime intentional weight loss (IWL) episodes of more than 5 kg at 25 years., Results: IWLs predicted accelerated weight gain and risk of overweight. The odds of becoming overweight (body mass index (BMI)≥ 25 kg m(-2)) by 25 years were significantly greater in subjects with one (OR 1.8, 95% CI 1.3-2.6, and OR 2.7, 1.7-4.3 in males and females, respectively), or two or more (OR 2.0, 1.3-3.3, and OR 5.2, 3.2-8.6, in males and females, respectively), IWLs compared with subjects with no IWL. In MZ pairs discordant for IWL, co-twins with at least one IWL were 0.4 kg m(-2) (P=0.041) heavier at 25 years than their non-dieting co-twins (no differences in baseline BMIs). In DZ pairs, co-twins with IWLs gained progressively more weight than non-dieting co-twins (BMI difference 1.7 kg m(-2) at 16 years and 2.2 kg m(-2) at 25 years, P<0.001)., Conclusion: Our results suggest that frequent IWLs reflect susceptibility to weight gain, rendering dieters prone to future weight gain. The results from the MZ pairs discordant for IWLs suggest that dieting itself may induce a small subsequent weight gain, independent of genetic factors.

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.

Coagulation and fibrinolytic activities are under strong genetic control. We studied the effects of acquired obesity, independent of genetic factors on coagulation and fibrinolysis activities in obesity-discordant healthy monozygotic (MZ) twin pairs. Fourteen obesity-discordant (BMI within-pair difference >3 kg/m(2)) and 10 concordant (BMI difference <2 kg/m(2)) MZ twin pairs were identified from the nationwide FinnTwin16 study. Body composition (dual-energy x-ray absorptiometry), abdominal fat distribution (magnetic resonance imaging), liver fat (magnetic resonance spectroscopy), high sensitivity C-reactive protein, insulin sensitivity (euglycemic hyperinsulinemic clamp), and a panel of different markers of blood coagulation and fibrinolysis in the fasting state were measured. Strong resemblance was observed in most coagulation factors within all twin pairs, with the intraclass correlations ranging from 0.73 to 0.97, P < 0.03. However, the activities of fibrinogen and FIX, FXI, and FXII, and plasminogen activator inhibitor-1 (PAI-1) activities were increased in the obese co-twins (P < 0.05) and strongly correlated with the measures of adiposity, inflammation, and insulin resistance (r = 0.32-0.73, P < 0.05) among the twin individuals. Intrapair differences in fibrinogen and PAI-1 correlated with those in BMI, adiposity, and fasting insulin levels (r = 0.40-0.58, P < 0.05) indicating the independent effect of obesity. Derangements of blood coagulation and fibrinolysis are present already in early adulthood in obese subjects. Acquired obesity, independent of genetic factors, increases the activities of fibrinogen and activities of FIX, FXI, FXII, and PAI-1. This study confirms the mechanisms of simultaneous activities of intrinsic coagulation factors and impaired fibrinolysis predisposing obese subjects to thrombosis.

Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.

Objective: Epidemiological studies suggest a relationship between midlife metabolism and old age cognition. We examined the effect of midlife BMI and related metabolic conditions on old age cognitive performance and whether there was evidence from direct causal pathways behind these associations in a large sample of Finnish twins., Design: Midlife variables of 2606 twin individuals were based on postal questionnaires and registry records. Old age cognitive status was measured by using a validated telephone interview., Results: Midlife BMI, cardiovascular disease, hypertension and diabetes were each associated with old age cognition when adjusted for sex, education, birth year and age at the interview. Similarly, overweight increased the risk for categories of mild impairment of cognitive function and likely dementia. Cardiovascular disease diminished the mean cognitive score also among discordant twin pairs (β-estimate=1.10, p-value= 0.012). Weight gain more than 1.7 kg/m(2) and loss more than 2 kg/m(2) within an average of 5.6 years were associated with lower cognitive performance independently of BMI. An additive genetic correlation explained the association between BMI and old age cognition (r(A)=-0.12, 95% CI -0.21; -0.03), but adjustment for education led to loss of significance (r(A)=-0.06, 95% CI -0.16; 0.03)., Conclusions: Midlife metabolic diseases, especially diabetes, are independently associated with impaired cognition in old age. Even a more subtle weight change than suggested previously was associated with lower old age cognition. There was evidence from direct causal pathway between cardiovascular disease and old age cognition, while the correlation between midlife BMI and old age cognition was explained mostly by genetic factors.

