A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

Common variants of human fat mass- and obesity-associated gene Fto have been linked with higher body mass index, but the biological explanation for the link has remained obscure. Recent findings suggest that these variants affect the homeobox protein IRX3. Here we report that FTO has a role in white adipose tissue which modifies its response to high-fat feeding. Wild type and Fto-deficient mice were exposed to standard or high-fat diet for 16 weeks after which metabolism, behavior and white adipose tissue morphology were analyzed together with adipokine levels and relative expression of genes regulating white adipose tissue adipogenesis and Irx3. Our results indicate that Fto deficiency increases the expression of genes related to adipogenesis preventing adipocytes from becoming hypertrophic after high-fat diet. In addition, we report a novel finding of increased Irx3 expression in Fto-deficient mice after high-fat feeding indicating a complex link between FTO, IRX3 and fat metabolism.

Genetic variants in the fat mass- and obesity-associated gene Fto are linked to the onset of obesity in humans. The causal role of the FTO protein in obesity is supported by evidence obtained from transgenic mice; however, the underlying molecular pathways pertaining to the role of FTO in obesity have yet to be established. In this study, we investigate the Fto gene in mouse brown adipose tissue and in the browning process of white adipose tissue. We analyze distinct structural and molecular factors in brown and white fat depots of Fto-deficient mice under normal and obesogenic conditions. We report significant alterations in the morphology of adipose tissue depots and the expression of mRNA and microRNA related to brown adipogenesis and metabolism in Fto-deficient mice. Furthermore, we show that high-fat feeding does not attenuate the browning process of Fto-deficient white adipose tissue as observed in wild-type tissue, suggesting a triggering effect of the FTO pathways by the dietary environment.

Objective and methods The impact of the rs9939609 FTO variant on cardiovascular events was investigated in the 19-year follow-up of subjects recruited to the OPERA study. Results A total of 212 cardiovascular disease (CVD) and 152 coronary heart disease (CHD) events or deaths occurred during follow-up. The logistic regression analysis revealed that among the AA genotype the incidence of CHD (OR 1.905; 95% CI 1.250–2.903, p = 0.001) and CVD (OR 1.849; 1.265–2.702, p = 0.003) events or death was significantly higher when adjusted for age, sex, and study group. After further adjustment with BMI, smoking status, systolic blood pressure, and low-density lipoprotein cholesterol, the higher incidence of CHD and CVD events or death among subjects with the AA genotype remained significant (OR 1.895; p = 0.002 and p = 0.004, respectively). In Cox regression analysis, the AA genotype displayed a higher rate of CVD and CHD death when the model was adjusted for sex, age, and study group (p = 0.006 and p = 0.046). FTO rs9939609 AA genotype improved the C-index of the final predictive model from 0.709 to 0.715. In reclassification analyses, the integrated discrimination index was significant 0.011 (p = 0.010). Conclusion The AA genotype of FTO rs9939609 seems to be associated with a higher risk of CVD, and this phenomenon seems to be independent of the traditional risk factors for atherosclerosis.

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.

Background: Smoking is the biggest preventable factor causing mortality and morbidity and the health benefits of smoking cessation are commonly known. Smoking cessation-related weight gain is well documented. We evaluated the association between smoking cessation and the incidence of obesity-related morbidities such as hypertension, diabetes and metabolic syndrome as well as mortality. We also evaluated telomere length related to smoking cessation. Material and methods: This study was part of the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study. The mean follow up time among the 600 study subjects was 20 years. We divided the study subjects into four groups by smoking status (“never”, “current”, “ex-smokers” and “quit”) and analyzed their health status. “Ex-smokers” had quit smoking before baseline and “quit” quit during the follow-up time. Information about total mortality between the years 2013–2020 was also utilized. Results: During the follow-up time systolic blood pressure decreased the most in the “current” and in the “ex-smoker” groups. Office SBP decreased the least in the “quit” group (p = 0.001). BMI increased the most in the “quit” and the least in the “ex-smokers” group (p = 0.001). No significant increases were seen in the incidence of obesity-related-diseases, such as metabolic syndrome, hypertension and diabetes was seen. There was no significant difference in the shortening of telomeres. Odds of short-term mortality was increased in the “current” group (2.43 (CI 95% 1.10; 5.39)), but not in the “quit” (1.43 (CI 95% 0.73–2.80)) or “ex-smoker” (1.02 (CI 95% 0.56–1.86)) groups when compared to “never” group. Conclusions: Even though, the blood pressure levels were unfavorable in the “quit” group, there was no significant increase in the incidence of obesity-related-diseases, and a noticeable benefit in short-term mortality was seen during the 6-year follow-up. The benefits of smoking cessation outweigh the disadvantages in the long-term.