| 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. |
- Anney, Richard, et al.
(författare)
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A genome-wide scan for common alleles affecting risk for autism.
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
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Tidskriftsartikel (refereegranskat)abstract
- Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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| 4. |
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| 5. |
- Kyberd, Peter, et al.
(författare)
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Introduction to assessment
- 2012
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Ingår i: Grasping the future. - : Bentham eBooks. - 9781608054381 - 9781608054398 ; , s. 39-58
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Assessment tools are vital in measuring the outcomes of any practice or procedure. In the development and use of a prosthetic limb, this can be divided into three areas; the basic functions of the design, activities the limb is used for, and the amount the user actually employs the hand in everyday life. Each area is distinct and different and it needs different tools designed specifically for each area in order to reliably measure these outcomes. The development of these tools must include means to make sure the tool measures what the tester thinks it measures and makes sure that such measurements are consistent across time and between testers. Once a consistent set of tools is developed it allows clinicians to discuss and compare devices, training methods and solutions. It also allows investigation of different designs.Currently, the emphasis is on the basic practical measurements of function, activity and participation. This uses simple methods based on observation, timing or questionnaires to measure the use of simple prostheses. With newer designs of multifunction hands and microprocessor controllers being introduced, there are more varied control methods for the different hands. This requires more sophisticated methods to measure the impact of the new designs. These new methods include the measurement of the motions of the body and upper limbs with optical methods, and looking at measuring the cognitive load that controlling such hands impose on the user. To allow simple comparisons between users, the tasks and methods have to be constrained. This creates more artificial activities which may themselves be too artificial to tell the observer what they need to know, so the choice of activity is a balance between realistic tasks and reliable results.
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| 6. |
- Mateos-Gonzalez, Fernando, et al.
(författare)
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Carotenoid coloration predicts escape performance in the House Finch (Haemorhous mexicanus)
- 2014
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Ingår i: The AUK. - 0004-8038 .- 1938-4254. ; 131:3, s. 275-281
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Tidskriftsartikel (refereegranskat)abstract
- Carotenoid coloration has been repeatedly shown to serve as a sexually selected signal of individual quality. Across different species, individuals showing brighter carotenoid-based signals have been found to have superior foraging abilities, to recover faster from diseases and, in general, to enjoy a better body condition. Experiments with birds have also shown that carotenoid supplementation can enhance flight performance, allowing birds to take off faster from the ground. Healthy, agile individuals should be better prepared to avoid predators, so it could be expected that individuals displaying brighter carotenoid-based coloration would show a higher escape ability from predator attacks. To test this prediction, we measured the escape ability of male House Finches (Haemorhous mexicanus) from a human with a net in a large aviary and related the escape ability of each individual to its breast coloration. Males with redder feathers showed a higher individual ability to escape than duller individuals. The superior flight performance of redder birds would be an important asset in escape from predators, as well as when foraging or maintaining a territory. In the specific case of the House Finch, the higher escape ability of redder individuals could be the reason for their higher overwinter survival rate.
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| 7. |
- Pinto, Dalila, et al.
(författare)
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Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
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Tidskriftsartikel (refereegranskat)abstract
- The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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| 8. |
- Yang, Jian, et al.
(författare)
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FTO genotype is associated with phenotypic variability of body mass index
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 267-272
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Tidskriftsartikel (refereegranskat)abstract
- There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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