| 1. |
|
|
| 2. |
- Brownstein, Catherine A., et al.
(författare)
-
An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
-
Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
|
|
| 3. |
|
|
| 4. |
- Ferrari, Raffaele, et al.
(författare)
-
Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
-
Ingår i: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
-
Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
|
|
| 5. |
- Palmer, Nicholette D, et al.
(författare)
-
A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
-
Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
-
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.
|
|
| 6. |
- Beecham, Ashley H, et al.
(författare)
-
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
-
Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
|
|
| 7. |
- Moller, Anders Pape, et al.
(författare)
-
Clutch-size variation in Western Palaearctic secondary hole-nesting passerine birds in relation to nest box design
- 2014
-
Ingår i: Methods in Ecology and Evolution. - 2041-210X. ; 5:4, s. 353-362
-
Tidskriftsartikel (refereegranskat)abstract
- Secondary hole-nesting birds that do not construct nest holes themselves and hence regularly breed in nest boxes constitute important model systems for field studies in many biological disciplines with hundreds of scientists and amateurs involved. Those research groups are spread over wide geographic areas that experience considerable variation in environmental conditions, and researchers provide nest boxes of varying designs that may inadvertently introduce spatial and temporal variation in reproductive parameters. We quantified the relationship between mean clutch size and nest box size and material after controlling for a range of environmental variables in four of the most widely used model species in the Western Palaearctic: great tit Parus major, blue tit Cyanistes caeruleus, pied flycatcher Ficedula hypoleuca and collared flycatcher F.albicollis from 365 populations and 79610 clutches. Nest floor area and nest box material varied non-randomly across latitudes and longitudes, showing that scientists did not adopt a random box design. Clutch size increased with nest floor area in great tits, but not in blue tits and flycatchers. Clutch size of blue tits was larger in wooden than in concrete nest boxes. These findings demonstrate that the size of nest boxes and material used to construct nest boxes can differentially affect clutch size in different species. The findings also suggest that the nest box design may affect not only focal species, but also indirectly other species through the effects of nest box design on productivity and therefore potentially population density and hence interspecific competition.
|
|
| 8. |
- Moller, Anders P., et al.
(författare)
-
Variation in clutch size in relation to nest size in birds
- 2014
-
Ingår i: Ecology and Evolution. - : Wiley. - 2045-7758. ; 4:18, s. 3583-3595
-
Tidskriftsartikel (refereegranskat)abstract
- Nests are structures built to support and protect eggs and/or offspring from predators, parasites, and adverse weather conditions. Nests are mainly constructed prior to egg laying, meaning that parent birds must make decisions about nest site choice and nest building behavior before the start of egg-laying. Parent birds should be selected to choose nest sites and to build optimally sized nests, yet our current understanding of clutch size-nest size relationships is limited to small-scale studies performed over short time periods. Here, we quantified the relationship between clutch size and nest size, using an exhaustive database of 116 slope estimates based on 17,472 nests of 21 species of hole and non-hole-nesting birds. There was a significant, positive relationship between clutch size and the base area of the nest box or the nest, and this relationship did not differ significantly between open nesting and hole-nesting species. The slope of the relationship showed significant intraspecific and interspecific heterogeneity among four species of secondary hole-nesting species, but also among all 116 slope estimates. The estimated relationship between clutch size and nest box base area in study sites with more than a single size of nest box was not significantly different from the relationship using studies with only a single size of nest box. The slope of the relationship between clutch size and nest base area in different species of birds was significantly negatively related to minimum base area, and less so to maximum base area in a given study. These findings are consistent with the hypothesis that bird species have a general reaction norm reflecting the relationship between nest size and clutch size. Further, they suggest that scientists may influence the clutch size decisions of hole-nesting birds through the provisioning of nest boxes of varying sizes.
|
|
| 9. |
- Nilsson, C. L., et al.
(författare)
-
Chromosome 19 Annotations with Disease Speciation: A First Report from the Global Research Consortium
- 2013
-
Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:1, s. 134-149
-
Tidskriftsartikel (refereegranskat)abstract
- A first research development progress report of the Chromosome 19 Consortium with members from Sweden, Norway, Spain, United States, China and India, a part of the Chromosome-centric Human Proteome Project (C-HPP) global initiative, is presented (http://www.c-hpp.org). From the chromosome 19 peptide-targeted library constituting 6159 peptides, a pilot study was conducted using a subset with 125 isotope-labeled peptides. We applied an annotation strategy with triple quadrupole, ESI-Qtrap, and MALDI mass spectrometry platforms, comparing the quality of data within and in between these instrumental set-ups. LC–MS conditions were outlined by multiplex assay developments, followed by MRM assay developments. SRM was applied to biobank samples, quantifying kallikrein 3 (prostate specific antigen) in plasma from prostate cancer patients. The antibody production has been initiated for more than 1200 genes from the entire chromosome 19, and the progress developments are presented. We developed a dedicated transcript microarray to serve as the mRNA identifier by screening cancer cell lines. NAPPA protein arrays were built to align with the transcript data with the Chromosome 19 NAPPA chip, dedicated to 90 proteins, as the first development delivery. We have introduced an IT-infrastructure utilizing a LIMS system that serves as the key interface for the research teams to share and explore data generated within the project. The cross-site data repository will form the basis for sample processing, including biological samples as well as patient samples from national Biobanks.
|
|
| 10. |
- Andersson, C, et al.
(författare)
-
The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes
- 2011
-
Ingår i: Autoimmunity. - : Taylor & Francis. - 0891-6934 .- 1607-842X. ; 44:5, s. 394-405
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.
|
|
