| 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. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 3. |
- Horikoshi, Momoko, et al.
(författare)
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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:1
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Tidskriftsartikel (refereegranskat)abstract
- Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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| 4. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 5. |
- Taal, H. Rob, et al.
(författare)
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Common variants at 12q15 and 12q24 are associated with infant head circumference
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 532-538
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
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| 6. |
- Alexandrov, Ludmil B., et al.
(författare)
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Signatures of mutational processes in human cancer
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 500:7463, s. 415-421
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Tidskriftsartikel (refereegranskat)abstract
- All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
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| 7. |
- Persson, Carina, 1964, et al.
(författare)
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Nitrogen hydrides in interstellar gas towards G10.6-0.4 (W31C) and W49N
- 2011
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Ingår i: IAU Symposium 280, Poster 76, Session 2, The Molecular Universe, Posters from the proceedings of the 280th Symposium of the International Astronomical Union held in Toledo, Spain, May 30-June 3, 2011, #296. ; 280:76
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The PRISMAS key programme has used the HIFI instrument on board Herschel to observe interstellar nitrogen hydrides along the sight-lines towards G10.6-0.4 (W31C) and W49N in order to elucidate the production pathways leading to nitrogen bearing species. We report observations of the NH N=1-0, J=2-1 and J=1-0, ortho-NH2 111-000, ortho-NH3 10-00 and 20-10, para-NH3 21-11 transitions, and unsuccessful searches for NH+ in both sources. All detections show emission and absorption associated directly with the hot-core source itself as well as absorption by foreground material over a wide range of velocities. The NH, NH2 and NH3 spectra show strikingly similar and non-saturated absorption features, which we attribute to diffuse molecular gas. The similarity of the profiles suggest fairly uniform abundances relative to hydrogen. The derived relative and absolute abundances are discussed with reference to models of gas-phase and surface chemistry.
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| 8. |
- Birdsell, Dawn N, et al.
(författare)
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Francisella tularensis subsp. tularensis group A.I, United States
- 2014
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Ingår i: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention (CDC). - 1080-6040 .- 1080-6059. ; 20:5, s. 861-865
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Tidskriftsartikel (refereegranskat)abstract
- We used whole-genome analysis and subsequent characterization of geographically diverse strains using new genetic signatures to identify distinct subgroups within Francisella tularensis subsp. tularensis group A.I: A.I.3, A.I.8, and A.I.12. These subgroups exhibit complex phylogeographic patterns within North America. The widest distribution was observed for A.I.12, which suggests an adaptive advantage.
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| 9. |
- Falgarone, E., et al.
(författare)
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CH+(1-0) and 13CH+(1-0) absorption lines in the direction of massive star-forming regions
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1
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Tidskriftsartikel (refereegranskat)abstract
- We report the detection of the ground-state rotational transition of the methylidyne cation CH+ and its isotopologue (CH+)-C-13 toward the remote massive star-forming regions W33A, W49N, and W51 with the HIFI instrument onboard the Herschel satellite. Both lines are seen only in absorption against the dust continuum emission of the star-forming regions. The CH+ absorption is saturated over almost the entire velocity ranges sampled by the lines-of-sight that include gas associated with the star-forming regions (SFR) and Galactic foreground material. The CH+ column densities are inferred from the optically thin components. A lower limit of the isotopic ratio [(CH+)-C-12]/[(CH+)-C-13]> 35.5 is derived from the absorptions of foreground material toward W49N. The column density ratio, N(CH+)/N(HCO+), is found to vary by at least a factor 10, between 4 and > 40, in the Galactic foreground material. Line-of-sight 12CH+ average abundances relative to total hydrogen are estimated. Their average value, N(CH+)/NH > 2.6 x 10(-8), is higher than that observed in the solar neighborhood and confirms the high abundances of CH+ in the Galactic interstellar medium. We compare this result to the predictions of turbulent dissipation regions (TDR) models and find that these high abundances can be reproduced for the inner Galaxy conditions. It is remarkable that the range of predicted N(CH+)/ N(HCO+) ratios, from 1 to similar to 50, is comparable to that observed.
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| 10. |
- Fich, M., et al.
(författare)
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Herschel-PACS spectroscopy of the intermediate mass protostar NGC 7129 FIRS 2
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518:Article Number: L86
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We present preliminary results of the first Herschel spectroscopic observations of NGC 7129 FIRS2, an intermediate mass star-forming region. We attempt to interpret the observations in the framework of an in-falling spherical envelope. Methods. The PACS instrument was used in line spectroscopy mode ( R = 1000-5000) with 15 spectral bands between 63 and 185 mu m. This provided good detections of 26 spectral lines seen in emission, including lines of H2O, CO, OH, O I, and C II. Results. Most of the detected lines, particularly those of H2O and CO, are substantially stronger than predicted by the spherical envelope models, typically by several orders of magnitude. In this paper we focus on what can be learned from the detected CO emission lines. Conclusions. It is unlikely that the much stronger than expected line emission arises in the (spherical) envelope of the YSO. The region hot enough to produce such high excitation lines within such an envelope is too small to produce the amount of emission observed. Virtually all of this high excitation emission must arise in structures such as as along the walls of the outflow cavity with the emission produced by a combination of UV photon heating and/or non-dissociative shocks.
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