Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10−8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms. Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution. In the first of a pair of Articles in this issue from the GIANT Consortium, genome-wide association meta-analyses of waist and hip circumference-related traits in more than 200,000 individuals have been used to identify 49 loci — 33 of them new — associated with waist-to-hip ratio adjusted for body mass index and an additional 19 loci associated with related waist and hip circumference measures. A subset of these loci shows significant sexual dimorphism, with many showing a stronger effect in women. Analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms and offer potential targets for interventions in the risks associated with abdominal fat accumulation.

Differences in methylation across tissues are critical to cell differentiation and are key to understanding the role of epigenetics in complex diseases. In this investigation, we found that locus-specific methylation differences between tissues are highly consistent across individuals. We developed a novel statistical model to predict locus-specific methylation in target tissue based on methylation in surrogate tissue. The method was evaluated in publicly available data and in two studies using the latest IlluminaBeadChips: a childhood asthma study with methylation measured in both peripheral blood leukocytes (PBL) and lymphoblastoid cell lines; and a study of postoperative atrial fibrillation with methylation in PBL, atrium and artery. We found that our method can greatly improve accuracy of cross-tissue prediction at CpG sites that are variable in the target tissue [R² increases from 0.38 (original R² between tissues) to 0.89 for PBL-to-artery prediction; from 0.39 to 0.95 for PBL-to-atrium; and from 0.81 to 0.98 for lymphoblastoid cell line-to-PBL based on cross-validation, and confirmed using cross-study prediction]. An extended model with multiple CpGs further improved performance. Our results suggest that large-scale epidemiology studies using easy-to-access surrogate tissues (e.g. blood) could be recalibrated to improve understanding of epigenetics in hard-to-access tissues (e.g. atrium) and might enable non-invasive disease screening using epigenetic profiles.

Survival analysis using gene expression profiles plays a crucial role in the interpretation of clinical research and assessment of disease therapy programs. Several prediction models have been developed to explore the relationship between patients’ covariates and survival. However, the high-dimensional genomic features limit the prediction performance of the survival model. Thus, an accurate and reliable prediction model is necessary for survival analysis using high-dimensional genomic data. In this study, we proposed an improved survival prediction model based on XGBoost framework called XGBLC, which used Lasso-Cox to enhance the ability to analyze high-dimensional genomic data. The novel first- and second-order gradient statistics of Lasso-Cox were defined to construct the loss function of XGBLC. We extensively tested our XGBLC algorithm on both simulated and real-world datasets, and estimated the performance of models with 5-fold cross-validation. Based on 20 cancer datasets from The Cancer Genome Atlas (TCGA), XGBLC outperforms five state-of-the-art survival methods in terms of C-index, Brier score and AUC. The results show that XGBLC still keeps good accuracy and robustness by comparing the performance on the simulated datasets with different scales. The developed prediction model would be beneficial for physicians to understand the effects of patient’s genomic characteristics on survival and make personalized treatment decisions. The implementation of XGBLC algorithm based on R language is available at: https://github.com/lab319/XGBLC Supplementary data are available at Bioinformatics online.

Objectives: Lung adenocarcinoma (LUAD) accounts for a majority of cancer-related deaths worldwide annually. The identification of prognostic biomarkers and prediction of prognosis for LUAD patients is necessary.