| 1. |
- Hirschhorn, J.N., et al.
(författare)
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Genomewide linkage analysis of stature in multiple populations reveals several regions with evidence of linkage to adult height
- 2001
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 69:1, s. 106-116
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Tidskriftsartikel (refereegranskat)abstract
- Genomewide linkage analysis has been extremely successful at identification of the genetic variation underlying single-gene disorders. However, linkage analysis has been less successful for common human diseases and other complex traits in which multiple genetic and environmental factors interact to influence disease risk. We hypothesized that a highly heritable complex trait, in which the contribution of environmental factors was relatively limited, might be more amenable to linkage analysis. We therefore chose to study stature (adult height), for which heritability is 75%-90% (Phillips and Matheny 1990; Carmichael and McGue 1995; Preece 1996; Silventoinen et al. 2000). We reanalyzed genomewide scans from four populations for which genotype and height data were available, using a variance-components method implemented in GENEHUNTER 2.0 (Pratt et al. 2000). The populations consisted of 408 individuals in 58 families from the Botnia region of Finland, 753 individuals in 183 families from other parts of Finland, 746 individuals in 179 families from Southern Sweden, and 420 individuals in 63 families from the Saguenay-Lac-St.-Jean region of Quebec. Four regions showed evidence of linkage to stature: 6q24-25, multipoint LOD score 3.85 at marker D6S1007 in Botnia (genomewide P<.06), 7q31.3-36 (LOD 3.40 at marker D7S2195 in Sweden, P<.02), 12p11.2-q14 (LOD 3.35 at markers D12S10990-D12S398 in Finland,P<.05) and 13q32-33 (LOD 3.56 at markers D13S779-D13S797 in Finland, P<.05). In a companion article (Perola et al. 2001 [in this issue]), strong supporting evidence is obtained for linkage to the region on chromosome 7. These studies suggest that highly heritable complex traits such as stature may be genetically tractable and provide insight into the genetic architecture of complex traits.
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| 2. |
- Rioux, John D., et al.
(författare)
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Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease
- 2001
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 29:2, s. 223-228
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Tidskriftsartikel (refereegranskat)abstract
- Linkage disequilibrium (LD) mapping provides a powerful method for fine-structure localization of rare disease genes, but has not yet been widely applied to common disease1. We sought to design a systematic approach for LD mapping and apply it to the localization of a gene (IBD5) conferring susceptibility to Crohn disease. The key issues are: (i) to detect a significant LD signal (ii) to rigorously bound the critical region and (iii) to identify the causal genetic variant within this region. We previously mapped the IBD5 locus to a large region spanning 18 cM of chromosome 5q31 (P<10−4). Using dense genetic maps of microsatellite markers and single-nucleotide polymorphisms (SNPs) across the entire region, we found strong evidence of LD. We bound the region to a common haplotype spanning 250 kb that shows strong association with the disease (P<2×10−7) and contains the cytokine gene cluster. This finding provides overwhelming evidence that a specific common haplotype of the cytokine region in 5q31 confers susceptibility to Crohn disease. However, genetic evidence alone is not sufficient to identify the causal mutation within this region, as strong LD across the region results in multiple SNPs having equivalent genetic evidence—each consistent with the expected properties of the IBD5 locus. These results have important implications for Crohn disease in particular and LD mapping in general.
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| 3. |
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| 4. |
- Florez, Jose C., et al.
(författare)
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Haplotype Structure and Genotype-Phenotype Correlations of the Sulfonylurea Receptor and the Islet ATP-Sensitive Potassium Channel Gene Region.
- 2004
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 53:5, s. 1360-1368
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Tidskriftsartikel (refereegranskat)abstract
- The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2 with risk of type 2 diabetes. Whether and how E23K itself—or other variant(s) in either of these two closely linked genes—influences type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate gene locus, we 1) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and both genes; 2) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously reported in the literature; and 3) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 (P = 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data (P = 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S) in the neighboring SUR1 gene (r2 > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion in glucose-tolerant control subjects, supporting a mechanism whereby β-cell dysfunction contributes to the common form of type 2 diabetes. Like peroxisome proliferator–activated receptor γ, the SUR1/Kir6.2 gene region both contributes to the inherited risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between the underlying mechanism of disease and validated targets for pharmacological treatment.
