ORCID Profile
0000-0002-9774-1539
Current Organisations
Steno Diabetes Center Copenhagen
,
University of Tasmania
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Cellular Nervous System | Central Nervous System | Neurosciences
Publisher: Springer Science and Business Media LLC
Date: 29-01-2020
Publisher: Springer Science and Business Media LLC
Date: 03-10-2018
DOI: 10.1038/S41380-018-0118-1
Abstract: Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes ( β = −0.71 to −1.37 P 0.0005). In an independent s le, consistent results were obtained, with significant effects in the pallidum ( β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV ( P = 0.0032, 8.9 × 10 −6 , 1.7 × 10 − 9 , 3.5 × 10 −12 and 1.0 × 10 −4 , respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
Publisher: American Medical Association (AMA)
Date: 04-2020
Publisher: American Society of Hematology
Date: 06-07-2017
Publisher: Spandidos Publications
Date: 24-10-2015
DOI: 10.3892/OR.2014.3568
Publisher: Springer Science and Business Media LLC
Date: 09-2018
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1194/JLR.P094433
Publisher: Springer Science and Business Media LLC
Date: 02-2021
DOI: 10.1038/S42003-021-01656-7
Abstract: Sea turtle populations are under threat from an epizootic tumor disease (animal epidemic) known as fibropapillomatosis. Fibropapillomatosis continues to spread geographically, with prevalence of the disease also growing at many longer-affected sites globally. However, we do not yet understand the precise environmental, mutational and viral events driving fibropapillomatosis tumor formation and progression. Here we perform transcriptomic and immunohistochemical profiling of five fibropapillomatosis tumor types: external new, established and postsurgical regrowth tumors, and internal lung and kidney tumors. We reveal that internal tumors are molecularly distinct from the more common external tumors. However, they have a small number of conserved potentially therapeutically targetable molecular vulnerabilities in common, such as the MAPK, Wnt, TGFβ and TNF oncogenic signaling pathways. These conserved oncogenic drivers recapitulate remarkably well the core pan-cancer drivers responsible for human cancers. Fibropapillomatosis has been considered benign, but metastatic-related transcriptional signatures are strongly activated in kidney and established external tumors. Tumors in turtles with poor outcomes (died/euthanized) have genes associated with apoptosis and immune function suppressed, with these genes providing putative predictive biomarkers. Together, these results offer an improved understanding of fibropapillomatosis tumorigenesis and provide insights into the origins, inter-tumor relationships, and therapeutic treatment for this wildlife epizootic.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Cold Spring Harbor Laboratory
Date: 09-06-2017
DOI: 10.1101/148510
Abstract: Phasing, the process of predicting haplotypes from genotype data, is an important undertaking in genetics and an ongoing area of research. Phasing methods, and associated software, designed specifically for pedigrees are urgently needed. Here we present a new method for phasing genotypes from whole genome sequencing data in pedigrees: PULSAR ( P hasing U sing L ineage S pecific A lleles / R are variants). The method is built upon the idea that alleles that are specific to a single founding chromosome within a pedigree, which we refer to as lineage-specific alleles, are highly informative for identifying haplotypes that are identical-by-decent between in iduals within a pedigree. Through extensive simulation we assess the performance of PULSAR in a variety of pedigree sizes and structures, and we explore the effects of genotyping errors and presence of non-sequenced in iduals on its performance. If the genotyping error rate is sufficiently low PULSAR can phase 99.9% of heterozygous genotypes with a switch error rate below 1 x 10 -4 in pedigrees where all in iduals are sequenced. We demonstrate that the method is highly accurate and consistently outperforms the long-range phasing approach used for comparison in our benchmarking. The method also holds promise for fixing genotype errors or imputing missing genotypes. The software implementation of this method is freely available.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2021
DOI: 10.1161/CIRCGEN.120.003232
Abstract: The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease is of fundamental importance given its global health and economic burden. Inhibition of ANGPTL3 (angiopoietin-like 3) has demonstrated a cardioprotective effect, showing promise for atherosclerotic cardiovascular disease treatment, and is currently the focus of ongoing clinical trials. Here, we assessed the genetic basis of variation in ANGPTL3 levels in the San Antonio Family Heart Study. We assayed ANGPTL3 protein levels in ≈1000 Mexican Americans from extended pedigrees. By drawing upon existing plasma lipidome profiles and genomic data we conducted analyses to understand the genetic basis to variation in ANGPTL3 protein levels, and accordingly the correlation with the plasma lipidome. In a variance components framework, we identified that variation in ANGPTL3 was significantly heritable (h 2 =0.33, P =1.31×10 −16 ). To explore the genetic basis of this heritability, we conducted a genome-wide linkage scan and identified significant linkage (logarithm of odds =6.18) to a locus on chromosome 1 at 90 centimorgans, corresponding to the ANGPTL3 gene location. In the genomes of 23 in iduals from a single pedigree, we identified a loss-of-function variant, rs398122988 (N121Kfs*2), in ANGPTL3 , that was significantly associated with lower ANGPTL3 levels (β=−1.69 SD units, P =3.367×10 −13 ), and accounted for the linkage signal at this locus. Given the known role of ANGPTL3 as an inhibitor of endothelial and lipoprotein lipase, we explored the association of ANGPTL3 protein levels and rs398122988 with the plasma lipidome and related phenotypes, identifying novel associations with phosphatidylinositols. Variation in ANGPTL3 protein levels is heritable and under significant genetic control. Both ANGPTL3 levels and loss-of-function variants in ANGPTL3 have significant associations with the plasma lipidome. These findings further our understanding of ANGPTL3 as a therapeutic target for atherosclerotic cardiovascular disease.
