Amar, D. | Search bioRxiv

bioRxiv2017

Biological Insights Into Muscular Strength: Genetic Findings in the UK Biobank

BackgroundHand grip strength, a simple indicator of muscular strength, has been associated with a range of health conditions, including fractures, disability, cardiovascular disease and premature death risk. Twin studies have suggested a high (50-60%) heritability, but genetic determinants are largely unknown.\n\nAimsIn this study, our aim was to study genetic variation associated with muscular strength in a large sample of 334,925 individuals of European descent from the UK Biobank, and to evaluate shared genetic aetiology with and causal effects of grip strength on physical and cognitive health.\n\nMethods and ResultsIn our discovery analysis of 223,315 individuals, we identified 101 loci associated with grip strength at genome-wide significance (P<5x10-8). Of these, 64 were associated (P<0.01 and consistent direction) also in the replication dataset (N=111,610). Many of the lead SNPs were located in or near genes known to have a function in developmental disorders (FTO, SLC39A8, TFAP2B, TGFA, CELF1, TCF4, BDNF, FOXP1, KIF1B, ANTXR2), and one of the most significant genes based on a gene-based analysis (ATP2A1) encodes SERCA1, the critical enzyme in calcium uptake to the sarcoplasmic reticulum, which plays a major role in muscle contraction and relaxation. Further, we demonstrated a significant enrichment of gene expression in brain-related transcripts among grip strength associations. Finally, we observed inverse genetic correlations of grip strength with cardiometabolic traits, and positive correlation with parents age of death and education; and showed that grip strength was causally related to fitness, physical activity and other indicators of frailty, including cognitive performance scores.\n\nConclusionsIn our study of over 330,000 individuals from the general population, the genetic findings for hand grip strength suggest an important role of the central nervous system in strength performance. Further, our results indicate that maintaining good muscular strength is important for physical and cognitive performance and healthy aging.

genomics↗

bioRxiv2017

An extensive enhancer-promoter map generated by genome-scale analysis of enhancer and gene activity patterns

Massive efforts have documented hundreds of thousands of putative enhancers in the human genome. A pressing genomic challenge is to identify which of these enhancers are functional and map them to the genes they regulate. We developed a novel method for inferring enhancer-promoter (E-P) links based on correlated activity patterns across many samples. Our method, called FOCS, uses rigorous statistical validation tailored for zero-inflated data, identifying the most important E-P links in each gene model. We applied FOCS to the wide epigenomic and transcriptomic datasets recorded by the ENCODE, Roadmap Epigenomics and FANTOM5 projects, together covering 2,630 samples of human primary cells, tissues and cell lines. In addition, building on expression of enhancer RNAs (eRNAs) as an exquisite mark of enhancer activity and on the robust detection of eRNAs by the GRO-seq technique, we compiled a compendium of eRNA and gene expression profiles based on public GRO-seq data from 245 samples and 23 human cell types. Applying FOCS to this compendium further expanded the coverage of our inferred E-P map. Benchmarking against gold standard E-P links from ChIA-PET and eQTL data, we demonstrate that FOCS prediction of E-P links outperforms extant methods. Collectively, we inferred >300,000 cross-validated E-P links spanning ~16K known genes. Our study presents an improved method for inferring regulatory links between enhancers and promoters, and provides an extensive resource of E-P maps that could greatly assist the functional interpretation of the noncoding regulatory genome. FOCS and our predicted E-P map are publicly available at http://acgt.cs.tau.ac.il/focs.

bioinformatics↗