Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality

Resting heart rate is a heritable trait correlated with life span. Little is known about the genetic contribution to resting heart rate and its relationship with mortality. We performed a genome-wide association discovery and replication analysis starting with 19.9 million genetic variants and studying up to 265,046 individuals to identify 64 loci associated with resting heart rate (P < 5 × 10$^{-8}$); 46 of these were novel. We then used the genetic variants identified to study the association between resting heart rate and all-cause mortality. We observed that a genetically predicted resting heart rate increase of 5 beats per minute was associated with a 20% increase in mortality risk (hazard ratio 1.20, 95% confidence interval 1.11-1.28, P = 8.20 × 10$^{-7}$) translating to a reduction in life expectancy of 2.9 years for males and 2.6 years for females. Our findings provide evidence for shared genetic predictors of resting heart rate and all-cause mortality.This research was conducted using the UK Biobank Resource. This project is supported by the Netherlands organization for health research and development (ZonMw grant 90.700.441). S.B. is supported by the Wellcome Trust (grant 100114). P.B.M. acknowledges support from the NIHR Cardiovascular Biomedical Research Unit at Barts and the London School of Medicine and Dentistry, Queen Mary University of London. N.V. is supported by Netherlands Heart Institute and Marie Sklodowska-Curie Global Fellowship (grant 661395)

The Parkinson's Disease Mendelian Randomization Research Portal

Background Mendelian randomization is a method for exploring observational associations to find evidence of causality. Objective To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research. Methods We used two‐sample Mendelian randomization in which the summary statistics relating to single‐nucleotide polymorphisms from 5,839 genome‐wide association studies of exposures were used to assess causal relationships with PD. We selected the highest‐quality exposure genome‐wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome‐wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest. Results We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol. Conclusions We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome‐wide association studies versus the largest PD genome‐wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of P

Evidence for Pervasive Adaptive Protein Evolution in Wild Mice

The relative contributions of neutral and adaptive substitutions to molecular evolution has been one of the most controversial issues in evolutionary biology for more than 40 years. The analysis of within-species nucleotide polymorphism and between-species divergence data supports a widespread role for adaptive protein evolution in certain taxa. For example, estimates of the proportion of adaptive amino acid substitutions (alpha) are 50% or more in enteric bacteria and Drosophila. In contrast, recent estimates of alpha for hominids have been at most 13%. Here, we estimate alpha for protein sequences of murid rodents based on nucleotide polymorphism data from multiple genes in a population of the house mouse subspecies Mus musculus castaneus, which inhabits the ancestral range of the Mus species complex and nucleotide divergence between M. m. castaneus and M. famulus or the rat. We estimate that 57% of amino acid substitutions in murids have been driven by positive selection. Hominids, therefore, are exceptional in having low apparent levels of adaptive protein evolution. The high frequency of adaptive amino acid substitutions in wild mice is consistent with their large effective population size, leading to effective natural selection at the molecular level. Effective natural selection also manifests itself as a paucity of effectively neutral nonsynonymous mutations in M. m. castaneus compared to humans

Firsthand Experience and The Subsequent Role of Reflected Knowledge in Cultivating Trust in Global Collaboration

While scholars contend that firsthand experience - time spent onsite observing the people, places, and norms of a distant locale - is crucial in globally distributed collaboration, how such experience actually affects interpersonal dynamics is poorly understood. Based on 47 semistructured interviews and 140 survey responses in a global chemical company, this paper explores the effects of firsthand experience on intersite trust. We find firsthand experience leads not just to direct knowledge of the other, but also knowledge of the self as seen through the eyes of the other - what we call “reflected knowledge”. Reflected and direct knowledge, in turn, affect trust through identification, adaptation, and reduced misunderstandings

A novel genetic variant of Streptococcus pneumoniae serotype 11A discovered in Fiji.

