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Background: Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence., Methods and Findings: We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries., Conclusions: This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DAL has received support from Roche Diagnostics and Medtronic in relation to biomarker research that is not related to the research presented in this paper. The other authors have declared that no competing interests exist., (Copyright: © 2023 Vinther et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The present study investigated the Danish secular trend of intelligence test scores among young men born between 1940 and 2000, as well as the possible associations of birth cohort changes in family size, nutrition, education, and intelligence test score variability with the increasing secular trend. The study population included all men born from 1940 to 2000 who appeared before a draft board before 2020 (N = 1,556,770). At the mandatory draft board examination, the approximately 19-year-old men underwent a medical examination and an intelligence test. In the statistical analyses, the IQ mean and standard deviation (SD) were estimated separately for each of the included annual birth cohorts based on information from birth cohorts with available total intelligence test scores for all tested individuals (i.e. 1940-1958 and 1987-2000; the mean and SD were interpolated for the intermediate birth cohorts). Moreover, the possible associations with birth cohort changes in family size, height as a proxy for nutritional status, education, and IQ variability were investigated among those birth cohorts for whom a secular increase in intelligence test scores was found. The results showed that the estimated mean IQ score increased from a baseline set to 100 (SD: 15) among individuals born in 1940 to 108.9 (SD: 12.2) among individuals born in 1980, since when it has decreased. Focusing on the birth cohorts of 1940-1980, for whom a secular increase in intelligence test scores was found, birth cohort changes in family size, height, and education explained large proportions of the birth cohort variance in mean intelligence test scores, suggesting that these factors may be important contributors to the observed Flynn effect in Denmark., Competing Interests: The authors have declared that no competing interests exist.

Body mass index (BMI) is a highly heritable polygenic trait. It is also affected by various environmental and behavioral risk factors. We used a BMI polygenic risk score (PRS) to study the interplay between the genetic and environmental factors defining BMI. First, we generated a BMI PRS that explained more variance than a BMI genetic risk score (GRS), which was using only genome-wide significant BMI-associated variants (R2 = 13.1% compared to 6.1%). Second, we analyzed interactions between BMI PRS and seven environmental factors. We found a significant interaction between physical activity and BMI PRS, even when the well-known effect of the FTO region was excluded from the PRS, using a small dataset of 6,179 samples. Third, we stratified the study population into two risk groups using BMI PRS. The top 22% of the studied populations were included in a high PRS risk group. Engagement in self-reported physical activity was associated with a 1.66 kg/m2 decrease in BMI in this group, compared to a 0.84 kg/m2 decrease in BMI in the rest of the population. Our results (i) confirm that genetic background strongly affects adult BMI in the general population, (ii) show a non-linear interaction between BMI genetics and physical activity, and (iii) provide a standardized framework for future gene-environment interaction analyses., Competing Interests: This submission contains original research. Novo Nordisk provided unrestricted grants for data collection. No authors were employed by or consulted Novo Nordisk during this study, and no conflict of interest exists in connection to patents, products in development, marketed products, or alike. This funding does not alter our adherence to PLOS ONE policies on sharing data and materials, and does not impose restrictions on sharing of data and/or material. AR and VI are employees of Genotek Ltd. and may own stock/stock options in the company. No other conflict of interest exists in connection to patents, products in development, marketed products, or alike. This funding does not alter our adherence to PLOS ONE policies on sharing data and materials, and does not impose restrictions on sharing of data and/or material. Other authors declare no conflict of interests.

