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Physical activity (PA), aerobic fitness, and cardiometabolic diseases (CMD) are highly heritable multifactorial phenotypes. Shared genetic factors may underlie the associations between higher levels of PA and better aerobic fitness and a lower risk for CMDs. We aimed to study how PA genotype associates with self-reported PA, aerobic fitness, cardiometabolic risk factors and diseases. PA genotype, which combined variation in over one million of gene variants, was composed using the SBayesR polygenic scoring methodology. First, we constructed a polygenic risk score for PA in the Trøndelag Health Study (N = 47,148) using UK Biobank single nucleotide polymorphism-specific weights (N = 400,124). The associations of the PA PRS and continuous variables were analysed using linear regression models and with CMD incidences using Cox proportional hazard models. The results showed that genotypes predisposing to higher amount of PA were associated with greater self-reported PA (Beta [B] = 0.282 MET-h/wk per SD of PRS for PA, 95% confidence interval [CI] = 0.211, 0.354) but not with aerobic fitness. These genotypes were also associated with healthier cardiometabolic profile (waist circumference [B = -0.003 cm, 95% CI = -0.004, -0.002], body mass index [B = -0.002 kg/m2, 95% CI = -0.004, -0.001], high-density lipoprotein cholesterol [B = 0.004 mmol/L, 95% CI = 0.002, 0.006]) and lower incidence of hypertensive diseases (Hazard Ratio [HR] = 0.97, 95% CI = 0.951, 0.990), stroke (HR = 0.94, 95% CI = 0.903, 0.978) and type 2 diabetes (HR = 0.94, 95 % CI = 0.902, 0.970). Observed associations were independent of self-reported PA. These results support earlier findings suggesting small pleiotropic effects between PA and CMDs and provide new evidence about associations of polygenic inheritance of PA and intermediate cardiometabolic risk factors. [ABSTRACT FROM AUTHOR]

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. Preadipocytes contribute to the pro-inflammatory environment in obesity, via unknown mechanisms. Here, comparing monozygotic twin pairs, the authors show that co-accessibility of chromatin in preadipocytes is altered in siblings with higher compared to lower BMI, and that variants in these regions contribute to systemic inflammation via interactions with BMI. [ABSTRACT FROM AUTHOR]

The understanding of the molecular genetic contributions to smoking is largely limited to the additive effects of individual single nucleotide polymorphisms (SNPs), but the underlying genetic risk is likely to also include dominance, epistatic, and gene-environment interactions. To begin to address this complexity, we attempted to identify genetic interactions between rs16969968, the most replicated SNP associated with smoking quantity, and all SNPs and genes across the genome. Using the UK Biobank European subsample, we found one SNP, rs1892967, and two genes, PCNA and TMEM230 , that showed a significant genome-wide interaction with rs16969968 for log10 CPD and raw CPD, respectively, in a sample of 116 442 individuals who self-reported currently or previously smoking. We extended these analyses to individuals of South Asian descent and meta-analyzed the combined sample of 117 212 individuals of European and South Asian ancestry. We replicated the gene findings in a meta-analysis of five Finnish samples (N=40 140): FinHealth, FINRISK, Finnish Twin Cohort, GeneRISK, and Health-2000–2011. To our knowledge, this represents the first reliable epistatic association between single nucleotide polymorphisms for smoking behaviors and provides a novel direction for possible future functional studies related to this interaction. Furthermore, this work demonstrates the feasibility of these analyses by pooling multiple datasets across various ancestries, which may be applied to other top SNPs for smoking and/or other phenotypes. • We explored interactions between rs16969968 and all SNPs and genes genome-wide. • One SNP, rs1892967, and two genes, PCNA and TMEM230 , significantly interacted with rs16969968 for smoking quantity. • We replicated the gene findings in a meta-analysis of five Finnish samples comprising over 40, 000 individuals. • This is the first reliable epistatic association between single nucleotide polymorphisms for smoking behaviors. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Purpose: Polygenic risk scores (PRS) summarize genome-wide genotype data into a single variable that produces an individual-level risk score for genetic liability. PRS has been used for prediction of chronic diseases and some risk factors. As PRS has been studied less for physical activity (PA), we constructed PRS for PA and studied how much variation in PA can be explained by this PRS in independent population samples. Methods: We calculated PRS for self-reported and objectively measured PA using UK Biobank genome-wide association study summary statistics, and analyzed how much of the variation in self-reported (MET-hours per day) and measured (steps and moderate-to-vigorous PA minutes per day) PA could be accounted for by the PRS in the Finnish Twin Cohorts (FTC; N = 759–11,528) and the Northern Finland Birth Cohort 1966 (NFBC1966; N = 3263–4061). Objective measurement of PA was done with wrist-worn accelerometer in UK Biobank and NFBC1966 studies, and with hip-worn accelerometer in the FTC. Results: The PRS accounted from 0.07% to 1.44% of the variation (R 2) in the self-reported and objectively measured PA volumes (P value range = 0.023 to <0.0001) in the FTC and NFBC1966. For both self-reported and objectively measured PA, individuals in the highest PRS deciles had significantly (11%–28%) higher PA volumes compared with the lowest PRS deciles (P value range = 0.017 to <0.0001). Conclusions: PA is a multifactorial phenotype, and the PRS constructed based on UK Biobank results accounted for statistically significant but overall small proportion of the variation in PA in the Finnish cohorts. Using identical methods to assess PA and including less common and rare variants in the construction of PRS may increase the proportion of PA explained by the PRS. [ABSTRACT FROM AUTHOR]