| 1. |
- Tragante, Vinicius, et al.
(författare)
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Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:3, s. 349-360
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
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| 2. |
- Asselbergs, Folkert W., et al.
(författare)
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Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
- 2012
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 91:5, s. 823-838
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
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| 3. |
- Ganesh, Santhi K., et al.
(författare)
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Loci influencing blood pressure identified using a cardiovascular gene-centric array
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:8, s. 1663-1678
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped 50 000 single-nucleotide polymorphisms (SNPs) that capture variation in 2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P 2.4 10(6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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| 4. |
- Gardiner, Nicholas J., et al.
(författare)
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The crustal architecture of Myanmar imaged through zircon U-Pb, Lu-Hf and O isotopes : Tectonic and metallogenic implications
- 2018
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Ingår i: Gondwana Research. - : Elsevier BV. - 1342-937X .- 1878-0571. ; 62, s. 27-60
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Tidskriftsartikel (refereegranskat)abstract
- The Tethys margin in central and eastern Asia is comprised of continental terranesseparated by suture zones, some of which remain cryptic. Determining the crustal architecture, and therefore the geological history, of the Eastern Tethyan margin remains challenging. Sited in the heart of this region, Myanmar is a highly prospective but poorly explored minerals jurisdiction. A better understanding of Myanmar's mineralization can only be realized through a better understanding of its tectonic history, itself reflected in at least four major magmatic belts. The Eastern and the Main Range Provinces are associated with the Late Permian to Early Triassic closure of Palaeo-Tethys. The Mogok–Mandalay–Mergui Belt and Wuntho–Popa Arc are a response to the Eocene closure of Neo-Tethys. However, magmatic ages outside these two orogenic events are also recorded. We present new zirconU-Pb, Lu-Hf and O isotope data from magmatic rocks across Myanmar, which we append to the existing dataset to isotopically characterize Myanmar's magmatic belts. Eastern Province Permian I-type magmatism has evolved εHf (−10.9 to −6.4), whilst Main Range Province Triassic S-type magmatism also records evolved εHf (−13.5 to −8.8). The Mogok-Mandalay-Mergui Belt is here divided into the Tin Province and the Mogok Metamorphic Belt. The Tin Province hosts ca. 77–50 Ma magmatism with evolved εHf (−1.2 to −15.2), and δ18O of 5.6–8.3‰. The Mogok Metamorphic Belt exhibits a more complex magmatic and metamorphic history, and granitoids record Jurassic, Late Cretaceous, and Eocene to Miocene phases of magmatism, all of which exhibit evolved εHf values between −4.6 and −17.6, and δ18O between 6.3 and 9.2‰. From the Tagaung-Myitkyina Belt, we report a magmatic age of 172 Ma and εHf of 18.1 to 10.8. To accommodate the geological evidence, we propose a tectonic model for Myanmar involving a greater Sibumasu – where the documented zircon isotopic variations reflect compositional variations in magmatic source – and invoke the role of a Tengchong Block. The Baoshan Block and Greater Sibumasu were likely assembled on or before the Triassic, a former Andean margin and suture which may lie across the Northern Shan Plateau, and reflected in isotopic differences between the northern and southern parts of the Mogok Metamorphic Belt. This contiguous Sibumasu–Baoshan Block then sutured onto the Indochina margin in the Late Triassic. We propose that a Tengchong Block within Myanmar provides for a southerly termination of the Meso-Tethys suture immediately north of the Mogok area. A discrete Tengchong Block may explain a discontinuous arc of Late Triassic to Jurassic I-type magmatism in central Myanmar, representing an Andean-type margin sited above a subducting Meso-Tethys on the margin of Sibumasu. The Tengchong Block sutured onto Greater Sibumasu before the Late Cretaceous, after which subduction of Neo-Tethys drove the magmatism of the Wuntho-Popa Arc and ultimately that of the Tin Province. The metallogenic character of granite belts in Myanmar reflects the crustal architecture of the region, which is remarkable for its prolific endowment of granite-hosted Sn-W mineralization in two quite distinct granite belts related to sequential Indosinian and Himalayan orogenesis.
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| 5. |
- Johansson, Åke, et al.
