Croteau-Chonka, D. C. | Search bioRxiv

bioRxiv2018

Meta-analysis of genome-wide association studies for body fat distribution in 694,649 individuals of European ancestry

One in four adults worldwide are either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, is most informative for predicting risk of obesity sequellae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio adjusted for BMI (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

genetics↗

bioRxiv2017

Gene co-expression networks in whole blood implicate multiple interrelated molecular pathways in obese asthma

BackgroundAsthmatic children who develop obesity have poorer outcomes compared to those that do not, including poorer control, more severe symptoms, and greater resistance to standard treatment. Gene expression networks are powerful statistical tools for characterizing the underpinnings of human disease that leverage the putative co-regulatory relationships of genes to infer biological pathways altered in disease states.\n\nObjectiveThe aim of this study was to characterize the biology of childhood asthma complicated by adult obesity.\n\nMethodsWe performed weighted gene co-expression network analysis (WGCNA) of gene expression data in whole blood from 514 adult subjects from the Childhood Asthma Management Program (CAMP). We then performed module preservation and association replication analyses in 418 subjects from two independent asthma cohorts (one pediatric and one adult).\n\nResultsWe identified a multivariate model in which four gene co-expression network modules were associated with incident obesity in CAMP (each P < 0.05). The module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-{kappa}B signaling, and Hedgehog signaling. The network structures of each of the four obese asthma modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in obese subjects in both replication cohorts (each P < 0.05).\n\nConclusionsOur gene co-expression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of obese asthma.\n\nKey MessagesO_LIWe hypothesized that individuals with asthma complicated by obesity had distinct blood gene expression signatures.\nC_LIO_LIGene co-expression network analysis implicated several inflammatory biological pathways in one form of obese asthma.\nC_LI\n\nCapsule SummaryThis work addresses a knowledge gap about the molecular relationship between asthma and obesity, suggesting that an endotype of obese asthma, known as asthma complicated by obesity, is underpinned by coherent biological mechanisms.\n\nAbbreviations

genomics↗