Wellcome Trust Sanger Institute

About: Wellcome Trust Sanger Institute is a nonprofit organization based out in Cambridge, United Kingdom. It is known for research contribution in the topics: Population & Genome. The organization has 4009 authors who have published 9671 publications receiving 1224479 citations.

Common Variants at 10 Genomic Loci Influence Hemoglobin A1C Levels via Glycemic and Nonglycemic Pathways

Abstract: OBJECTIVE Glycated hemoglobin (HbA 1c ), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA 1c . We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA 1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA 1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA 1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA 1c , including six new loci near FN3K (lead SNP/ P value, rs1046896/ P = 1.6 × 10 −26 ), HFE (rs1800562/ P = 2.6 × 10 −20 ), TMPRSS6 (rs855791/ P = 2.7 × 10 −14 ), ANK1 (rs4737009/ P = 6.1 × 10 −12 ), SPTA1 (rs2779116/ P = 2.8 × 10 −9 ) and ATP11A/TUBGCP3 (rs7998202/ P = 5.2 × 10 −9 ), and four known HbA 1c loci: HK1 (rs16926246/ P = 3.1 × 10 −54 ), MTNR1B (rs1387153/ P = 4.0 × 10 −11 ), GCK (rs1799884/ P = 1.5 × 10 −20 ) and G6PC2/ABCB11 (rs552976/ P = 8.2 × 10 −18 ). We show that associations with HbA 1c are partly a function of hyperglycemia associated with 3 of the 10 loci ( GCK, G6PC2 and MTNR1B ). The seven nonglycemic loci accounted for a 0.19 (% HbA 1c ) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA 1c . CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA 1c . Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA 1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA 1c .

Common variants in WFS1 confer risk of type 2 diabetes

Abstract: We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.

Chromosomal transposition of PiggyBac in mouse embryonic stem cells

Abstract: Transposon systems are widely used for generating mutations in various model organisms. PiggyBac (PB) has recently been shown to transpose efficiently in the mouse germ line and other mammalian cell lines. To facilitate PB's application in mammalian genetics, we characterized the properties of the PB transposon in mouse embryonic stem (ES) cells. We first measured the transposition efficiencies of PB transposon in mouse embryonic stem cells. We next constructed a PB/SB hybrid transposon to compare PB and Sleeping Beauty (SB) transposon systems and demonstrated that PB transposition was inhibited by DNA methylation. The excision and reintegration rates of a single PB from two independent genomic loci were measured and its ability to mutate genes with gene trap cassettes was tested. We examined PB's integration site distribution in the mouse genome and found that PB transposition exhibited local hopping. The comprehensive information from this study should facilitate further exploration of the potential of PB and SB DNA transposons in mammalian genetics.

The genome of the simian and human malaria parasite Plasmodium knowlesi

Abstract: Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or 'hypnozoite' in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome and other sequenced Plasmodium genomes. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.

Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension

Abstract: Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.