Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes.

BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.

Smoking during pregnancy is associated with child overweight independent of maternal pre-pregnancy BMI and genetic predisposition to adiposity.

High maternal body mass index (BMI) and smoking during pregnancy are risk factors for child overweight. Maternal smoking tends to reduce her BMI and the association of smoking with child overweight may be confounded by or interacting with maternal genetic predisposition to adiposity. In the Danish National Birth Cohort, we investigated whether smoking during pregnancy is associated with child BMI/overweight independent of pre-pregnancy BMI and maternal genetic predisposition to adiposity estimated as total, transmitted and non-transmitted genetic risk scores (GRSs) based on 941 common genetic variants associated with BMI. Smoking during pregnancy was associated with higher child BMI and higher odds of child overweight in a dose-response relationship. The odds ratio (95% CI) for smoking 11 + cigarettes in third trimester versus no smoking was 2.42 (1.30; 4.50), irrespective of maternal BMI and maternal GRSs (total, transmitted or non-transmitted). There were no statistically significant interactions between maternal GRSs and smoking (all p-values for interactions > 0.05). In conclusion, in this study, smoking during pregnancy exhibits a dose-response association with increased child BMI/overweight, independent of maternal pre-pregnancy BMI, maternal transmitted, and non-transmitted genetic predisposition to adiposity. Avoidance of smoking during pregnancy may help prevent childhood obesity irrespective of the mother-child genetic predisposition.

Genetic markers of abdominal obesity and weight loss after gastric bypass surgery.

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 (ß = -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 (ß = -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 (ß = -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 (ß = -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.

Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis.

Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10-15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10-12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10-9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10-14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10-11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (ß)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10-8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.

The effects of a 2-year physical activity and dietary intervention on plasma lipid concentrations in children: the PANIC Study.

PURPOSE: We studied the effects of a physical activity and dietary intervention on plasma lipids in a general population of children. We also investigated how lifestyle changes contributed to the intervention effects. METHODS: We carried out a 2-year controlled, non-randomized lifestyle intervention study among 504 mainly prepubertal children aged 6-9 years at baseline. We assigned 306 children to the intervention group and 198 children to the control group. We assessed plasma concentrations of total, LDL, HDL, and VLDL cholesterol, triglycerides, HDL triglycerides, and VLDL triglycerides. We evaluated the consumption of foods using 4-day food records and physical activity using a movement and heart rate sensor. We analyzed data using linear mixed-effect models adjusted for age at baseline, sex, and pubertal stage at both time points. Furthermore, specific lifestyle variables were entered in these models. RESULTS: Plasma LDL cholesterol decreased in the intervention group but did not change in the control group ( - 0.05 vs. 0.00 mmol/L, regression coefficient (ß) = - 0.0385, p = 0.040 for group*time interaction). This effect was mainly explained by the changes in the consumption of high-fat vegetable oil-based spreads (ß = - 0.0203, + 47% change in ß) and butter-based spreads (ß = - 0.0294, + 30% change in ß), moderate-to-vigorous physical activity (ß = - 0.0268, + 30% change in ß), light physical activity (ß = - 0.0274, + 29% change in ß) and sedentary time (ß = - 0.0270, + 30% change in ß). The intervention had no effect on other plasma lipids. CONCLUSION: Lifestyle intervention resulted a small decrease in plasma LDL cholesterol concentration in children. The effect was explained by changes in quality and quantity of dietary fat and physical activity. CLINICAL TRIAL REGISTRY NUMBER: NCT01803776, ClinicalTrials.gov.

A 2 year physical activity and dietary intervention attenuates the increase in insulin resistance in a general population of children: the PANIC study.

AIMS/HYPOTHESIS: We studied for the first time the long-term effects of a combined physical activity and dietary intervention on insulin resistance and fasting plasma glucose in a general population of predominantly normal-weight children. METHODS: We carried out a 2 year non-randomised controlled trial in a population sample of 504 children aged 6-9 years at baseline. The children were allocated to a combined physical activity and dietary intervention group (306 children at baseline, 261 children at 2-year follow-up) or a control group (198 children, 177 children) without blinding. We measured fasting insulin and fasting glucose, calculated HOMA-IR, assessed physical activity and sedentary time by combined heart rate and body movement monitoring, assessed dietary factors by a 4 day food record, used the Finnish Children Healthy Eating Index (FCHEI) as a measure of overall diet quality, and measured body fat percentage (BF%) and lean body mass by dual-energy x-ray absorptiometry. The intervention effects on insulin, glucose and HOMA-IR were analysed using the intention-to-treat principle and linear mixed-effects models after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The measures of physical activity, sedentary time, diet and body composition at baseline and 2 year follow-up were entered one-by-one as covariates into the models to study whether changes in these variables might partly explain the observed intervention effects. RESULTS: Compared with the control group, fasting insulin increased 4.65 pmol/l less (absolute change +8.96 vs +13.61 pmol/l) and HOMA-IR increased 0.18 units less (+0.31 vs +0.49 units) over 2 years in the combined physical activity and dietary intervention group. The intervention effects on fasting insulin (regression coefficient ß for intervention effect -0.33 [95% CI -0.62, -0.04], p = 0.026) and HOMA-IR (ß for intervention effect -0.084 [95% CI -0.156, -0.012], p = 0.023) were statistically significant after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The intervention had no effect on fasting glucose, BF% or lean body mass. Changes in total physical activity energy expenditure, light physical activity, moderate-to-vigorous physical activity, total sedentary time, the reported consumption of high-fat (≥60%) vegetable oil-based spreads, and FCHEI, but not a change in BF% or lean body mass, partly explained the intervention effects on fasting insulin and HOMA-IR. CONCLUSIONS/INTERPRETATION: The combined physical activity and dietary intervention attenuated the increase in insulin resistance over 2 years in a general population of predominantly normal-weight children. This beneficial effect was partly mediated by changes in physical activity, sedentary time and diet but not changes in body composition. TRIAL REGISTRATION: ClinicalTrials.gov NCT01803776 Graphical abstract.

