| 1. |
- Craddock, Nick, et al.
(författare)
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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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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 3. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 4. |
- Drezner, Jonathan A, et al.
(författare)
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Electrocardiographic interpretation in athletes : the 'Seattle criteria'.
- 2013
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Ingår i: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 47:3, s. 122-4
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Tidskriftsartikel (refereegranskat)abstract
- Sudden cardiac death (SCD) is the leading cause of death in athletes during sport. Whether obtained for screening or diagnostic purposes, an ECG increases the ability to detect underlying cardiovascular conditions that may increase the risk for SCD. In most countries, there is a shortage of physician expertise in the interpretation of an athlete's ECG. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from abnormal findings suggestive of pathology. On 13-14 February 2012, an international group of experts in sports cardiology and sports medicine convened in Seattle, Washington, to define contemporary standards for ECG interpretation in athletes. The objective of the meeting was to develop a comprehensive training resource to help physicians distinguish normal ECG alterations in athletes from abnormal ECG findings that require additional evaluation for conditions associated with SCD.
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| 5. |
- Drezner, Jonathan A, et al.
(författare)
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Normal electrocardiographic findings : recognising physiological adaptations in athletes.
- 2013
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Ingår i: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 47:3, s. 125-36
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Tidskriftsartikel (refereegranskat)abstract
- Electrocardiographic changes in athletes are common and usually reflect benign structural and electrical remodelling of the heart as a physiological adaptation to regular and sustained physical training (athlete's heart). The ability to identify an abnormality on the 12-lead ECG, suggestive of underlying cardiac disease associated with sudden cardiac death (SCD), is based on a sound working knowledge of the normal ECG characteristics within the athletic population. This document will assist physicians in identifying normal ECG patterns commonly found in athletes. The ECG findings presented as normal in athletes were established by an international consensus panel of experts in sports cardiology and sports medicine.
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| 6. |
- Franke, Andre, et al.
(författare)
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Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1118-1125
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Tidskriftsartikel (refereegranskat)abstract
- We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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| 7. |
- Su, Zhan, et al.
(författare)
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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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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Bellenguez, Celine, et al.
(författare)
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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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| 9. |
- Campbell, Heather, et al.
(författare)
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COSMOLOGY WITH PHOTOMETRICALLY CLASSIFIED TYPE Ia SUPERNOVAE FROM THE SDSS-II SUPERNOVA SURVEY
- 2013
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 763:2, s. 88-
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Tidskriftsartikel (refereegranskat)abstract
- We present the cosmological analysis of 752 photometrically classified Type Ia Supernovae (SNe Ia) obtained from the full Sloan Digital Sky Survey II (SDSS-II) Supernova (SN) Survey, supplemented with host-galaxy spectroscopy from the SDSS-III Baryon Oscillation Spectroscopic Survey. Our photometric-classification method is based on the SN classification technique of Sako et al., aided by host-galaxy redshifts (0.05 < z < 0.55). SuperNova ANAlysis simulations of our methodology estimate that we have an SN Ia classification efficiency of 70.8%, with only 3.9% contamination from core-collapse (non-Ia) SNe. We demonstrate that this level of contamination has no effect on our cosmological constraints. We quantify and correct for our selection effects (e. g., Malmquist bias) using simulations. When fitting to a flat.CDM cosmological model, we find that our photometric sample alone gives Omega(m) = 0.24(-0.05)(+0.07) (statistical errors only). If we relax the constraint on flatness, then our sample provides competitive joint statistical constraints on Omega(m) and Omega(Lambda), comparable to those derived from the spectroscopically confirmed Three-year Supernova Legacy Survey (SNLS3). Using only our data, the statistics-only result favors an accelerating universe at 99.96% confidence. Assuming a constant wCDM cosmological model, and combining with H-0, cosmic microwave background, and luminous red galaxy data, we obtain w = -0.96(-0.10)(+0.10), Omega(m) = 0.29(-0.02)(+0.02), and Omega(k) = 0.00(-0.02)(+0.03)(statistical errors only), which is competitive with similar spectroscopically confirmed SNe Ia analyses. Overall this comparison is reassuring, considering the lower redshift leverage of the SDSS-II SN sample (z < 0.55) and the lack of spectroscopic confirmation used herein. These results demonstrate the potential of photometrically classified SN Ia samples in improving cosmological constraints.
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| 10. |
- Davis, Tamara M., et al.
(författare)
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The Effect of Peculiar Velocities on Supernova Cosmology
- 2011
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 741, s. 67-
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Tidskriftsartikel (refereegranskat)abstract
- We analyze the effect that peculiar velocities have on the cosmological inferences we make using luminosity distance indicators, such as Type Ia supernovae. In particular we study the corrections required to account for (1) our own motion, (2) correlations in galaxy motions, and (3) a possible local under- or overdensity. For all of these effects we present a case study showing the impact on the cosmology derived by the Sloan Digital Sky Survey-II Supernova Survey (SDSS-II SN Survey). Correcting supernova (SN) redshifts for the cosmic microwave background (CMB) dipole slightly overcorrects nearby SNe that share some of our local motion. We show that while neglecting the CMB dipole would cause a shift in the derived equation of state of Δw ~ 0.04 (at fixed Ω m ), the additional local-motion correction is currently negligible (Δw <~ 0.01). We then demonstrate a covariance-matrix approach to statistically account for correlated peculiar velocities. This down-weights nearby SNe and effectively acts as a graduated version of the usual sharp low-redshift cut. Neglecting coherent velocities in the current sample causes a systematic shift of Δw ~ 0.02. This will therefore have to be considered carefully when future surveys aim for percent-level accuracy and we recommend our statistical approach to down-weighting peculiar velocities as a more robust option than a sharp low-redshift cut.
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