| 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. |
- Nicholson, George, et al.
(författare)
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A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection
- 2011
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 7:9, s. e1002270-
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Tidskriftsartikel (refereegranskat)abstract
- We have performed a metabolite quantitative trait locus (mQTL) study of the 1H nuclear magnetic resonance spectroscopy (1H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by 1H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10−11<p<2.8×10−23). Three of these—trimethylamine, 3-amino-isobutyrate, and an N-acetylated compound—were measured in urine. The other—dimethylamine—was measured in plasma. Trimethylamine and dimethylamine mapped to a single genetic region (hence we report a total of three implicated genomic regions). Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2) that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%–64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from the corresponding mQTL effects.
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| 3. |
- Fox, Elaine, et al.
(författare)
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Travellers' Tales in Cognitive Bias Modification Research : A Commentary on the Special Issue
- 2014
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Ingår i: Cognitive Therapy and Research. - : SPRINGER/PLENUM PUBLISHERS. - 0147-5916 .- 1573-2819. ; 38:2, s. 239-247
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- This brief commentary reflects on the current Special Issue on "Cognitive Bias Modification Techniques: Current findings and future challenges". We consider past perspectives, present findings and future applications of "cognitive bias modification" (CBM) training procedures. In an interview with Marcella L. Woud, Bundy Mackintosh responds with her thoughts as an experienced 'traveler', given her pioneering work at the early stages of CBM research. Elaine Fox provides an overview of developments since the last special issue on CBM that she helped to co-edit in 2009, and Emily A. Holmes reflects on what might need to be done in order to translate the results of CBM research into therapeutic practice. All three conclude that, much as we might wish for a CBM 'tardis' time travel machine, there is much basic and translational science work to be done before the fruits of CBM research will be seen in the clinic. Systematic, thorough, and collaborative efforts will be needed, and we urge researchers to pay more attention to developing appropriate methodologies to enable the 'transfer' of training to clinical symptoms. Given the colossal clinical need to innovate and develop the content and delivery of mental health treatments, CBM research needs to keep travelling slowly, surely, and further. It is important to note that given low intensity of delivery, even studies with small effect sizes may be beneficial at a public health level. We should keep going, but retain strong roots in experimental psychopathology to maintain the quality and understanding of how cognitive factors are central to mental health and to the effectiveness of therapeutic interventions.
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