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  • 1
    Keywords: POPULATION ; ASSOCIATION ; SCHIZOPHRENIA ; PERVASIVE DEVELOPMENTAL DISORDERS ; INDIVIDUALS ; SPECTRUM DISORDERS ; Copy number variation ; GENETIC ARCHITECTURE ; NEUROPSYCHIATRIC CONDITIONS ; PTEN MUTATIONS
    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 x 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 x 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
    Type of Publication: Journal article published
    PubMed ID: 20663923
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  • 2
    Abstract: BACKGROUND: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) 〈1.15). METHODS: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). RESULTS: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 x 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. CONCLUSIONS: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.
    Type of Publication: Journal article published
    PubMed ID: 28540026
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  • 3
    Keywords: GENE ; DELETIONS ; MENTAL-RETARDATION ; LOCI ; GENOME-WIDE ASSOCIATION ; CNTNAP2 ; Copy number variation ; DE-NOVO MUTATIONS ; LINKAGE ANALYSES ; DEVELOPMENTAL DISORDERS
    Abstract: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm〈 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
    Type of Publication: Journal article published
    PubMed ID: 22843504
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  • 4
    Keywords: RISK ; DELETIONS ; GENOME-WIDE ASSOCIATION ; DUPLICATIONS ; STRUCTURAL VARIATION ; COPY NUMBER VARIANTS ; FRAGILE-X-SYNDROME ; DE-NOVO MUTATIONS ; INTELLECTUAL DISABILITY ; PHENOTYPE ONTOLOGY
    Abstract: Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 x 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 x 10(-15), approximately 3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
    Type of Publication: Journal article published
    PubMed ID: 24768552
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  • 5
    Keywords: proliferation ; COMBINATION ; PATHWAY ; PATHWAYS ; GENE ; GENES ; COMPLEX ; FAMILY ; IMPACT ; ASSOCIATION ; DISORDER ; FREQUENCY ; LINKAGE ; VARIANTS ; TARGET ; COPY NUMBER ; ARRAYS ; NUMBER ; genotyping ; MUTATIONS ; REVEALS ; TARGETS ; CHILDREN ; DISORDERS ; VARIANT ; DETERMINANTS ; SCIENCE ; development ; LOCUS ; MOTILITY ; LOCI ; SPECTRUM DISORDERS ; Genetic ; RANGE ; Lead ; COPY NUMBER VARIANTS ; Copy number variation ; ANCESTRY ; GENETIC DISORDER ; HIDDEN-MARKOV MODEL ; SNP GENOTYPING DATA
    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(1). Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability(2). Although ASDs are known to be highly heritable (similar to 90%)(3), 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
    Type of Publication: Journal article published
    PubMed ID: 20531469
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  • 6
    ISSN: 1432-0703
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Notes: Abstract Activities of the petroleum-inducible mixed function oxygenase CYP1A (EROD) were measured in livers of inshore demersal fish species at various sites around the coast of Shetland to determine the sub-lethal impact of oil spilled after the wreck of the tanker M.V. Braer in January 1993. Visible coastal pollution by the oil was only apparent for some two weeks after the incident and tissue PAH levels in muscle of gadoid fish such as rockling from these areas were not elevated 3 months afterwards, while hepatic EROD activities were elevated some 7-to 9-fold. A 6.5-fold elevation was still observed 5 months afterwards; however, the levels had returned to those of fish from non-polluted environments 7 months after the incident and remained at baseline levels after the following winter's storm action. These data demonstrate the usefulness of enzymatic analysis as a sensitive method for assessing the temporal and spatial impact of an oil spill.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] We have placed 7,600 cytogenetically defined landmarks on the draft sequence of the human genome to help with the characterization of genes altered by gross chromosomal aberrations that cause human disease. The landmarks are large-insert clones mapped to chromosome bands by fluorescence in situ ...
