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- Anney, Richard, et al.
(author)
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A genome-wide scan for common alleles affecting risk for autism.
- 2010
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:20, s. 4072-4082
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Journal article (peer-reviewed)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. |
- Anney, Richard, et al.
(author)
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Individual common variants exert weak effects on the risk for autism spectrum disorders.
- 2012
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:21, s. 4781-92
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Journal article (peer-reviewed)abstract
- While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASD), the contribution of common variation to ASD risk 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 association of individual SNPs, we also sought evidence that common variants, en masse, might affect 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. By 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 ASD risk but their individual effects are modest.
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| 5. |
- Pinto, Dalila, et al.
(author)
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Functional impact of global rare copy number variation in autism spectrum disorders.
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7304, s. 368-372
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Journal article (peer-reviewed)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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| 6. |
- Szatmari, Peter, et al.
(author)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Journal article (peer-reviewed)abstract
- Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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| 7. |
- Casey, Jillian P, et al.
(author)
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A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
- 2012
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In: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
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Journal article (peer-reviewed)abstract
- Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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| 8. |
- Bjelić, A., et al.
(author)
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Hydrogenation and hydrodeoxygenation of aromatic lignin monomers over Cu/C, Ni/C, Pd/C, Pt/C, Rh/C and Ru/C catalysts: Mechanisms, reaction micro-kinetic modelling and quantitative structure-activity relationships
- 2019
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In: Chemical Engineering Journal. - : Elsevier BV. - 1385-8947. ; 359, s. 305-320
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Journal article (peer-reviewed)abstract
- In this integrated in silico and experimental study, the activity, selectivity and mechanisms of commercially-available noble and transition metal heterogeneous catalysts, on neutral (carbon) support were investigated for hydrodeoxygenation (HDO) of eugenol. The latter was selected as a model compound of lignin building blocks. An influence of the process operating conditions (temperature, pressure and initial solid loading) on the reaction pathway and product distribution was studied as well. The previously-proposed reaction network for phenols HDO over Ru/C was found valid also for other platinum-group- (Pd, Pt and Rh) and non-noble (Cu or Ni) metallic clusters supported on C. Ru/C system exhibited the best HDO turnover performance, followed by the Rh/C, which especially demonstrated an excellent hydrogenation activity. Pt and Pd showed low deoxygenation and moderate hydrogenation activity. Kinetic parameters for all reactions on the surface were determined for all tested metals with a micro-kinetic model, by regression analysis on the foundation of 5760 experimentally-determined concentration values. Computation took into account resistances caused by transport phenomena, adsorption/desorption kinetics, and especially surface and bulk reaction kinetics. Ratio between adsorption and desorption rate constants for dissolved saturated, aromatic and hydrogen species were predicted, indicating a notable coverage effect on the catalyst reactivity. The saturation of functionalised benzene ring was approximately 3-, 11-, 32-, 10-, and 6-times faster than the C–O hydrogenolysis over ruthenium, platinum, palladium, rhodium and nickel, respectively. Methoxy group removal is easier from aromatics, compared to aliphatic species and also compared to the hydroxyl group removal. The heteroatom bond breaking for 2-methoxy-4-propylcyclohexanol proceed mostly via catechol-type diol formation, and subsequently, de-hydroxylation, particularly observable on Pt.
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| 9. |
- Hočevar, Brigita, et al.
(author)
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Mechanism, ab initio calculations and microkinetics of straight-chain alcohol, ether, ester, aldehyde and carboxylic acid hydrodeoxygenation over Ni-Mo catalyst
- 2019
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In: Chemical Engineering Journal. - : Elsevier BV. - 1385-8947. ; 359, s. 1339-1351
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Journal article (peer-reviewed)abstract
- Hydrotreatment of bio-based model compounds was investigated in a three-phase slurry reactor over pre-sulphided NiMo/γ-Al2O3 bifunctional catalyst. Experimental results were supported by comprehensive in silico studies. Mathematical microkinetic model was developed for mass transfer phenomena, adsorption, desorption and surface kinetics description, while quantum chemical calculations were performed for the proposed reaction mechanism validation. Every moiety followed the same chemical reduction sequence as its predecessor down the oxidation ladder, except of aldehyde. Experiments using hexanal as a model compound resulted in its extraordinary high concentrations in liquid phase and on the catalyst surface, which led to mutual aldol condensation. However, this reaction was not observed when aldehyde was formed as an intermediate from hexanoic acid or methyl hexanoate, due to its low concentration and high hydrogen availability which promoted further hydrogenation into hexanol. C12/C6 (aldol condensation/hydrogenation) product ratio increased with higher temperature, reflecting higher activation energy (EA) for hexanal condensation compared to negligible hydrogenation energy barrier, confirmed by density functional theory (DFT) calculations. Primary alcohols are more resistant to HDO compared to secondary counterpart (studied in previous work) over NiMo/γ-Al2O3, specifically; the activation energy of 1-hexanol deoxygenation to olefin was 43% higher compared to secondary hexanols according to microkinetic model, and 45% higher according to quantum mechanics calculations. Primary alcohols are also extensively dehydrated into ethers, which was never the case for secondary alcohols at tested reaction conditions, while aldehydes are much easier to hydrogenate than ketones, which cannot undergo C–C coupling reactions.
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| 10. |
- Hus, Matej, 1988, et al.
(author)
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Going Beyond Silver in Ethylene Epoxidation with First-Principles Catalyst Screening
- 2023
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In: Angewandte Chemie - International Edition. - 1433-7851 .- 1521-3773. ; 62:31
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Journal article (peer-reviewed)abstract
- Ethylene epoxidation is industrially and commercially one of the most important selective oxidations. Silver catalysts have been state-of-the-art for decades, their efficiency steadily improving with empirical discoveries of dopants and co-catalysts. Herein, we perform a computational screening of the metals in the periodic table, identify prospective superior catalysts and experimentally demonstrate that Ag/CuPb, Ag/CuCd and Ag/CuTl outperform the pure-Ag catalysts, while they still confer an easily scalable synthesis protocol. Furthermore, we show that to harness the potential of computationally-led discovery of catalysts fully, it is essential to include the relevant in situ conditions e.g., surface oxidation, parasitic side reactions and ethylene epoxide decomposition, as neglecting such effects leads to erroneous predictions. We combine ab initio calculations, scaling relations, and rigorous reactor microkinetic modelling, which goes beyond conventional simplified steady-state or rate-determining modelling on immutable catalyst surfaces. The modelling insights have enabled us to both synthesise novel catalysts and theoretically understand experimental findings, thus, bridging the gap between first-principles simulations and industrial applications. We show that the computational catalyst design can be easily extended to include larger reaction networks and other effects, such as surface oxidations. The feasibility was confirmed by experimental agreement.
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