Publisher: Frontiers Media SA
Date: 11-02-2022
DOI: 10.3389/FCDHC.2021.707553
Abstract: Little is known about the psychosocial experiences and care needs of young children under the age of 7 years who have been diagnosed with type 1 diabetes. To address this knowledge gap, we examine children’s psychosocial care needs through the lens of child-centred care and the framework of Zone of Proximal Development. To explore current care practices for young children with diabetes and identify aspects of child-centred care already successfully integrated into current practice. In idual face-to-face, semi-structured interviews were conducted with 20 Healthcare Professionals, representing 11 of 17 paediatric diabetes clinics in Denmark. Our data provided valuable insights into existing child-centred practices. Our analysis identified practices covering four main themes: 1. Accommodating immediate emotional needs, 2. Putting children before diabetes, 3. Encouraging meaningful participation, 4. Playful communication. Healthcare Professionals provided child-centred care, largely through play-based approaches that make diabetes care meaningful and relevant. Such practices provide the scaffolding necessary to enable young children to gradually engage, comprehend and participate in their own care.
Publisher: Hindawi Limited
Date: 04-04-2019
DOI: 10.1155/2019/2310235
Abstract: Measurements of fasting glucose (FG) or glycated hemoglobin A1c (HbA1c) are two clinically approved approaches commonly used to determine glycemia, both of which are influenced by genetic factors. Obtaining accurate measurements of FG or HbA1c is not without its challenges, though. Measuring glycated serum protein (GSP) offers an alternative approach for assessing glycemia. The aim of this study was to estimate the heritability of GSP and GSP expressed as a percentage of total serum albumin (%GA) using a variance component approach and localize genomic regions (QTLs) that harbor genes likely to influence GSP and %GA trait variation in a large extended multigenerational pedigree from Jiri, Nepal ( n = 1,800 ). We also performed quantitative bivariate analyses to assess the relationship between GSP or %GA and several cardiometabolic traits. Additive genetic effects significantly influence variation in GSP and %GA levels ( p values: 1.15 × 10 − 5 and 3.39 × 10 − 5 , respectively). We localized a significant (LOD score = 3.18 ) and novel GSP QTL on chromosome 11q, which has been previously linked to type 2 diabetes. Two common ( MAF 0.4 ) SNPs within the chromosome 11 QTL were associated with GSP (adjusted p value 5.87 × 10 − 5 ): an intronic variant (rs10790184) in the DSCAML1 gene and a 3 ′ UTR variant (rs8258) in the CEP164 gene. Significant positive correlations were observed between GSP or %GA and blood pressure, and lipid traits ( p values: 0.0062 to 1.78 × 10 − 9 ). A significant negative correlation was observed between %GA and HDL cholesterol ( p = 1.12 × 10 − 5 ). GSP is influenced by genetic factors and can be used to assess glycemia and diabetes risk. Thus, GSP measurements can facilitate glycemic studies when accurate FG and/or HbA1c measurements are difficult to obtain. GSP can also be measured from frozen blood (serum) s les, which allows the prospect of retrospective glycemic studies using archived s les.