OBJECTIVES: As part of annual cross-sectional Streptococcus pneumoniae carriage surveys in Fiji (2012-2015), we detected pneumococci in over 100 nasopharyngeal swabs that serotyped as '11F-like' by microarray. We examined the genetic basis of this divergence in the 11F-like capsular polysaccharide (cps) locus compared to the reference 11F cps sequence. The impact of this diversity on capsule phenotype, and serotype results using genetic and serologic methods were determined. METHODS: Genomic DNA from representative 11F-like S. pneumoniae isolates obtained from the nasopharynx of Fijian children was extracted and subject to whole genome sequencing. Genetic and phylogenetic analyses were used to identify genetic changes in the cps locus. Capsular phenotypes were evaluated using the Quellung reaction and latex agglutination. RESULTS: Compared to published 11F sequences, the wcwC and wcrL genes of the 11F-like cps locus are phylogenetically divergent, and the gct gene contains a single nucleotide insertion within a homopolymeric region. These changes within the DNA sequence of the 11F-like cps locus have modified the antigenic properties of the capsule, such that 11F-like isolates serotype as 11A by Quellung reaction and latex agglutination. CONCLUSIONS: This study demonstrates the ability of molecular serotyping by microarray to identify genetic variants of S. pneumoniae and highlights the potential for discrepant results between phenotypic and genotypic serotyping methods. We propose that 11F-like isolates are not a new serotype but rather are a novel genetic variant of serotype 11A. These findings have implications for invasive pneumococcal disease surveillance as well as studies investigating vaccine impact

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Allelic spectrum of the natural variation in CRP

With the recent completion of the International HapMap Project, many tools are in hand for genetic association studies seeking to test the common variant/common disease hypothesis. In contrast, very few tools and resources are in place for genotype–phenotype studies hypothesizing that rare variation has a large impact on the phenotype of interest. To create these tools for rare variant/common disease studies, much interest is being generated towards investing in re-sequencing either large sample sizes of random chromosomes or smaller sample sizes of patients with extreme phenotypes. As a case study for rare variant discovery in random chromosomes, we have re-sequenced ~1,000 chromosomes representing diverse populations for the gene C-reactive protein (CRP). CRP is an important gene in the fields of cardiovascular and inflammation genetics, and its size (~2 kb) makes it particularly amenable medical or deep re-sequencing. With these data, we explore several issues related to the present-day candidate gene association study including the benefits of complete SNP discovery, the effects of tagSNP selection across diverse populations, and completeness of dbSNP for CRP. Also, we show that while deep re-sequencing uncovers potentially medically relevant coding SNPs, these SNPs are fleetingly rare when genotyped in a population-based survey of 7,000 Americans (NHANES III). Collectively, these data suggest that several different types re-sequencing and genotyping approaches may be required to fully understand the complete spectrum of alleles that impact human phenotypes. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available for this article at http://dx.doi.org/10.1007/s00439-006-0160-y and is accessible for authorized users

Power analysis for genome-wide association studies

Abstract Background Genome-wide association studies are a promising new tool for deciphering the genetics of complex diseases. To choose the proper sample size and genotyping platform for such studies, power calculations that take into account genetic model, tag SNP selection, and the population of interest are required. Results The power of genome-wide association studies can be computed using a set of tag SNPs and a large number of genotyped SNPs in a representative population, such as available through the HapMap project. As expected, power increases with increasing sample size and effect size. Power also depends on the tag SNPs selected. In some cases, more power is obtained by genotyping more individuals at fewer SNPs than fewer individuals at more SNPs. Conclusion Genome-wide association studies should be designed thoughtfully, with the choice of genotyping platform and sample size being determined from careful power calculations.</p

Sequence variation in the human transcription factor gene POU5F1

<p>Abstract</p> <p>Background</p> <p>POU5F1 expression is required to maintain stem cell pluripotency and for primordial germ cells to retain proliferative capability in embryonic development. Recent evidence suggests that <it>POU5F1 </it>may also be a testicular germ cell carcinoma (TGCC) oncogene, and <it>POU5F1 </it>variation may influence TGCC risk. As an important first step to a genetic association study, we sought to identify all common sequence variants in an 11.3 kb region containing <it>POU5F1</it>, and to describe the linkage disequilibrium patterns, using DNA from individuals of African-descent (AD) and European-descent (ED).</p> <p>Results</p> <p>A higher number of polymorphisms was observed in the AD (n = 102) versus ED (n = 82) population. Among the 41 observed haplotypes, 21 (51%) and 12 (29%) were unique to the AD and ED populations, respectively, while 8 (20%) were observed in both. The number of tagging polymorphisms necessary to explain at least 80% of common variation (minor allele frequency ≥ 0.10) due to the remaining untyped polymorphisms was 17 for an AD and 10 for an ED population, providing a 4.0- and 7.0-fold gain in genotyping efficiency for characterizing nucleotide variation, respectively.</p> <p>Conclusion</p> <p><it>POU5F1 </it>is highly polymorphic, however a smaller subset of polymorphisms can tag the observed genetic variation with little loss of information.</p