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- 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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| 3. |
- Gray, Marcus A, et al.
(författare)
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Following one's heart: cardiac rhythms gate central initiation of sympathetic reflexes.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 29:6, s. 1817-25
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Tidskriftsartikel (refereegranskat)abstract
- Central nervous processing of environmental stimuli requires integration of sensory information with ongoing autonomic control of cardiovascular function. Rhythmic feedback of cardiac and baroreceptor activity contributes dynamically to homeostatic autonomic control. We examined how the processing of brief somatosensory stimuli is altered across the cardiac cycle to evoke differential changes in bodily state. Using functional magnetic resonance imaging of brain and noninvasive beat-to-beat cardiovascular monitoring, we show that stimuli presented before and during early cardiac systole elicited differential changes in neural activity within amygdala, anterior insula and pons, and engendered different effects on blood pressure. Stimulation delivered during early systole inhibited blood pressure increases. Individual differences in heart rate variability predicted magnitude of differential cardiac timing responses within periaqueductal gray, amygdala and insula. Our findings highlight integration of somatosensory and phasic baroreceptor information at cortical, limbic and brainstem levels, with relevance to mechanisms underlying pain control, hypertension and anxiety.
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- Gray, Marcus A, et al.
(författare)
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Modulation of emotional appraisal by false physiological feedback during fMRI.
- 2007
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Ingår i: PLoS ONE. - 1932-6203. ; 2:6, s. e546-
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Tidskriftsartikel (refereegranskat)abstract
- James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories ofemotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions.Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover,anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiologicalarousal. However, the neural underpinnings of these phenomena previously have not been examined. Methodology/Principal Findings. We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and secondorderlevels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of trueand false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faceswas enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behaviouralinteraction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anteriorinsula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change inperceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLDactivity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at botha group and an individual level. Conclusions/Significance. Our findings identify the neural substrates supportingbehavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states,including the importance of the right anterior insula in guiding second-order ‘‘cognitive’’ representations of bodily arousalstate.
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