Obesity-related traits have been associated with coronary artery disease (CAD) in observational studies, but these associations may be biased by confounding factors and reverse causation. In this study, we specifically conducted two-sample Mendelian randomization (MR) analyses to overcome these limitations and test the associations of obesity-related traits (other than body mass index (BMI)) (n = 322,154) with CAD (22,233 cases and 64,762 controls) by using summary-level data from previous studies. The methods utilized to estimate these associations included the inverse-variance weighted method, the weighted median method and MR-Egger regression. Our results supported causal effects of BMI, hip circumference (HC), waist circumference (WC), and waist-hip ratio (WHR) on CAD. The associations of BMI-adjusted HC and WC with CAD were reversed, unlike that of WHR. In MR analyses excluding overlapping single nucleotide polymorphisms (SNPs) from obesity-related traits, the associations of these traits with CAD were preserved. The associations of BMI-adjusted HC and WC with CAD require further investigation, as collider stratification may be occurring. Additionally, central adiposity (measured by WHR) separated from general adiposity (measured by BMI) and general adiposity might pose similar risks for CAD. In clinical practice, physicians should pay attention to the potential effects of different obesity-related traits on CAD.

Genome-wide association studies (GWASs) have been performed extensively in diverse populations to identify single nucleotide polymorphisms (SNPs) associated with complex diseases or traits. However, to date, the SNPs identified fail to explain a large proportion of the variance of the traits/diseases. GWASs on type 2 diabetes (T2D) and obesity are generally focused on individual traits independently, and genetic intercommunity (common genetic contributions or the product of over correlated phenotypic world) between them are largely unknown, despite extensive data showing that these two phenotypes share both genetic and environmental risk factors. Here, we applied a recently developed genetic pleiotropic conditional false discovery rate (cFDR) approach to discover novel loci associated with BMI and T2D by incorporating the summary statistics from existing GWASs of these two traits. Conditional Q-Q and fold enrichment plots were used to visually demonstrate the strength of pleiotropic enrichment. Adopting a cFDR nominal significance level of 0.05, 287 loci were identified for BMI and 75 loci for T2D, 23 of which for both traits. By incorporating related traits into a conditional analysis framework, we observed significant pleiotropic enrichment between obesity and T2D. These findings may provide novel insights into the etiology of obesity and T2D, individually and jointly.

Although gut microbiota influences osteoporosis risk, the individual species involved, and underlying mechanisms, are unknown. We performed integrative analyses in a Chinese cohort with metagenomics/targeted metabolomics/whole-genome sequencing. Bacteroides vulgatus was found negatively associated with bone mineral density (BMD), this association was validated in US Caucasians. Serum valeric acid was positively associated with BMD, and B.vulgatus causally downregulated it. Ovariectomized mice fed B.vulgatus had decreased bone formation and increased bone resorption, lower BMD and poorer bone micro-structure. Valeric acid suppressed NF-κB p65 protein production (pro-inflammatory), and enhanced IL-10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells, and enhanced maturation of osteoblasts in vitro. B.vulgatus and valeric acid represent promising targets for osteoporosis prevention/treatment.