1,721,036 research outputs found
Genome variation: a review of Web resources
No full textAn enormous number of high-quality Web-based resources are now available to facilitate research into genome variation. Although identification of the most appropriate and informative resources can be challenging, a number of key sites provide links to more specialized resources that may be useful to follow up. Given ongoing research, focussing on the sequencing of many different genomes, we can expect sequence databases and their associated polymorphism-based resources to greatly increase in depth and complexity in a relatively short period of time. However, databases and tools developed to date, and described here, provide a sound basis for accommodating this next generation of genomic data. As well as sequence-oriented resources this review presents databases providing genotypic and common disease phenotype data, copy number variation, genetic maps, cytogenetic data, and gives an overview of key software tools, with the emphasis on analysis of the genetic basis of common disease.</p
Predicting pancreatic cancer in the UK Biobank cohort using polygenic risk scores and diabetes mellitus
No full textBackground & aims: diabetes mellitus (DM) is known to be associated with pancreatic ductal adenocarcinoma (PDAC), particularly new-onset DM (NODM). Others have developed polygenic risk scores (PRS) associated with PDAC risk. We aimed to compare the performance of these PRS in an independent cohort to determine if they can discriminate between NODM and long-standing DM patients with PDAC. Methods: cases (1042) and matched cancer-free controls (10,420) were drawn from the UK Biobank. Five PRS models were calculated using single nucleotide polymorphisms (SNPs) from previous studies (Nakatochi, Galeotti, Molina, Jia, and Rashkin) and a combination of these. Regression models were used to assess the association between PDAC and PRS adjusted for ancestry, smoking, DM, waist circumference, and family history of digestive cancer. Receiver operator characteristic curves and area under the curve metrics (AUC) were used to assess the performance of each PRS for classifying PDAC risk. Results: the combined PRS model achieved the highest AUC (0.605), and significantly improved a clinical risk model in this cohort (AUC = 0.83; P = .0002). Individuals within the fifth quintile have a 2.74-fold increased risk of developing PDAC vs those in the first quintile (P < .001), and have a 3.05-fold increased risk of developing PDAC if they have DM vs those without DM (P < .001). The positive predictive value was 11.9% in participants without DM, 23.9% with long-standing DM, and 86.7% with NODM. Conclusions: the PDAC-related common genetic variants are more strongly associated with DM. This PRS has the potential for targeting individuals with NODM for PDAC secondary screening measures.</p
Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at CDH22/CD40
No full textTo identify genetic variants that influence myeloproliferative neoplasm (MPN) phenotype, we undertook a two-stage case-only genome-wide association study using cohorts from the UK (including UK Biobank), Spain, Germany and Italy. MPN subtype [essential thrombocythemia (ET); polycythemia vera (PV)] were compared to each other, to healthy controls and stratified analyses was performed based on chromosome 9p aberrations, JAK2 V617F mutation burden and sex. The ET versus PV analysis identified known associations: (i) at HBS1L-MYB that increased ET risk (PMETA=7.93x10-6, OR=1.28) and reduced PV risk (PMETA=9.43x10-5, OR=0.81) and (ii) at GFI1B-GTF3C5 that predisposed to PV only (PMETA=1.43x10-9, OR=1.38). Two further linked intronic SNPs, rs2425786 and rs2425788, at CDH22/CD40 were significant in females only (PMETA=2.67x10-8) with predisposition to PV (PMETA=0.0006, OR=1.3) and reduction of ET risk (PMETA=7.82x10-5, OR=0.75). Associations with JAK2, TERT, ATM, TET2, PINT, GFI1B and SH2B3 were confirmed (PMETA<5x10-8) and nine further loci were replicated (PMETA<0.05). A polygenic risk score consisting of 48 SNPs from 31 loci demonstrated moderate discriminative performance for ET and PV (AUC=0.718) and was improved by optimization for disease subtype (AUCET=0.724 and AUCPV=0.755). Overall, our results reveal that multiple germline variants influence MPN phenotype with HBS1L-MYB and a novel sex-specific association with CDH22/CD40 being the strongest determinants
Linkage disequilibrium in human populations