Animal studies have suggested that angiopoietin-like 4 (Angptl4) regulates adiposity through central and peripheral mechanisms. The aim of this study was to investigate whether serum concentration and adipose tissue expression of Angptl4 are associated with obesity-related parameters in humans. Altogether, 75 dizygotic (DZ) and 46 monozygotic (MZ) twin pairs were studied, from the FinnTwin12 and FinnTwin16 cohorts. Among the MZ pairs, 21 were discordant for body mass index (BMI) (intra-pair BMI-difference >2.5 kg/m², age 23-33 years). Serum Angptl4 (s-Angptl4) levels were measured by ELISA, and adipose tissue gene expression was analyzed by genome-wide transcript profiling. In MZ twin pairs discordant for BMI, s-Angptl4 and adipose tissue ANGPTL4 mRNA (at-ANGPTL4) levels were significantly decreased (P = 0.04 and P = 0.03, respectively) in obese twins as compared with their nonobese cotwins. In all twins, intra-pair differences in s-Angptl4 levels were inversely correlated with intra-pair differences in BMI (r = -0.27, P = 0.003). In individual MZ twins, at-ANGPTL4 expression was inversely correlated with BMI (r = -0.44, P = 0.001) and positively correlated with at-LIPE (r = 0.24, P = 0.01) and at-ABHD5 (r = 0.41, P = 0.005) expression. Our results demonstrated that variation in Angptl4 concentration was only modestly accounted for by genetic factors and suggest a role for Angptl4 in acquired obesity in humans.

Objective: To investigate whether bacterial lipopolysaccharide (LPS) activity in human serum is associated with the components of the metabolic syndrome (MetS) in type 1 diabetic patients with various degrees of kidney disease and patients with IgA glomerulonephritis (IgAGN)., Research Design and Methods: Serum LPS activity was determined with the Limulus Amoebocyte Lysate chromogenic end point assay in type 1 diabetic patients with a normal albumin excretion rate (n = 587), microalbuminuria (n = 144), macroalbuminuria (n = 173); patients with IgAGN (n = 98); and in nondiabetic control subjects (n = 345). The relationships of the LPS/HDL ratio and MetS-associated variables were evaluated with Pearson correlation., Results: The MetS was more prevalent in type 1 diabetic patients (48%) than in patients with IgAGN (15%). Diabetic patients with macroalbuminuria had a significantly higher serum LPS/HDL ratio than patients with IgAGN. In the normoalbuminuric type 1 diabetic group, patients in the highest LPS/HDL quartile were diagnosed as having the MetS three times more frequently than patients in the lowest quartile (69 vs. 22%; P < 0.001). High LPS activity was associated with higher serum triglyceride concentration, earlier onset of diabetes, increased diastolic blood pressure, and elevated urinary excretion of monocyte chemoattractant protein-1., Conclusions: High serum LPS activity is strongly associated with the components of the MetS. Diabetic patients with kidney disease seem to be more susceptible to metabolic endotoxemia than patients with IgAGN. Bacterial endotoxins may thus play an important role in the development of the metabolic and vascular abnormalities commonly seen in obesity and diabetes-related diseases.

Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect., Competing Interests: The authors have declared that no competing interests exist.

To get beyond the "low-hanging fruits" so far identified by genome-wide association (GWA) studies, new methods must be developed in order to discover the numerous remaining genes that estimates of heritability indicate should be contributing to complex human phenotypes, such as obesity. Here we describe a novel integrative method for complex disease gene identification utilizing both genome-wide transcript profiling of adipose tissue samples and consequent analysis of genome-wide association data generated in large SNP scans. We infer causality of genes with obesity by employing a unique set of monozygotic twin pairs discordant for BMI (n = 13 pairs, age 24-28 years, 15.4 kg mean weight difference) and contrast the transcript profiles with those from a larger sample of non-related adult individuals (N = 77). Using this approach, we were able to identify 27 genes with possibly causal roles in determining the degree of human adiposity. Testing for association of SNP variants in these 27 genes in the population samples of the large ENGAGE consortium (N = 21,000) revealed a significant deviation of P-values from the expected (P = 4x10(-4)). A total of 13 genes contained SNPs nominally associated with BMI. The top finding was blood coagulation factor F13A1 identified as a novel obesity gene also replicated in a second GWA set of approximately 2,000 individuals. This study presents a new approach to utilizing gene expression studies for informing choice of candidate genes for complex human phenotypes, such as obesity., Competing Interests: The authors have declared that no competing interests exist.