Background: Weight loss after bariatric surgery varies widely between individuals, partly due to genetic differences. In addition, genetic determinants of abdominal obesity have been shown to attenuate weight loss after dietary intervention with special attention paid to the rs1358980-T risk allele in the VEGFA locus. Here we aimed to test if updated genetic risk scores (GRSs) for adiposity measures and the rs1358980-T risk allele are linked with weight loss following gastric bypass surgery., Methods: Five hundred seventy six patients with morbid obesity underwent Roux-en-Y gastric bypass. A GRS for BMI and a GRS for waist-hip-ratio adjusted for BMI (proxy for abdominal obesity), respectively, were constructed. All patients were genotyped for the rs1358980-T risk allele. Associations between the genetic determinants and weight loss after bariatric surgery were evaluated., Results: The GRS for BMI was not associated with weight loss (β = -2.0 kg/100 risk alleles, 95% CI -7.5 to 3.3, p = 0.45). Even though the GRS for abdominal obesity was associated with an attenuated weight loss response adjusted for age, sex and center (β = -14.6 kg/100 risk alleles, 95% CI -25.4 to -3.8, p = 0.008), it was not significantly associated with weight loss after adjustment for baseline BMI (β = -7.9 kg/100 risk alleles, 95% CI -17.5 to 1.6, p = 0.11). Similarly, the rs1358980-T risk allele was not significantly associated with weight loss (β = -0.8 kg/risk allele, 95% CI -2.2 to 0.6, p = 0.25)., Discussion: GRSs for adiposity derived from large meta-analyses and the rs1358980-T risk allele in the VEGFA locus did not predict weight loss after gastric bypass surgery. The association between a GRS for abdominal obesity and the response to bariatric surgery may be dependent on the association between the GRS and baseline BMI., Competing Interests: The authors have declared that no competing interests exist.

Background: Congenital heart defects (CHDs) are the most common congenital malformations. The aetiology of CHDs is complex. Large cohort studies and systematic reviews and meta-analyses based on these have reported an association between higher risk of CHDs in the offspring and individual maternal metabolic disorders such as obesity, diabetes, hypertension, and preeclampsia, all conditions that can be related to insulin resistance or hyperglycaemia. However, the clinical reality is that these conditions often occur simultaneously. The aim of this review is, in consequence, both to evaluate the existing evidence on the association between maternal metabolic disorders, defined as obesity, diabetes, hypertension, preeclampsia, dyslipidaemia and CHDs in the offspring, as well as the significance of combinations, such as metabolic syndrome, as risk factors., Methods: A systematic literature search of papers published between January 1, 1990 and January 14, 2021 was conducted using PubMed and Embase. Studies were eligible if they were published in English and were case-control or cohort studies. The exposures of interest were maternal overweight or obesity, hypertension, preeclampsia, diabetes, dyslipidaemia, and/or metabolic syndrome, and the outcome of interest was CHDs in the offspring. Furthermore, the studies were included according to a quality assessment score., Results: Of the 2,250 identified studies, 32 qualified for inclusion. All but one study investigated only the individual metabolic disorders. Some disorders (obesity, gestational diabetes, and hypertension) increased risk of CHDs marginally whereas pre-gestational diabetes and early-onset preeclampsia were strongly associated with CHDs, without consistent differences between CHD subtypes. A single study suggested a possible additive effect of maternal obesity and gestational diabetes., Conclusions: Future studies of the role of aberrations of the glucose-insulin homeostasis in the common aetiology and mechanisms of metabolic disorders, present during pregnancy, and their association, both as single conditions and-particularly-in combination, with CHDs are needed., Competing Interests: The authors have declared that no competing interests exist.

Background: One-fourth of women experience substantially higher weight years after childbirth. We examined weight change from prepregnancy to 18 months postpartum according to subsequent maternal risk of hypertension and cardiovascular disease (CVD)., Methods and Findings: We conducted a cohort study of 47,966 women with a live-born singleton within the Danish National Birth Cohort (DNBC; 1997-2002). Interviews during pregnancy and 6 and 18 months postpartum provided information on height, gestational weight gain (GWG), postpartum weights, and maternal characteristics. Information on pregnancy complications, incident hypertension, and CVD was obtained from the National Patient Register. Using Cox regression, we estimated adjusted hazard ratios (HRs; 95% confidence interval [CI]) for hypertension and CVD through 16 years of follow-up. During this period, 2,011 women were diagnosed at the hospital with hypertension and 1,321 with CVD. The women were on average 32.3 years old (range 18.0-49.2) at start of follow-up, 73% had a prepregnancy BMI <25, and 27% a prepregnancy BMI ≥25. Compared with a stable weight (±1 BMI unit), weight gains from prepregnancy to 18 months postpartum of >1-2 and >2 BMI units were associated with 25% (10%-42%), P = 0.001 and 31% (14%-52%), P < 0.001 higher risks of hypertension, respectively. These risks were similar whether weight gain presented postpartum weight retention or a new gain from 6 months to 18 months postpartum and whether GWG was below, within, or above the recommendations. For CVD, findings differed according to prepregnancy BMI. In women with normal-/underweight, weight gain >2 BMI units and weight loss >1 BMI unit were associated with 48% (17%-87%), P = 0.001 and 28% (6%-55%), P = 0.01 higher risks of CVD, respectively. Further, weight loss >1 BMI unit combined with a GWG below recommended was associated with a 70% (24%-135%), P = 0.001 higher risk of CVD. No such increased risks were observed among women with overweight/obesity (interaction by prepregnancy BMI, P = 0.01, 0.03, and 0.03, respectively). The limitations of this observational study include potential confounding by prepregnancy metabolic health and self-reported maternal weights, which may lead to some misclassification., Conclusions: Postpartum weight retention/new gain in all mothers and postpartum weight loss in mothers with normal-/underweight may be associated with later adverse cardiovascular health., Competing Interests: The authors have declared that no competing interests exist.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: MMcC: The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. He serves on advisory panels for Pfizer, NovoNordisk, Zoe Global; has received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly; has stock options in Zoe Global; has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier & Takeda. MS receives funding from Pfizer Inc. for a project not related to this research. IB and spouse own stock in GlaxoSmithKline and Incyte Corp. ZE and CDB currently serve on the editorial board of PLOS Genetics. AC reports personal fees from Novartis, personal fees from Thermo Fisher Scientific, personal fees from Philips, personal fees from Sanofi, personal fees from Stallergenes Greer, outside the submitted work. KC in involved in consultancy for Danone Research, LNC-therapeutic and Confo-therapeutic but no personal funding is received and this activity not linked to the present research.