No full textWhereas the human linkage map appears on limited evidence to be constant over populations, maps of linkage disequilibrium (LD) vary among populations that differ in gene history. The greatest difference is between populations of sub-Saharan origin and populations remotely derived from Africa after a major bottleneck that reduced their heterozygosity and altered their Malecot parameters, increasing the intercept M that reflects association in founders and decreasing the exponential decline . Variation among populations within this ethnic dichotomy is much smaller. These observations validate use of a cosmopolitan LD map based on a sizeable sample representing a large population reliably typed for markers at high density. Then an LD map for a region or isolate within an ethnic group may be created by fitting the sample LD to the cosmopolitan map, estimating Malecot parameters simultaneously. The cosmopolitan map scaled by recovers 95% of the information that a local map at the same density gives and therefore more than the information in a low-resolution local map. Relative to a Eurasian cosmopolitan map the scaling factors are estimated to be 0.82 for isolates of European descent, 1.53 for Yorubans, and 1.74 for African Americans. These observations are consistent with a common bottleneck (perhaps but not necessarily speciation) 173,500 years ago, if the bottleneck associated with migration out of Africa was 100,000 years ago. Eurasian populations (especially isolates with numerous cases) are efficient for genome scans, and populations of recent African origin (such as African Americans) are efficient for identification of causal polymorphisms within a candidate sequence
Age-related loss of chromosome Y is associated with levels of sex hormone binding globulin and clonal hematopoiesis defined by TET2, TP53, and CBL mutations
No full textMosaic loss of the Y-chromosome (LOY) is the most common somatic alteration in men. We aimed to assess the relationship between LOY and serum biomarkers in UK Biobank and explore the interaction with constitutional and somatic genetics. LOY was strongly associated with levels of sex hormone binding globulin (SHBG, β=0.12, PFDR= P = 7.44×10−36, adjusted for age, age squared, gender, smoking status, smoking intensity and principal genetic components), a key regulator of testosterone bioavailability associated with diverse disorders including cancer and autoimmune diseases. Furthermore, LOY was associated with total testosterone (TT, β=0.09, PFDR=2.23 × 10−20), but not bioavailable testosterone (PFDR=0.46) or free testosterone (PFDR=0.75). These relationships remained significant after sensitivity analysis that included comorbidities and body mass index (SHBG, β = 0.08, PFDR = 4.61×10−21; TT, β = 0.05, PFDR = 4.13 × 10−9). Mendelian randomisation suggested a causal effect of SHBG on LOY in BioBank Japan (P=6.58×10−4) but there was no evidence for an effect of LOY on SHBG (P=0.46). Assessment of cis-eQTLs for 13 genes associated with LOY identified two SNPs that were also associated with levels of SHBG, however only rs7141210 (imprinted DLK1-MEG3 locus) modified the relationship between SHBG and LOY (rs7141210-T/T; Pinteraction=0.04) with low levels of SHBG seen specifically in men without LOY (β=-0.02, P=0.001), but not those with LOY (P=0.41). Age-related clonal hematopoiesis (CH) defined by somatic driver mutations was not associated with sex hormone levels but was associated with LOY at clonal fractions >30% (OR=1.52, P=2.92×10−4). TET2, TP53, and CBL mutations were enriched in high level LOY cases, but not DNMT3A or ASXL1. Our findings thus identify independent relationships between LOY, sex hormones and CH
A sequence-based integrated map of chromosome 22
No full textThe near-completion of the sequence for chromosome 22q revolutionizes map integration. We describe a sequence-based integrated map containing 968 loci including 516 known or predicted gene sequences, 317 STSs not included in these sequences, and 135 nonexpressed multinucleotide polymorphisms. The published sequence spans 34.6 Mb, inclusive of gaps estimated to total 1.1 Mb, compared with a top-down estimate of 43 Mb. This discrepancy is discussed, but will not be resolved until more of the genome is analyzed. The radiation hybrid map has 5% error in order and 34% error in location exceeding 1 Mb. The utility of a composite location based on evidence other than sequence is limited to regions not yet sequenced. A genetic map conditional on sequence order was constructed from pairwise lods. Its length of 74.8 cM in males and 80.2 cM in females is slightly less than the previous estimate not constrained by sequence order. Five recombination hot spots are detected, with differences in location between the sexes. Male recombination correlates with repetitive DNA, whereas female recombination does not. It remains to be seen whether this is true for other human chromosomes. An algorithm to improve the fit of cytogenetic bands sequence location reduces the discrepancies in cytogenetic assignment from 61 to 38. This sequence-based integrated map is represented in the genetic location database (LDB2000), which is available at http://cedar.genetics.soton.ac.uk/public_html/LDB2000.html
Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease
No full textWe sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = −0.75, P = 2.37 × 10
–4), but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys < 60 (OR = 1.02, P = 8.44 × 10
–8). In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA (n = 148, β = −3.36, P = 0.01) and somatic driver mutations (n = 3241, β = −1.08, P = 6.25 × 10
–5) associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL, TET2, JAK2, PPM1D and GNB1 but not DNMT3A or ASXL1. In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD (HR = 1.6, P = 0.002) compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD (P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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