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| 5. |
- Hansson, Lars Johan, et al.
(författare)
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Massive recruitment of the barnacle Semibalanus balanoides in the Clyde Sea (Scotland, UK) in the spring of 2000
- 2003
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Ingår i: Journal of the Marine Biological Association of the United Kingdom. - 0025-3154. ; 83:5, s. 923-924
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Tidskriftsartikel (refereegranskat)abstract
- In April 2000 a massive recruitment of the barnacle Semibalanus balanoides was observed in the Clyde Sea. At one location 700 cyprids l(-1) of this species were recorded. This is similar to3500 times more abundant than previously recorded, and resulted in metamorphosis of some cyprids whilst still in the plankton, as well as massive settlement, with recruits found on adults and in the splash zone. The maximum density recorded was 109 settlers cm(-2). Over the next 60 d mortality averaged 85%, resulting in a mean density of 8.4 recruits cm(-2) in June 2000. Recruitment varied spatially at the kin and in scale (site, shore height) but there was no evidence that it was affected by the presence of adult conspecifics.
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| 6. |
- Hudson, J. A., et al.
(författare)
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Coupled T-H-M issues relating to radioactive waste repository design and performance
- 2001
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Ingår i: International Journal of Rock Mechanics And Mining Sciences. - 1365-1609 .- 1873-4545. ; 38:1, s. 143-161
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Tidskriftsartikel (refereegranskat)abstract
- In this paper. coupled thermo-hydro-mechanical (THM) issues relating to nuclear waste repository design and performance are reviewed. Concise statements. that were developed from DECOVALEX discussions, on the current state-of-knowledge are presented. Section 1 describes the THM background and the interface with performance assessment (PA). The role of THM issues in the overall repository design context is amplified in Section 2, which includes a review of the processes in terms of repository excavation. operation and post-closure stages. It is important to understand the overall context, the detailed THM issues, the associated modelling and how these issues will be resolved in the wider framework. Also, because uncoupled and coupled numerical codes have been used fur this subject, there is discussion in Section 3 on the nature of the codes and how the content of the codes can be audited. To what extent does a particular code capture the essence of the problem in hand? Consideration is also given to the associated question of code selection and the future of numerical codes. The state-of-knowledge statements are presented in Section 4 under 11 headings which follow the repository design sequence. The overview conclusion is that A predictive THM capability is required to support repository design because precedent practice information is insufficient. Many aspects of THM processes and modelling are now well understood and there is a variety of numerical codes available to provide solutions for different host rock and repository conditions. However, modelling all the THM mechanisms in space and time is extremely complex and simplifications will have to be made - if only because it is not possible to obtain all the necessary detailed supporting information. Therefor, an important step is to clarify the THM modelling requirement within the PA context. This will help to indicate the complexity of THM modelling required and hence the models. mechanisms, type of computing, supporting data, laboratory and in situ testing, etc, required. An associated transparent and open audit trail should be developed. We also include comments from reviewers and highlight four outstanding issues which are currently being studied in the DECOVALEX III programme.
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| 7. |
- Laitinen, T, et al.
(författare)
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Characterization of a common susceptibility locus for asthma-related traits
- 2004
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 304:5668, s. 300-304
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Tidskriftsartikel (refereegranskat)abstract
- Susceptibility to asthma depends on variation at an unknown number of genetic loci. To identify susceptibility genes on chromosome 7p, we adopted a hierarchical genotyping design, leading to the identification of a 133-kilobase risk-conferring segment containing two genes. One of these coded for an orphan G protein–coupled receptor named GPRA (G protein–coupled receptor for asthma susceptibility), which showed distinct distribution of protein isoforms between bronchial biopsies from healthy and asthmatic individuals. In three cohorts from Finland and Canada, single nucleotide polymorphism–tagged haplotypes associated with high serum immunoglobulin E or asthma. The murine ortholog of GPRA was up-regulated in a mouse model of ovalbumin-induced inflammation. Together, these data implicate GPRA in the pathogenesis of atopy and asthma.