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1095-8649
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology
    Notes: Predation on adult salmon, Salmo salur L., by otters, Lurra lutra (L.), varied seasonally on the R. Dee, Aberdeenshire, Scotland, being highest during the spawning season in winter. Predation is described for some tributaries of the river. Male fish were caught by otters more often than females, and it is suggested that they were most vulnerable during their extensive excursions up and down stream, particularly as they negotiated shallow riffles. Otters appeared to prey upon healthy fish rather than those infested with Saprolegnia sp. but there was no difference in the size, freshwater- or sea-age offish killed by otterscompared with ‘kelts’ which had died non-violently. At least some of the otters obtained most of their daily food requirements by catching a single salmon per night.Considerable numbers of adult salmon may be killed by otters during the spawning period but it is suggested that, because most are males, this is unlikely to affect the breeding success of the salmon population. Most predation occurs outside the fishing season and so is unlikely to reduce the numbers of salmon caught by anglers.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-8604
    Keywords: Papio ; microsatellite loci ; DNA polymorphism ; population structure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We investigated genetic variation at six microsatellite (simple sequence repeat) loci in yellow baboons (Papio hamadryas cynocephalus) at two localities: the Tana River Primate Reserve in eastern Kenya and Mikumi National Park, central Tanzania. The six loci (D1S158, D2S144, D4S243, D5S1466, D16S508, and D17S804) were all originally cloned from and characterized in the human genome. These microsatellites are polymorphic in both baboon populations, with the average heterozygosity across loci equal to 0.731 in the Tana River sample and 0.787 in the Mikumi sample. The genetic differentiation between the two populations is substantial. Kolmogornov–Smirnov tests indicate that five of the six loci are significantly different in allele frequencies in the two populations. The mean F ST across loci is 0.069, and Shriver's measure of genetic distance, which was developed for microsatellite loci (Shriver et al., 1995), is 0.255. This genetic distance is larger than corresponding distances among human populations residing in different continents. We conclude that (a) the arrays of alleles present at these six microsatellite loci in two geographically separated populations of yellow baboons are quite similar, but (b) the two populations exhibit significant differences in allele frequencies. This study illustrates the potential value of human microsatellite loci for analyses of population genetic structure in baboons and suggests that this approach will be useful in studies of other Old World monkeys.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1365-3040
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology
    Notes: C4 grasses of the NAD-ME type (Astrebla lappacea, Eleusine coracana, Eragrostis superba, Leptochloa dubia, Panicum coloratum, Panicum decompositum) and the NADP-ME type (Bothriochloa bladhii, Cenchrus ciliaris, Dichanthium sericeum, Panicum antidotale, Paspalum notatum, Pennisetum alopecuroides, Sorghum bicolor) were used to investigate the role of O2 as an electron acceptor during C4 photosynthesis. Mass spectrometric measurements of gross O2 evolution and uptake were made concurrently with measurements of net CO2 uptake and chlorophyll fluorescence at different irradiances and leaf temperatures of 30 and 40 °C. In all C4 grasses gross O2 uptake increased with increasing irradiance at very high CO2 partial pressures (pCO2) and was on average 18% of gross O2 evolution. Gross O2 uptake at high irradiance and high pCO2 was on average 3.8 times greater than gross O2 uptake in the dark. Furthermore, gross O2 uptake in the light increased with O2 concentration at both high CO2 and the compensation point, whereas gross O2 uptake in the dark was insensitive to O2 concentration. This suggests that a significant amount of O2 uptake may be associated with the Mehler reaction, and that the Mehler reaction varies with irradiance and O2 concentration. O2 exchange characteristics at high pCO2 were similar for NAD-ME and NADP-ME species. NAD-ME species had significantly greater O2 uptake and evolution at the compensation point particularly at low irradiance compared to NADP-ME species, which could be related to different rates of photorespiratory O2 uptake. There was a good correlation between electron transport rates estimated from chlorophyll fluorescence and gross O2 evolution at high light and high pCO2.
    Type of Medium: Electronic Resource
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