| 1. |
- Su, Zhan, et al.
(author)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Journal article (peer-reviewed)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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| 2. |
- Craddock, Nick, et al.
(author)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Journal article (peer-reviewed)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 3. |
- Estrada, Karol, et al.
(author)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Journal article (peer-reviewed)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 4. |
- Ferrari, Raffaele, et al.
(author)
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Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
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In: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
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Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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| 5. |
- Moayyeri, Alireza, et al.
(author)
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Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:11, s. 3054-3068
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Journal article (peer-reviewed)abstract
- Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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| 6. |
- O'Seaghdha, Conall M., et al.
(author)
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Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations
- 2013
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:9, s. e1003796-
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Journal article (peer-reviewed)abstract
- Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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| 7. |
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| 8. |
- Brown, Ian A.
(author)
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Assessing eco-scarcity as a cause of the outbreak of conflict in Darfur : a remote sensing approach
- 2010
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In: International Journal of Remote Sensing. - : Informa UK Limited. - 0143-1161 .- 1366-5901. ; 31:10, s. 2513-2520
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Journal article (peer-reviewed)abstract
- The conflict in Darfur, Western Sudan, is frequently represented in the media as a dispute over access to resources by competing communities. Environmental degradation is often cited as either a causal or a contributory factor to the outbreak of the conflict and its prolongation. In this paper, Normalized Difference Vegetation Index (NDVI) data are used as a measure of 'eco-scarcity' to assess the notion that the outbreak of conflict was the result of competition for resources between communities. It is shown that there is no evidence in the vegetation mapping for a worsening of the ecological situation in Western and Northern Darfur states around the outbreak of the conflict. On the contrary, the years prior to the outbreak of the conflict experienced better than average vegetation growth in the context of the past 25 years.
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| 9. |
- Brown, Ian A.
(author)
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Synthetic Aperture Radar Measurements of a Retreating Firn Line on a Temperate Icecap
- 2012
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In: IEEE Journal of Selected Topics in Applied Earth Observations and Remote Sensing. - 1939-1404 .- 2151-1535. ; 5:1, s. 153-160
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Journal article (peer-reviewed)abstract
- The firn line, like other glacier facies, is mapped operationally as part of glacier monitoring activities for glaciological and climate studies. Synthetic aperture radar (SAR) images are commonly used to determine the firn line in dry snow imagery. The radiometric response of retreating firn has not previously been investigated. Rather, it has been assumed that firn line mapping is only useful where large scale advances or retreats of the lower limit of continuous firn have occurred. In this paper the radiometric signal of retreating firn on an icecap in north Norway is analyzed using multi-temporal SAR imagery. Using comparisons with firn well above the firn line and field investigations of the firn properties, backscattering mechanisms are inferred. It is found that retreating firn has a distinctive radiometric signal that can be used to identify the inception and progression of firn down-wasting prior to and during firn line retreat.
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| 10. |
- Brown, Ian, 1971-
(author)
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Polarimetric scattering from shallow firn and forests with snow cover
- 2010
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In: Proceedings of the ESA Living Planet SymposiumBergen, Norway. - Noordwijk, Netherlands : European Space Agency. - 9789292212506
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Conference paper (other academic/artistic)abstract
- In this paper the potential for inferring shallow firn depth from polarimetric SAR (PolSAR) data at L- and C-band is investigated. Using ALOS PALSAR and Radarsat-2 SAR imagery, and field data including Ground Penetrating Radar profiles and shallow cores, we investigate the spatial distribution of backscatter and decompose backscatter using polarimetric methods to analyse how polarimetric scattering is affected by firn depth near the firn line. The investigation is aimed at a more refined delineation of glacier firn lines and a better understanding of scattering from firn, superimposed ice and the bare ice facies. We found that PolSAR can be used to infer shallow firn thicknesses up to depths of at least 2 m water equivalent (m w.e.) and that old and contemporary firn surfaces can be differentiated using PolSAR. Contrary to many previous investigations the importance of surface scattering in the firn area is also emphasised in the scattering decompositions. Volume scattering was found to have a secondary or tertiary importance. This has important implications for the analysis of backscatter using semi-empirical models.The effect of snow depth on backscatter in pro-glacial a sub-Arctic forest and its potential for improving forest mapping is also discussed. Snow depth data were acquired by manual probing and snowpit measurements. In addition forest stand densities were assessed in situ and NDVI and tasseled cap transformations were made in optical remote sensing data (SPOT-4) to parameterise the forest. Scatterer decomposition and pedestal height products were found to be related to snowpack depth. It was not possible to separate the influences of snow cover and forest structure due to the partial dependence of the former on the latter. Nevertheless it can be concluded that PolSAR improves our ability to map the forest margins of low density, sub-Arctic forests. Our findings have implications for the implementation of algorithms for the exploitation of future SAR missions including Sentinel-1.
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