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The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context. We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks. Analysis of 2·6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death— TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported. Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients. National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.

Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (<1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.

Purpose Lack of data on the in vivo morphology and morphometry of the normal adult coccyx hampers understanding of radiological abnormalities in idiopathic coccydynia. The aim of this study was to investigate normal adult sacrococcygeal morphometry. Methods Retrospective analysis of 112 adult CT scans (mean age 63 ± 14.6 years, 50 males) evaluated the following: number of coccygeal segments; joint fusion; coccygeal spicules, subluxation, sacralization, and scoliosis; sacrococcygeal straight and curved lengths and curvature indices; sacrococcygeal and intercoccygeal angles; and lateral deviation of the coccyx tip. Results Four coccygeal segments were present in 76 % of scans. Sacrococcygeal fusion was present in 57 % and intercoccygeal fusion was increasingly common more caudally; there was no significant association with age or gender. A bony spicule was present in 23 %. Subluxation was rare. Nine of 12 coccyges with a retroverted tip were female. Mean coccygeal curved length was 4.4 ± 0.8 cm in men and 4.0 ± 0.8 cm in women ( P  < 0.01). Mean angle between first and last coccygeal segments was 138° ± 25° in men and 147° ± 25° in women ( P  = 0.08). There was no significant correlation between coccygeal length or curvature and stature, age or BMI. Conclusions In this first detailed study of the CT morphology and morphometry of the adult coccyx, sacrococcygeal and intercoccygeal joint fusion was common. Female coccyges were shorter, straighter, and may be more prone to retroversion, factors that may be relevant to the markedly higher prevalence of idiopathic coccydynia in women.

Uterine natural killer cells (uNK) play an important role in promoting successful pregnancy by regulating trophoblast invasion and spiral artery remodelling in the first trimester. Recently, single-cell RNA sequencing (scRNAseq) on first-trimester decidua showed that uNK can be divided into three subsets, which may have different roles in pregnancy. Here we present an integration of previously published scRNAseq datasets, together with novel flow cytometry data to interrogate the frequency, phenotype, and function of uNK1–3 in seven stages of the reproductive cycle (menstrual, proliferative, secretory phases of the menstrual cycle; first, second, and third trimester; and postpartum). We found that uNK1 and uNK2 peak in the first trimester, but by the third trimester, the majority of uNK are uNK3. All three subsets are most able to degranulate and produce cytokines during the secretory phase of the menstrual cycle and express KIR2D molecules, which allow them to interact with HLA-C expressed by placental extravillous trophoblast cells, at the highest frequency during the first trimester. Taken together, our findings suggest that uNK are particularly active and able to interact with placental cells at the time of implantation and that uNK1 and uNK2 may be particularly involved in these processes. Our findings are the first to establish how uNK frequency and function change dynamically across the healthy reproductive cycle. This serves as a platform from which the relationship between uNK function and impaired implantation and placentation can be investigated. This will have important implications for the study of subfertility, recurrent miscarriage, pre-eclampsia, and pre-term labour.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D) 1 , 2 ; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1 , PTF1A , SIX3 , ALDH2 , a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells 3 . At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes— NKX6-3 and ANK1 —in different tissues 4 – 6 . Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways. A meta-analysis of genome-wide association study data from 77,418 individuals of East Asian ancestry with type 2 diabetes identifies novel variants associated with increased risk of type 2 diabetes.

This study presents pooled analyses of the associations between BMI and risk of death in more than 1.1 million people from 19 cohorts in Asia after a mean follow-up of 9.2 years. Underweight was associated with a substantially increased risk of death in all Asian populations. Over the past few decades, there has been a dramatic increase in the prevalence of obesity in many countries. The World Health Organization (WHO) estimates that more than 1 billion adults worldwide are overweight; of these, at least 300 million are obese. 1 A large number of epidemiologic studies have evaluated the associations between body weight and, more often, the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) and a wide range of health outcomes. Obesity is associated with multiple chronic diseases, including type 2 diabetes, hypertension, coronary heart disease, stroke, and several . . .

To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type. Nested case-control study. 20 population based cohort studies in Asia, Europe, Australia, and the United States. 5299 patients with incident lung cancer, with individually incidence density matched controls. Circulating hsCRP concentrations in prediagnostic serum or plasma samples. Incident lung cancer diagnosis. A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up. Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.

Background The inner retinal complex is a well-defined layer in spectral-domain OCT scans of the retina. The central edge of this layer at the fovea provides anatomical landmarks that can be observed in serial OCT scans of developing full-thickness macular holes (FTMH). Measurement of the movement of these points may clarify the mechanism of FTMH formation. Method This is a retrospective study of primary FTMH that had a sequence of two OCT scans showing progression of the hole. Measurements were made of the dimensions of the hole, including measurements using the central edge of the inner retinal complex (CEIRC) as markers. The inner retinal separation (distance between the CEIRC across the centre of the fovea) and the Height-IRS (average height of CEIRC above the retinal pigment epithelium) were measured. Results Eighteen cases were identified in 17 patients. The average increase in the base diameter (368 microns) and the average increase in minimum linear dimension (187 microns) were much larger than the average increase in the inner retinal separation (73 microns). The average increase in Height-IRS was 103 microns. Conclusion The tangential separation of the outer retina to produce the macular hole is much larger than the tangential separation of the inner retinal layers. A model based on the histology of the Muller cells at the fovea is proposed to explain the findings of this study.

A significant proportion of recurrent miscarriage, recurrent implantation failure and infertility are unexplained, and these conditions have been proposed to have an etiology of immunological dysfunction at the maternal-fetal interface. Uterine Natural Killer cells (uNK) comprise three subsets and are the most numerous immune cells found in the uterine mucosa at the time of implantation. They are thought to play an important role in successful pregnancy by regulation of extravillous trophoblast (EVT) invasion and spiral artery remodelling. Here, we examine the frequency, phenotype and function of uNK1-3 from the uterine mucosa of 16 women with unexplained reproductive failure compared to 11 controls with no reproductive problems, during the window of implantation. We report that KIR2DL1/S1 and LILRB1 expression is lower in the reproductive failure group for both uNK (total uNK, uNK 2 and 3) and pNK. We also show that degranulation activity is significantly reduced in total uNK, and that TNF-α production is lower in all uNK subsets in the reproductive failure group. Taken together, our findings suggest that reproductive failure is associated with global reduction in expression of uNK receptors important for interaction with HLA-C and HLA-G on EVT during early pregnancy, leading to reduced uNK activation. This is the first study to examine uNK subsets during the window of implantation in women with reproductive failure and will serve as a platform to focus on particular aspects of phenotype and function of uNK subsets in future studies. Further understanding of uNK dysregulation is important to establish potential diagnostic and therapeutic targets in the population of women with unexplained reproductive failure.