Predictors of weight loss after bariatric surgery-a cross-disciplinary approach combining physiological, social, and psychological measures.

BACKGROUND: Bariatric surgery leads to a substantial weight loss (WL), however, a subset of patients undergoing surgery fails to achieve adequate WL. The reason for the individual variation in WL remains unexplained. Using an exploratory cross-disciplinary approach, we aimed to identify preoperative and early postoperative factors explaining the variation in WL after bariatric surgery. METHODS: Sixty-one subjects were recruited. Eighteen subjects did not receive surgery and three subjects dropped out, leaving a total sample of 40 subjects. Physiological, social, and psychological data were collected before and 6 months after surgery. All variables were analyzed in combination using a least absolute shrinkage and selection operator (LASSO) regression to explain the variation in WL 18 months after Roux-en-Y gastric bypass (n = 30) and sleeve gastrectomy (n = 10). RESULTS: Mean WL was 31% (range: 10-52%). The following preoperative factors predicted 59% of the variation in WL: type of surgery (14%), diabetes status (12%), economic resources (9%), sex (7%), binge eating disorder (7%), degree of depression (5%), household type (3%), and physical activity (1%). Including information on early responses after surgery increased the ability to predict WL to 78% and was explained by early WL (47%), changes in energy density of food consumed from a buffet meal (9%), changes in glicentin (5%), degree of depression (5%), sex (5%), type of surgery (2%), economic resources (2%), and changes in drive for thinness (1%). CONCLUSIONS: Using a cross-disciplinary approach, a substantial part of the individual variation in WL was explained by a combination of basic patient characteristics, psychological profile, and social conditions as well as physiological, psychological and behavioral responses to surgery. These results suggest that patient characteristics collected in a cross-disciplinary approach may help determine predictors for less successful WL after bariatric surgery. If verified in larger cohorts this may form the basis for individualized postoperative support to optimize WL outcome.

Obesity, unfavourable lifestyle and genetic risk of type 2 diabetes: a case-cohort study.

AIMS/HYPOTHESIS: We aimed to investigate whether the impact of obesity and unfavourable lifestyle on type 2 diabetes risk is accentuated by genetic predisposition. METHODS: We examined the joint association of genetic predisposition, obesity and unfavourable lifestyle with incident type 2 diabetes using a case-cohort study nested within the Diet, Cancer and Health cohort in Denmark. The study sample included 4729 individuals who developed type 2 diabetes during a median 14.7 years of follow-up, and a randomly selected cohort sample of 5402 individuals. Genetic predisposition was quantified using a genetic risk score (GRS) comprising 193 known type 2 diabetes-associated loci (excluding known BMI loci) and stratified into low (quintile 1), intermediate and high (quintile 5) genetic risk groups. Lifestyle was assessed by a lifestyle score composed of smoking, alcohol consumption, physical activity and diet. We used Prentice-weighted Cox proportional-hazards models to test the associations of the GRS, obesity and lifestyle score with incident type 2 diabetes, as well as the interactions of the GRS with obesity and unfavourable lifestyle in relation to incident type 2 diabetes. RESULTS: Obesity (BMI ≥ 30 kg/m2) and unfavourable lifestyle were associated with higher risk for incident type 2 diabetes regardless of genetic predisposition (p > 0.05 for GRS-obesity and GRS-lifestyle interaction). The effect of obesity on type 2 diabetes risk (HR 5.81 [95% CI 5.16, 6.55]) was high, whereas the effects of high genetic risk (HR 2.00 [95% CI 1.76, 2.27]) and unfavourable lifestyle (HR 1.18 [95% CI 1.06, 1.30]) were relatively modest. Even among individuals with low GRS and favourable lifestyle, obesity was associated with a >8-fold risk of type 2 diabetes compared with normal-weight individuals in the same GRS and lifestyle stratum. CONCLUSIONS/INTERPRETATION: Having normal body weight is crucial in the prevention of type 2 diabetes, regardless of genetic predisposition.