Publisher: Wiley
Date: 21-03-2021
DOI: 10.1111/IMCB.12451
Abstract: Immune evasion is critical to the growth and survival of cancer cells. This is especially pertinent to transmissible cancers, which evade immune detection across genetically erse hosts. The Tasmanian devil ( Sarcophilus harrisii ) is threatened by the emergence of Devil Facial Tumour Disease (DFTD), comprising two transmissible cancers (DFT1 and DFT2). The development of effective prophylactic vaccines and therapies against DFTD has been restricted by an incomplete understanding of how allogeneic DFT1 and DFT2 cells maintain immune evasion upon activation of tumour‐specific immune responses. In this study, we used RNA sequencing to examine tumours from three experimental DFT1 cases. Two devils received a vaccine prior to inoculation with live DFT1 cells, providing an opportunity to explore changes to DFT1 cancers under immune pressure. Analysis of DFT1 in the non‐immunised devil revealed a ‘myelinating Schwann cell’ phenotype, reflecting both natural DFT1 cancers and the DFT1 cell line used for the experimental challenge. Comparatively, immunised devils exhibited a ‘dedifferentiated mesenchymal’ DFT1 phenotype. A third ‘immune‐enriched’ phenotype, characterised by increased PDL1 and CTLA‐4 expression, was detected in a DFT1 tumour that arose after immunotherapy. In response to immune pressure, mesenchymal plasticity and upregulation of immune checkpoint molecules are used by human cancers to evade immune responses. Similar mechanisms are associated with immune evasion by DFTD cancers, providing novel insights that will inform modification of DFTD vaccines. As DFT1 and DFT2 are clonal cancers transmitted across genetically distinct hosts, the Tasmanian devil provides a ‘natural’ disease model for more broadly exploring these immune evasion mechanisms in cancer.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2019
Publisher: Springer Science and Business Media LLC
Date: 31-01-2019
Publisher: Springer Science and Business Media LLC
Date: 06-07-2019
Publisher: Cold Spring Harbor Laboratory
Date: 29-10-2020
DOI: 10.1101/2020.10.29.360834
Abstract: Sea turtle fibropapillomatosis (FP) is a tumor promoting disease that is one of several threats globally to endangered sea turtle populations. The prevalence of FP is highest in green sea turtle ( Chelonia mydas ) populations, and historically has shown considerable temporal growth. FP tumors can significantly affect the ability of turtles to forage for food and avoid predation and can grow to debilitating sizes. In the current study, based in South Texas, we have applied transcriptome sequencing to FP tumors and healthy control tissue to study the gene expression profiles of FP. By identifying differentially expressed turtle genes in FP, and matching these genes to their closest human ortholog we draw on the wealth of human based knowledge, specifically human cancer, to identify new insights into the biology of sea turtle FP. We show that several genes aberrantly expressed in FP tumors have known tumor promoting biology in humans, including CTHRC1 and NLRC5 , and provide support that disruption of the Wnt signaling pathway is a feature of FP. Further, we profiled the expression of current targets of immune checkpoint inhibitors from human oncology in FP tumors and identified potential candidates for future studies.
Publisher: Cold Spring Harbor Laboratory
Date: 10-2023
Publisher: Springer Science and Business Media LLC
Date: 09-2018
Publisher: Springer Science and Business Media LLC
Date: 09-2018
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: Frontiers Media SA
Date: 03-05-2017
Publisher: Springer Science and Business Media LLC
Date: 22-03-2021
DOI: 10.1038/S41398-021-01213-0
Abstract: Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural ersity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippoc al volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2017
DOI: 10.1038/S41598-017-18217-W
Abstract: The HOXB13 G84E variant is associated with risk of prostate cancer (PCa), however the role this variant plays in PCa development is unknown. This study examined 751 cases, 450 relatives and 355 controls to determine the contribution of this variant to PCa risk in Tasmania and investigated HOXB13 gene and protein expression in tumours from nine G84E heterozygote variant and 13 wild-type carriers. Quantitative PCR and immunohistochemistry showed that HOXB13 gene and protein expression did not differ between tumour s les from variant and wild-type carriers. Allele-specific transcription revealed that two of seven G84E carriers transcribed both the variant and wild-type allele, while five carriers transcribed the wild-type allele. Methylation of surrounding CpG sites was lower in the variant compared to the wild-type allele, however overall methylation across the region was very low. Notably, tumour characteristics were less aggressive in the two variant carriers that transcribed the variant allele compared to the five that did not. This study has shown that HOXB13 expression does not differ between tumour tissue of G84E variant carriers and non-carriers. Intriguingly, the G84E variant allele was rarely transcribed in carriers, suggesting that HOXB13 expression may be driven by the wild-type allele in the majority of carriers.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2018
DOI: 10.1007/S10072-017-3177-1
Abstract: Despite extensive studies focusing on the changes in expression of microRNAs (miRNAs) in multiple sclerosis (MS) compared to healthy controls, few studies have evaluated the association of genetic variants of miRNAs with MS clinical course. We investigated whether a functional polymorphism in the MS associated miR-146a gene predicted clinical course (hazard of conversion to MS and of relapse, and annualized change in disability), using a longitudinal cohort study of persons with a first demyelinating event followed up to their 5-year review. We found the genotype (GC+CC) of rs2910164 predicted relapse compared with the GG genotype (HR=2.09 (95% CI 1.42, 3.06), p=0.0001), as well as a near-significant (p=0.07) association with MS conversion risk. Moreover, we found a significant additive interaction between rs2910164 and baseline anti-EBNA-1 IgG titers predicting risk of conversion to MS (relative excess risk due to interaction [RERI] 2.39, p=0.00002) and of relapse (RERI 1.20, p=0.006). Supporting these results, similar results were seen for the other EBV-correlated variables: anti-EBNA-2 IgG titers and past history of infectious mononucleosis. There was no association of rs2910164 genotype for disability progression. Our findings provide evidence for miR-146a and EBV infection in modulating MS clinical course.
Publisher: Public Library of Science (PLoS)
Date: 20-06-2018
Publisher: Public Library of Science (PLoS)
Date: 11-11-2015
Location: United States of America
Start Date: 02-2022
End Date: 02-2025
Amount: $428,000.00
Funder: Australian Research Council
View Funded Activity