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| 8. |
- Engert, JC, et al.
(författare)
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5 ' flanking variants of resistin are associated with obesity
- 2002
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 51:5, s. 1629-1634
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes and obesity have long been known to be related. The recently characterized adipocyte hormone resistin (also called FIZZ3/ADSF) has been implicated as a molecular link between impaired glucose tolerance (IGT) and obesity in mice. A search for sequence variants at the human resistin locus identified nine single-nucleotide polymorphisms (SNPs) but no coding variants. An investigation into the association of these SNPs with diabetes and obesity revealed two 5' flanking variants (g.-537 and g.-420), in strong linkage disequilibrium, that are associated with BMI. In nondiabetic individuals from the Quebec City area and the Saguenay-Lac-St-Jean region of Quebec, the g.-537 mutation (allelic frequency = 0.04) was significantly associated with an increase in BMI (P = 0.03 and P = 0.01, respectively). When the data from these two populations were combined and adjusted for age and sex, both the g.-537 (odds ratio [OR] 2.72, 95% Cl 1.28-5.81) and the g.-420 variants (1.58, 1.06-2.35) were associated with an increased risk for a BMI greater than or equal to30 kg/m(2). In contrast, in case/control and family-based study populations from Scandinavia, we saw no effect on BMI with either of these promoter variants. No association was seen with diabetes in any of the population samples.
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| 9. |
- Jing, Lanru, et al.
(författare)
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Fundamentals of the hydro-mechanical behaviour of rock fractures : roughness characterization and experimental aspects
- 2004
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Ingår i: International Journal of Rock Mechanics And Mining Sciences. - : Elsevier BV. - 1365-1609 .- 1873-4545. ; 41:3, s. 383-383
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Tidskriftsartikel (refereegranskat)abstract
- The coupled hydro-mechanical behaviour of rock fractures plays an important role in design, performance and safety assessments of rock engineering projects. However, due to the complexity in the mathematical representation of the fracture surface geometry and its effects on the stress-flow behaviour of the fractures, and the limitations in the test conditions in laboratories, significant lack of knowledge still exists in testing and modelling approaches regarding rock fractures. Based on a general review of the roughness characterization and shear-flow testing of rock fractures, this paper presents the definition of the stationarity threshold of roughness, and a combined experimental-numerical approach for simulating rock fracture testing conditions for more general fluid flow behaviour of the rock fractures. The conclusions are that fracture roughness characterization must be conducted and represented in three-dimensions and the more general fluid flow behaviour cannot be observed with conventional parallel shear-flow tests or compressionradial flow tests. Numerical simulations are needed to reveal more general behaviour of stress-flow processes of rock fractures with boundary and loading conditions that are difficult or impractical in laboratory tests.
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| 10. |
- Jing, Lanru, et al.
(författare)
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Numerical methods in rock mechanics
- 2002
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Ingår i: International Journal of Rock Mechanics And Mining Sciences. - 1365-1609 .- 1873-4545. ; 39:4, s. 409-427
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Forskningsöversikt (refereegranskat)abstract
- The purpose of this CivilZone review paper is to present the techniques, advances, problems and likely future development directions in numerical modelling for rock mechanics and rock engineering. Such modelling is essential for Studying the fundamental processes occurring in rock,, for assessing the anticipated and actual performance of structures built on and in rock masses, and C hence for Supporting rock engineering design. We begin by providing the rock engineering design backdrop to the review in Section 1. The states-of-the-art of different types of numerical methods are outlined in Section 2, with focus on representations of fractures in the rock mass. In Section 3, the numerical methods for incorporating couplings between the thermal, hydraulic and mechanical processes are described. In Section 4, inverse solution techniques are summarized. Finally, in Section 5, we list the issues of special difficulty and importance in the subject. In the reference Est, 'significant' references are asterisked and 'very significant' references are doubly asterisked.
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