| 1. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- 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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| 3. |
- 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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| 4. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 5. |
- Ganio, Matthew S., et al.
(författare)
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Aerobic Fitness Is Disproportionately Low in Adult Burn Survivors Years After Injury
- 2015
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Ingår i: Journal of Burn Care & Research. - 1559-047X .- 1559-0488. ; 36:4, s. 513-519
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Tidskriftsartikel (refereegranskat)abstract
- A maximal aerobic capacity below the 20th percentile is associated with an increased risk of all-cause mortality (Blair 1995). Adult Adult burn survivors have a lower aerobic capacity compared with nonburned adults when evaluated 38 +/- 23 days postinjury (deLateur 2007). However, it is unknown whether burn survivors with well-healed skin grafts (ie, multiple years postinjury) also have low aerobic capacity. This project tested the hypothesis that aerobic fitness, as measured by maximal aerobic capacity (VO2max), is reduced in well-healed adult burn survivors when compared with normative values from nonburned individuals. Twenty-five burn survivors (36 +/- 12 years old; 13 females) with well-healed split-thickness grafts (median, 16 years postinjury; range, 1-51 years) covering at least 17% of their BSA (mean, 40 +/- 16%; range, 17-75%) performed a graded cycle ergometry exercise to test volitional fatigue. Expired gases and minute ventilation were measured via a metabolic cart for the determination of VO2max. Each subject's VO2max was compared with sex- and age-matched normative values from population data published by the American College of Sports Medicine, the American Heart Association, and recent epidemiological data (Aspenes 2011). Subjects had a VO2max of 29.4 +/- 10.1ml O-2/kg body mass/min (median, 27.5; range, 15.9-53.3). The use of American College of Sports Medicine normative values showed that mean VO2max of the subjects was in the lower 24th percentile (median, 10th percentile). A total of 88% of the subjects had a VO2max below American Heart Association age-adjusted normative values. Similarly, 20 of the 25 subjects had a VO2max in the lower 25% percentile of recent epidemiological data. Relative to nongrafted subjects, 80 to 88% of the evaluated skin-graft subjects had a very low aerobic capacity. On the basis of these findings, adult burn survivors are disproportionally unfit relative to the general U.S. population, and this puts them at an increased risk of all-cause mortality (Blair 1995).
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| 6. |
- Hutchinson, David K., et al.
(författare)
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The Eocene-Oligocene transition : a review of marine and terrestrial proxy data, models and model data comparisons
- 2021
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 17:1, s. 269-315
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Forskningsöversikt (refereegranskat)abstract
- The Eocene-Oligocene transition (EOT) was a climate shift from a largely ice-free greenhouse world to an icehouse climate, involving the first major glaciation of Antarctica and global cooling occurring similar to 34 million years ago (Ma) and lasting similar to 790 kyr. The change is marked by a global shift in deep-sea delta O-18 representing a combination of deep-ocean cooling and growth in land ice volume. At the same time, multiple independent proxies for ocean temperature indicate sea surface cooling, and major changes in global fauna and flora record a shift toward more cold-climateadapted species. The two principal suggested explanations of this transition are a decline in atmospheric CO2 and changes to ocean gateways, while orbital forcing likely influenced the precise timing of the glaciation. Here we review and synthesise proxy evidence of palaeogeography, temperature, ice sheets, ocean circulation and CO2 change from the marine and terrestrial realms. Furthermore, we quantitatively compare proxy records of change to an ensemble of climate model simulations of temperature change across the EOT. The simulations compare three forcing mechanisms across the EOT: CO2 decrease, palaeogeographic changes and ice sheet growth. Our model ensemble results demonstrate the need for a global cooling mechanism beyond the imposition of an ice sheet or palaeogeographic changes. We find that CO2 forcing involving a large decrease in CO2 of ca. 40 % (similar to 325 ppm drop) provides the best fit to the available proxy evidence, with ice sheet and palaeogeographic changes playing a secondary role. While this large decrease is consistent with some CO2 proxy records (the extreme endmember of decrease), the positive feedback mechanisms on ice growth are so strong that a modest CO2 decrease beyond a critical threshold for ice sheet initiation is well capable of triggering rapid ice sheet growth. Thus, the amplitude of CO2 decrease signalled by our data-model comparison should be considered an upper estimate and perhaps artificially large, not least because the current generation of climate models do not include dynamic ice sheets and in some cases may be undersensitive to CO2 forcing. The model ensemble also cannot exclude the possibility that palaeogeographic changes could have triggered a reduction in CO2.
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| 7. |
- Hutchinson, David K., et al.
(författare)
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The Eocene-Oligocene transition: a review of marine and terrestrial proxy data, models and model-data comparisons
- 2021
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Ingår i: Climate of the Past. - : European Geosciences Union (EGU). - 1814-9324 .- 1814-9332. ; 17:1, s. 269-315
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Tidskriftsartikel (refereegranskat)abstract
- The Eocene–Oligocene transition (EOT) was a climate shift from a largely ice-free greenhouse world to an icehouse climate, involving the first major glaciation of Antarctica and global cooling occurring ∼ 34 million years ago (Ma) and lasting ∼ 790 kyr. The change is marked by a global shift in deep-sea δ18O representing a combination of deep-ocean cooling and growth in land ice volume. At the same time, multiple independent proxies for ocean tempera- ture indicate sea surface cooling, and major changes in global fauna and flora record a shift toward more cold-climate- adapted species. The two principal suggested explanations of this transition are a decline in atmospheric CO2 and changes to ocean gateways, while orbital forcing likely influenced the precise timing of the glaciation. Here we review and synthesise proxy evidence of palaeogeography, temperature, ice sheets, ocean circulation and CO2 change from the marine and terrestrial realms. Furthermore, we quantitatively com- pare proxy records of change to an ensemble of climate model simulations of temperature change across the EOT. The simulations compare three forcing mechanisms across the EOT: CO2 decrease, palaeogeographic changes and ice sheet growth. Our model ensemble results demonstrate the need for a global cooling mechanism beyond the imposition of an ice sheet or palaeogeographic changes. We find that CO2 forcing involving a large decrease in CO2 of ca. 40 % (∼ 325 ppm drop) provides the best fit to the available proxy evidence, with ice sheet and palaeogeographic changes play- ing a secondary role. While this large decrease is consistent with some CO2 proxy records (the extreme endmember of decrease), the positive feedback mechanisms on ice growth are so strong that a modest CO2 decrease beyond a critical threshold for ice sheet initiation is well capable of triggering rapid ice sheet growth. Thus, the amplitude of CO2 decrease signalled by our data–model comparison should be consid- ered an upper estimate and perhaps artificially large, not least because the current generation of climate models do not in- clude dynamic ice sheets and in some cases may be under- sensitive to CO2 forcing. The model ensemble also cannot exclude the possibility that palaeogeographic changes could have triggered a reduction in CO2.
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| 8. |
- Ikram, M. Arfan, et al.
(författare)
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Common variants at 6q22 and 17q21 are associated with intracranial volume
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 539-544
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Tidskriftsartikel (refereegranskat)abstract
- During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
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| 9. |
- 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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| 10. |
- 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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