Background: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight., Methods and Findings: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations., Conclusions: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: AvB has received reimbursement for speaking at symposia sponsored by Nestlé and Mead Johnson, who partly financially supported the 15-year follow-up examination of the GINIplus study. KMG has received reimbursement for speaking at conferences sponsored by companies selling nutritional products and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, and Danone. DAL has received support from Roche Diagnostics and Medtronic in relation to biomarker research that is not related to the research presented in this paper. The other authors have declared that no competing interests exist.

Background and Aims: Increased body mass index (BMI = weight/height2; kg/m2) and weight gain is associated with increased mortality, wherefore weight loss and avoided weight gain should be followed by lower mortality. This is achieved in clinical settings, but in the general population weight loss appears associated with increased mortality, possibly related to the struggles with body weight control (BWC). We investigated whether attitudes to and experiences with BWC in combination with recent changes in body weight influenced long-term mortality among normal weight and overweight individuals., Population and Methods: The study population included 6,740 individuals attending the 3rd cycle in 1991-94 of the Copenhagen City Heart Study, providing information on BMI, educational level, health behaviours, well-being, weight half-a-year earlier, and answers to four BWC questions about caring for body weight, assumed benefit of weight loss, current and past slimming experiences. Participants reporting previous unintended weight loss (> 4 kg during one year) were excluded. Cox regression models estimated the associations of prior changes in BMI and responses to the BWC questions with approximately 22 years all-cause mortality with age as 'time scale'. Participants with normal weight (BMI < 25.0 kg/m2) and overweight (BMI ≥ 25.0 kg/m2) were analysed separately, and stratified by gender and educational level, health behaviours and well-being as co-variables., Results: Compared with stable weight, weight loss was associated with significantly increased mortality in the normal weight group, but not in the overweight group, and weight gain was not significantly associated with mortality in either group. Participants with normal weight who claimed that it would be good for their health to lose weight or that they were currently trying to lose weight had significantly higher mortality than those denying it. There were no other significant associations with the responses to the BWC questions in either the normal weight or the overweight group. When combining the responses to the BWC questions with the weight changes, using the weight change as either a continuous or categorical variable, there were no significant interaction in their relation to mortality in either the normal weight or the overweight group., Conclusion: Attitudes to and experiences with BWC did not notably modify the association of changes in body weight with mortality in either people with normal weight or people with overweight., Competing Interests: The authors have declared that no competing interests exist.

Background: Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact., Methods and Findings: We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations., Conclusions: In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KMG has received reimbursement for speaking at conferences sponsored by companies selling nutritional products, and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. HL has participated as an advisory board member, consultant and speaker for Nestlé Nutrition Institute and Nestlé Finland. DAL has received support from several National and International Government and Charity Funders and from Roche Diagnostics and Medtronic for research unrelated to that presented here. All support had been administered via DAL's institution; not directly to her. The other authors have declared that no competing interests exist.

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.

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.