(författare)
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A geochronological review of magmatism along the external margin of Columbia and in the Grenville-age orogens forming the core of Rodinia
- 2022
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Ingår i: Precambrian Research. - : Elsevier BV. - 0301-9268 .- 1872-7433. ; 371, s. 1-43
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Tidskriftsartikel (refereegranskat)abstract
- A total of 4344 magmatic U-Pb ages in the range 2300 to 800 Ma have been compiled from the Great Proterozoic Accretionary Orogen along the margin of the Columbia / Nuna supercontinent and from the subsequent Grenvillian collisional orogens forming the core of Rodinia. The age data are derived from Laurentia (North America and Greenland, n = 1212), Baltica (NE Europe, n = 1922), Amazonia (central South America, n = 625), Kalahari (southern Africa and Dronning Maud Land in East Antarctica, n = 386), and western Australia (n = 199). Laurentia, Baltica, and Amazonia (and possibly other cratons) most likely formed a ca. 10 000-km-long external active continental margin of Columbia from its assembly at ca. 1800 Ma until its dispersal at ca. 1260 Ma, after which all cratons studied were involved in the Rodinia-forming Grenvillian orogeny. However, the magmatic record is not smooth and even but highly irregular, with marked peaks and troughs, both for individual cratons and the combined data set. Magmatic peaks typically range in duration from a few tens of million years up to around hundred million years, with intervening troughs of comparable length. Some magmatic peaks are observed on multiple cratons, either by coincidence or because of paleogeographic proximity and common tectonic setting, while others are not. The best overall correlation, 0.617, is observed between Baltica and Amazonia, consistent with (but not definitive proof of) their being close neighbours in a SAMBA-like configuration at least in Columbia, and perhaps having shared the same peri-Columbian subduction system for a considerable time. Correlation factors between Laurentia and Baltica, or Laurentia and Amazonia, are below 0.14. Comparison between the Grenville Province in northeastern Laurentia and the Sveconorwegian Province in southwestern Fennoscandia (Baltica) shows some striking similarities, especially in the Mesoproterozoic, but also exhibits differences in the timing of events, especially during the final Grenville-Sveconorwegian collision, when the Sveconorwegian evolution seems to lag behind by some tens of million years. Between the other cratons, the evolution before and during the final Grenvillian collision is also largely diachronous. After 900 Ma, magmatic activity had ceased in all areas investigated, attesting to the position of most of them within the stable interior of Rodinia.
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| 6. |
- Chew, David M., et al.
(författare)
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Timing of ophiolite obduction in the Grampian orogen
- 2010
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Ingår i: Geological Society of America Bulletin. - 0016-7606. ; 122:11-12, s. 1787-1799
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Tidskriftsartikel (refereegranskat)abstract
- This study addresses the timing and pressure-temperature (P-T) conditions of ophiolite obduction, one of the proposed causes of the ca. 470 Ma Grampian orogeny of Scotland and Ireland. This event gave rise to the main structural and metamorphic characteristics of the Grampian terrane-the type area for Barrovian metamorphism, the cause of which remains enigmatic despite a century of research. Zircons from the Highland Border ophiolite, Scotland, define a 499 +/- 8 Ma U-Pb concordia age, which is interpreted as dating magmatism. Its metamorphism is dated by a 490 +/- 4 Ma Ar-40-Ar-39 hornblende age, and a 488 +/- 1 Ma Ar-40-Ar-39 muscovite age from a metasedimentary xenolith within it, from which P-T estimates of 5.3 kbar and 580 degrees C relate to ophiolite obduction. Metamorphism of the Deerpark complex ophiolitic melange (Irish correlative of the Highland Border ophiolite) is constrained by a 514 +/- 3 Ma Ar-40-Ar-39 hornblende age, while mica schist slivers within it yield detrital zircon U-Pb ages consistent with Laurentian provenance and Rb-Sr and Ar-40-Ar-39 muscovite ages of ca. 482 Ma. P-T values of 3.3 kbar and 580 degrees C for the mica schist constrain the conditions of ophiolite obduction. Metamorphic mineral ages from the Grampian terrane (Dalradian Supergroup) are substantially younger (ca. 475-465 Ma) than those from the ophiolites. If conductive heating in overthickened crust was the cause of Barrovian metamorphism, then collisional thickening must have started soon after ophiolite obduction at ca. 490 Ma in order to generate the ca. 470 Ma metamorphic peak in the Grampian terrane.
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| 9. |
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| 10. |
- Yoneyama, Sachiko, et al.
(författare)
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Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:9, s. 2498-2510
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Tidskriftsartikel (refereegranskat)abstract
- Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBIs Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 2080 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes 50 000 cosmopolitan tagged SNPs across 2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P 2.4 10(6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR ( SE, 0.048 0.008, P 7.7 10(9)) as was rs7302703-G in HOXC10 ( 0.044 0.008, P 2.9 10(7)) and rs936108-C in PEMT ( 0.035 0.007, P 1.9 10(6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 ( 0.10 0.02, P 1.9 10(6)) and rs1037575-A in ATBDB4 ( 0.046 0.01, P 2.2 10(6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
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