| 1. |
- 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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| 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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| 3. |
- Hemann, Michael T, et al.
(författare)
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Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants.
- 2005
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Ingår i: Nature. - 1476-4687. ; 436:7052, s. 807-11
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Tidskriftsartikel (refereegranskat)abstract
- The c-Myc oncoprotein promotes proliferation and apoptosis, such that mutations that disable apoptotic programmes often cooperate with MYC during tumorigenesis. Here we report that two common mutant MYC alleles derived from human Burkitt's lymphoma uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein Bim (a member of the B cell lymphoma 2 (Bcl2) family) and effectively inhibit Bcl2. Disruption of apoptosis through enforced expression of Bcl2, or loss of either Bim or p53 function, enables wild-type MYC to produce lymphomas as efficiently as mutant MYC. These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesis.
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| 4. |
- Silfverdal, Sven Arne, et al.
(författare)
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13-Valent pneumococcal conjugate vaccine (PCV13) in children partially immunized with 7-valent pneumococcal conjugate vaccine (PCV7): A phase 3, open-label trial
- 2013
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Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 31:9, s. 1284-1292
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Tidskriftsartikel (refereegranskat)abstract
- Background: As 13-valent pneumococcal conjugate vaccine (PCV13) is introduced, children who began vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) may complete their vaccination with PCV13. This open-label phase 3 study evaluated immunogenicity and safety of PCV13 in Swedish infants and toddlers previously given 1 or 2 doses of PCV7 during infancy. Methods: Healthy infants previously given PCV7 at ages 3 months (group 1; n = 118) or 3 and 5 months (group 2; n = 116) received PCV13 at ages 5 (group 1) and 12 months (both groups). IgG responses were assessed 1 month after each PCV13 dose and before the 12-month dose. Local reactions and systemic events were collected for 7 days postvaccination. Other adverse events were also collected. Results: Post-5-month dose, IgG geometric mean concentrations (GMCs) in group 1 were 1.56-4.70 mu g/ml for most PCV7 serotypes except 6B (0.40 mu g/ml) and 23F (0.57 mu g/ml) and 0.72-1.88 mu g/ml for most of the 6 additional serotypes, except 6A (0.28 mu g/ml). Post-12-month dose, IgG GMCs for the PCV7 serotypes were 2.93-9.63 mu g/ml (group 1) and 3.33-9.30 mu g/ml (group 2); and for the 6 additional serotypes, 1.85-14.65 mu g/ml (group 1) and 1.34-13.16 mu g/ml (group 2). GMCs increased by >4-fold in both groups from pre- to post-12-month dose. Proportions of subjects in group 1 with pneumococcal serotype-specific IgG concentrations >= 0.35 mu g/ml (WHO-designated postprimary reference antibody level) post-5-month dose were 92.2-99.1% for most PCV7 serotypes except 6B (53.0%) and 23F (62.6%) and 80.9-100.0% for most of the 6 additional serotypes except 6A (36.8%). Local reactions and fever were mostly mild or moderate. Conclusions: PCV13 was immunogenic and safe in infants and toddlers previously partially immunized with PCV7. Even a single dose in an infant or toddler induces an immune response to the 6 additional serotypes. (C) 2013 Published by Elsevier Ltd.
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