https://nova.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:50624 Wed 28 Feb 2024 16:07:02 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:38821 DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.]]> Wed 28 Feb 2024 14:57:16 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:23230 Wed 24 Aug 2016 17:36:49 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:38581 Wed 23 Feb 2022 15:53:14 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:48569 Wed 22 Mar 2023 15:26:43 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:39776 Wed 22 Jun 2022 12:26:08 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:36496 Wed 20 May 2020 17:35:27 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:38237 Wed 18 Aug 2021 09:19:04 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34568 Wed 17 Nov 2021 16:28:59 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:24389 -6 and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. Results: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5x10^-9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII.activating protease levels, a product of HABP2. Conclusions: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.]]> Wed 15 Dec 2021 16:09:44 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:36509 Wed 15 Dec 2021 16:07:52 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:47091 Wed 14 Dec 2022 09:37:26 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:49099 Wed 13 Mar 2024 13:56:45 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:33716 Wed 12 Dec 2018 14:03:45 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:52462 Wed 11 Oct 2023 15:08:04 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:52461 Wed 11 Oct 2023 15:01:35 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:11479 Wed 11 Apr 2018 16:22:04 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:23272 Wed 11 Apr 2018 14:52:43 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:28423 Wed 11 Apr 2018 14:49:25 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:15068 Wed 11 Apr 2018 13:50:10 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:13675 Wed 11 Apr 2018 13:42:55 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:13635 Wed 11 Apr 2018 13:35:28 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:10691 Wed 11 Apr 2018 12:41:02 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:22235 −6). Network analysis of cases and controls sharing haplotypes on chromosome 19 further strengthened the association as there are more large networks of cases sharing haplotypes than controls. This linkage region includes a cluster of zinc finger genes of unknown function. Analysis of genome wide transcriptome data suggests that genes in this zinc finger cluster may be involved in very early developmental regulation of the CNS. Our study also indicates that BEAGLE fastIBD allowed identification of rare variants in large unrelated population with moderate computational intensity. Even with the development of whole-genome sequencing, IBD mapping still may be a promising way to narrow down the region of interest for sequencing priority.]]> Wed 11 Apr 2018 11:41:58 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:9007 Wed 11 Apr 2018 11:27:26 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:14169 Wed 11 Apr 2018 10:06:22 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27386 -9, MIR2113; rs17522122, P=2.55 x 10^-8, AKAP6; rs10119, P=5.67 x 10^-9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 x 10^-6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 x 10^-17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.]]> Wed 11 Apr 2018 09:51:21 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:13946 Wed 11 Apr 2018 09:27:26 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21916 Wed 10 Jul 2019 15:18:42 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:29905 Wed 09 Mar 2022 16:00:44 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34119 -4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10^-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.]]> Wed 04 Sep 2019 09:40:14 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:45604 Wed 02 Nov 2022 14:06:59 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:49012 Wed 01 May 2024 15:54:23 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:26146 Tue 31 Jul 2018 16:35:15 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:33133 Tue 28 Aug 2018 13:03:47 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:47666 Tue 24 Jan 2023 15:47:40 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:16085 Tue 24 Aug 2021 14:27:51 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27769 SNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. Methods: WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate H_SNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. Results: A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (H_SNP=0.23; P=0.0026). H_SNP estimates were higher among hypertensive individuals (H_SNP=0.45; P=7.99x10^-5); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (H_SNP=0.13; P=0.13). Conclusions: A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction.]]> Tue 21 Jul 2020 09:44:12 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:43460 SCN1A mutations that cause Dravet Syndrome (DS). DNA samples (n = 7) from DS patients previously shown to carry SCN1A mutations via Ion Torrent and Sanger sequencing were sequenced using the MinION. SCN1A amplicons for 8 exons were sequenced using the MinION with 1D chemistry on an R9.4 flow cell. All known missense mutations were detected in all samples showing 100 % concordance with results from other methods. However, the MinION failed to detect the insertions/deletions (INDELs) present in these patients. Nevertheless, these results indicate that MinION is a cost-effective platform for use as an initial screening step in the detection of nucleotide substitution mutations in in SCN1A, especially in under-resourced laboratories or hospitals. Further improvements are required to reliably detect INDELS in this gene.]]> Tue 20 Sep 2022 08:42:26 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:33797 Tue 15 Jan 2019 15:29:29 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:39166 Tue 14 Nov 2023 12:24:12 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:48335 Tue 14 Mar 2023 17:16:01 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:20561 Tue 10 Oct 2023 08:38:59 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:45927 Tue 08 Nov 2022 09:53:06 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34283 −15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10⁻⁶). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10⁻¹¹) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10⁻⁵). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.]]> Tue 03 Sep 2019 18:30:49 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:33809 -4). We did not find evidence that SNP genotype was influencing the DMR in this cohort. A smaller MHC DMR was also identified at HCG4B, and two non-MHC DMRs at PM20D1 on chr1 and ERICH1 on chr8 were also identified. Conclusions: The findings from this study confirm our previous results of a DMR at HLA-DRB1 and also suggest hypermethylation in an independent MHC locus, RNF39, is associated with MS. Taken together, our results highlight the importance of epigenetic factors at the MHC locus in MS independent of treatment, age and sex. Prospective studies are now required to discern whether methylation at MHC is involved in influencing risk of disease onset or whether the disease itself has altered the methylation profile.]]