Adam R. Smith

An integrated genetic-epigenetic analysis of schizophrenia: Evidence for co-localization of genetic associations and differential DNA methylation

BackgroundSchizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated.ResultsWe performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease.ConclusionsThis study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.

Measurement of radiation dose to the thyroid using positron emission tomography.

Measurements of the functioning volume of thyroid tissue have been made in 22 patients undergoing radioiodine therapy for thyrotoxicosis, using a prototype multiwire proportional counter positron camera. Tomographic images were produced of the distribution of 124I in the thyroid. Functioning volumes were found to be in the range 21-79 cm3 with volume errors of the order of +/- 4% to +/- 14%. Radioiodine uptake varied from 28% to 98%. Using a value of 6 days for the effective half-life of radioiodine in hyperactive thyroids, radiation doses from a standard therapy administration of 75 MBq of 131I varied from 11 to 48 Gy (compared with a recommended 50-70 Gy). In five cases PET imaging showed a non-uniform distribution of radioiodine in thyroids thought to have uniform uptake from conventional pinhole scintigraphy.

A clinical evaluation of a prototype positron camera for longitudinal emission tomography

A multiwire proportional-chamber positron camera, developed at the Rutherford Laboratory, has been evaluated at The Royal Marsden Hospital. The prototype camera consists of two opposing 30 X 30 cm2 chambers. Longitudinal tomograms of a positron-emitting radioactive distribution placed between the detectors are obtained via back-projection and 2D-deconvolution. Due to the limited stereoscopic angle achieved with stationary detectors, only five planes parallel to the detector faces are reconstructed. A selection of images is presented of phantoms using 68Ga and of patients using 18F, 18F fluorodeoxyglucose and Na124I, to illustrate the tomographic performance of the positron camera. A comparison between back-projected and deconvoluted images shows that the 2D-deconvolution process, which includes filtration of image noise, successfully removes the background due to scattered photons. The spatial resolution achieved depends on the half-height frequency cut-off used in the filtering process, and this parameter was chosen according to the count density in the back-projected images. A qualitative visual comparison was made between the positron images and equivalent single photon studies on the same patient. The results justify further development of this new detector, especially for use with generator-produced positron-emitting radionuclides. Three-dimensional deconvolution resulted in improved tomographic performance for phantom data, but was less successful for patient data. These problems associated with limited-angle tomography will be overcome by multi-view acquisition. This study has shown that a relatively low-cost positron imaging system can be used for routine organ imaging. Further developments in hardware and software should yield images which are superior to those from single-photon planar or tomographic studies.

Position and ventilatory response to added dead space in prematurely born infants.

Prematurely born infants are at increased risk of sudden infant death syndrome (SIDS) if slept prone.

Elucidating novel dysfunctional pathways in Alzheimer's disease by integrating loci identified in genetic and epigenetic studies

Abstract Alzheimers disease is a complex neurodegenerative disorder. A large number of genome-wide association studies have been performed, which have been supplemented more recently by the first epigenome-wide association studies, leading to the identification of a number of novel loci altered in disease. Twin studies have shown monozygotic twin discordance for Alzheimers disease ( Gatz et al., 2006 ), leading to the conclusion that a combination of genetic and epigenetic mechanisms is likely to be involved in disease etiology (Lunnon & Mill, 2013). This review focuses on identifying overlapping pathways between published genome-wide association studies and epigenome-wide association studies, highlighting dysfunctional synaptic, lipid metabolism, plasma membrane/cytoskeleton, mitochondrial, and immune cell activation pathways. Identifying common pathways altered in genetic and epigenetic studies will aid our understanding of disease mechanisms and identify potential novel targets for pharmacological intervention.

3D positron emission tomography: Preliminary results

Quantitative radionuclide imaging has been a principal objective of most groups working with emission tomography. Positron emission tomography (PET) has been shown to be capable of providing quantitative images (Beller et al, 1982; Bergstrom et al, 1983; Beaney, 1984) which have contributed much to the understanding of cerebral and myocardial disease. Recently we have shown how a low cost prototype multiwire proportional chamber (MWPC) positron camera can produce longitudinal tomograms from limited-angle data acquisition via large area detectors (Ott et al, 1983; Flower et al, 1984). These tomograms were essentially qualitative in nature but provided enhanced image contrast when compared with conventional planar scintigraphy. In this paper we describe preliminary results of multiprojection acquisitions performed with the same detector providing 3D volume images. These images are intrinsically quantitative in nature and provide high-resolution, multipleslice tomograms of the object being imaged. Two exampl...

Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology

Alzheimers disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain.

A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex

We quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer’s disease (AD) cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing. We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (false discovery rate < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of amyloid-β and tau pathology (for example, APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease.Widespread differences in H3K27ac, a key histone modification, are associated with Alzheimer’s disease. H3K27ac differences were enriched in genomic regions containing loci involved in the progression of Aβ and tau pathology.

Application of a novel molecular method to age free-living wild Bechstein's bats

The age profile of populations fundamentally affects their conservation status. Yet, age is frequently difficult to assess in wild animals. Here, we assessed the use of DNA methylation of homologous genes to establish the age structure of a rare and elusive wild mammal: the Bechsteins bat (Myotis bechsteinii). We collected 62 wing punches from individuals whose ages were known as a result of a long‐term banding study. DNA methylation was measured at seven CpG sites from three genes, which have previously shown age‐associated changes in humans and laboratory mice. All CpG sites from the tested genes showed a significant relationship between DNA methylation and age, both individually and in combination (multiple linear regression R2 = 0.58, p < 0.001). Despite slight approximation around estimates, the approach is sufficiently precise to place animals into practically useful age cohorts. This method is of considerable practical benefit as it can reliably age individual bats. It is also much faster than traditional capture–mark–recapture techniques, with the potential to collect information on the age structure of an entire colony from a single sampling session to better inform conservation actions for Bechsteins bats. By identifying three genes where DNA methylation correlates with age across distantly related species, this study also suggests that the technique can potentially be applied across a wide range of mammals.

A histone acetylome-wide association study of Alzheimer's disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of Aβ and tau pathology (e.g. APP, PSEN1, PSEN2, MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.