Hypertension genetic risk score is associated with burden of coronary heart disease among patients referred for coronary angiography.

BACKGROUND: Recent GWAS studies have identified more than 300 SNPs associated with variation in blood pressure. We investigated whether a genetic risk score constructed from these variants is associated with burden of coronary heart disease. METHODS: From 2010-2014, 4,809 individuals admitted to coronary angiography in Capital Region of Copenhagen were genotyped. We calculated hypertension GRS comprised of GWAS identified SNPs associated with blood pressure. We performed logistic regression analyses to estimate the risk of hypertension and prevalent CHD. We also assessed the severity of CHD associated with the GRS. The analyses were performed using GRS quartiles. We used the Inter99 cohort to validate our results and to investigate for possible pleiotropy for the GRS with other CHD risk factors. RESULTS: In COGEN, adjusted odds ratios comparing the 2nd, 3rd and 4th cumulative GRS quartiles with the reference were 1.12(95% CI 0.95-1.33), 1.35(95% CI 1.14-1.59) and 1.29(95% CI 1.09-1.53) respectively, for prevalent CHD. The adjusted multinomial logistic regression showed that 3rd and 4th GRS quartiles were associated with increased odds of developing two(OR 1.33, 95% CI 1.04-1.71 and OR 1.36, 95% CI 1.06-1.75, respectively) and three coronary vessel disease(OR 1.77, 95% CI 1.36-2.30 and OR 1.65, 95% CI 1.26-2.15, respectively). Similar results for incident CHD were observed in the Inter99 cohort. The hypertension GRS did not associate with type 2 diabetes, smoking, BMI or hyperlipidemia. CONCLUSION: Hypertension GRS quartiles were associated with an increased risk of hypertension, prevalent CHD, and burden of coronary vessel disease in a dose-response pattern. We showed no evidence for pleiotropy with other risk factors for CHD.

Exercise Increases Glucose Transporter-4 Levels on Peripheral Blood Mononuclear Cells.

PURPOSE: Glucose transporter 4 (GLUT4) plays a key role in the pathophysiology of type 2 diabetes. Glucose transporter 4 is upregulated in response to exercise, enhancing cellular glucose transport in skeletal muscle tissue. This mechanism appears to remain intact in individuals with insulin resistance. Details of the mechanism are poorly understood and are challenging to study due to the invasive nature of muscle biopsy. Peripheral blood mononuclear cells (PBMC) have documented insulin-sensitive GLUT4 activity and may serve as a proxy tissue for studying skeletal muscle GLUT4. The purpose of this study was to investigate whether GLUT4 in PBMC is affected by conditioning. METHODS: We recruited 16 student athletes from the cross-country running and skiing teams and fifteen sedentary students matched for age and sex from the University of Alaska Fairbanks. Peripheral blood mononuclear cells were collected with mononuclear cell separation tubes. The GLUT4 concentrations were measured using a commercially available enzyme linked immunosorbent assay. Additionally, correlations between PBMC GLUT4 and common indicators of insulin resistance were examined. RESULTS: Results indicate significantly higher PBMC GLUT4 levels in conditioned athletes than in their sedentary counterparts, similar to what has been documented in myocytes. Females were observed to have higher PBMC GLUT4 levels than males. Correlations were not detected between PBMC GLUT4 and hemoglobin A1c, glucose, insulin, homeostatic model assessment of insulin resistance, body mass index, or body fat. CONCLUSIONS: This study provides evidence to support exploration of PBMC as a proxy tissue for studying GLUT4 response to exercise or other noninsulin factors.

25(OH)D levels in trained versus sedentary university students at 64° north.

PURPOSE: 25-hydroxyvitamin D (25[OH]D) deficiency is associated with compromised bone mineralisation, fatigue, suppressed immune function and unsatisfactory skeletal muscle recovery. We investigated the risk of 25(OH)D insufficiency or deficiency in endurance athletes compared to sedentary non-athletes living at 64° north. METHODS: University student-athletes (TS) and sedentary students (SS) volunteered to participate in this study. TS engaged in regular exercise while SS exercised no more than 20 minutes/week. Metabolic Equivalent of Task (MET) scores for participants were determined. Vitamin D intake was assessed using the National Cancer Institute's 24-hour food recall (ASA24). Fasting plasma 25(OH)D levels were quantified via enzyme-linked immunosorbent assay. RESULTS: TS reported higher activity levels than SS as assessed with MET-minutes/week and ranking of physical activity levels (p < 0.05). The reported mean daily intake of vitamin D was higher in TS compared to SS (p < 0.05) while 25(OH)D plasma levels were lower in TS than in SS (p < 0.05). In total, 43.8% of the TS were either insufficient (31.3%) or deficient (12.5%) in 25(OH)D, while none of the SS were insufficient and 13.3% were deficient. CONCLUSION: TS are at increased risk of 25(OH)D insufficiency or deficiency compared to their sedentary counterparts residing at the same latitude, despite higher vitamin D intake.

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.