> Tue 03 Sep 2019 18:30:43 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:53491 Thu 30 Nov 2023 15:43:58 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:33786 -8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.]]> Thu 30 Mar 2023 15:49:49 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:52120 Thu 28 Sep 2023 15:04:45 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:45361 BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10⁻⁹) and missense (OR 1.27, p = 3.96 × 10⁻⁷³) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.]]> Thu 27 Oct 2022 15:32:46 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:45310 Thu 27 Oct 2022 13:56:22 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:39755 Thu 21 Jul 2022 09:10:24 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:26066 Thu 20 Aug 2020 09:19:59 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:41704 -7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r² > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 x 10^-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.]]> Thu 11 Aug 2022 15:21:17 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27063 2000 trait-associated genetic variants. Because most of these variants have individually small effects on disease risk, successful gene discovery efforts have required large sample sizes (involving thousands, tens, or hundreds of thousands of cases and controls) to achieve sufficient study power. Amassing such sample sizes has depended on international collaboration on a scale never seen before in human genetics or even in clinical research. Disease-specific consortia bringing together many individual sites and collaborators have now evolved for many major diseases. Each consortium has faced with ≥2 fundamental questions: how to assemble a study sample of sufficient size, homogeneity, and phenotypic quality and how to retain and analyze, sometimes repeatedly over several years, biological samples from enrolled subjects.]]> Thu 10 Sep 2020 18:07:31 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:42951 KCNJ2 gene involved in the transduction of sour taste have been linked to variations in sour taste and non-gustatory functions. However, relationships between sour taste genetics, mild cognitive impairment, and diet quality are yet to be elucidated. This study investigated the associations between the presence of the KCNJ2-rs236514 variant (A) allele, diet quality indices, and mild cognitive impairment evaluated by the Mini-Mental State Examination (MMSE), in a secondary cross-sectional analysis of data from the Retirement Health & Lifestyle Study. Data from 524 elderly Australians (≥65y) were analyzed, using standard least squares regression and nominal logistic regression modeling, with demographic adjustments applied. Results showed that the presence of the KCNJ2-A allele is associated with increased proportions of participants scoring in the range indicative of mild or more severe cognitive impairment (MMSE score of ≤26) in the total cohort, and males. These associations remained statistically significant after adjusting for age, sex, and diet quality indices. The absence of association between the KCNJ2-A allele and cognitive impairment in women may be related to their higher diet quality scores in all indices. The potential link between sour taste genotype and cognitive impairment scores may be due to both oral and extra-oral functions of sour taste receptors. Further studies are required on the role and relationship of neurotransmitters, sour taste genotypes and sour taste receptors in the brain, and dietary implications, to identify potential risk groups or avenues for therapeutic or prophylactic interventions.]]> Thu 08 Sep 2022 14:04:41 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:44054 Thu 06 Oct 2022 09:06:18 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:33895 BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10^-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.]]> Thu 04 Nov 2021 10:39:41 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:7108 Sat 24 Mar 2018 08:34:12 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:13657 s) was similar across all sites. The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the λ_s is similar to the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture.]]> Sat 24 Mar 2018 08:25:18 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:12767 T polymorphisms in IBS, and interactions between 5-HTT LPR with life events have been reported in the psychiatric literature, but gene–environment studies in IBS are lacking. Aims: The purpose of this study was to assess the association of two polymorphisms with IBS and age of onset, and whether there are gene–environment interactions with IBS. Methods: Outpatients with IBS and controls completed a validated questionnaire and provided blood for DNA. Comparisons of genotype/allele frequencies between cases and controls were performed with logistic regression. Linear regression was used to evaluate the association between the variants and age of onset. Environmental variables tested included abuse, parental alcohol abuse, parental psychiatric disorders, and gastrointestinal infections. Results: Genotyping was performed in 385 cases and 262 controls with median age of 50 years (range, 18.0–70.0) and 498 (77 %) females. The IBS subtype distribution among cases was: 102 (26 %) D-IBS, 40 (10 %) C-IBS, 125 (32 %) M-IBS, 118 (31 %) other. No association was observed between IBS or age of onset and both variants. Significant interactions were observed between GI infection and the GNβ3 825T allele. For those reporting gastrointestinal infection, the OR for IBS was 3.9 (95 % CI 1.2–12.7) whereas the OR was 0.86 (95 % CI 0.65–1.13) for those without prior infection. Conclusions: There was a significant interaction between the GNβ3 polymorphism and infection in the development of IBS, suggesting that its etiology is the result of a combination of specific genetic and environmental risk factors.]]> Sat 24 Mar 2018 08:18:21 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:10036 Sat 24 Mar 2018 08:12:16 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:10808 Sat 24 Mar 2018 08:11:50 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:20807 V1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Na_V1.5. Methods: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. Results: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P <.05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na_V1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na_V1.5 had the greatest effect in reducing Na_V1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. Conclusions: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na_V1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.]]> Sat 24 Mar 2018 08:05:59 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21442 x10^-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (P_IS=1.62x10^-7) and ABO (P_IS=2.6x10^-4), as well as at HDAC9 (P_LAS=2.32x10-12), 9p21 (P_LAS=3.70x10^-6), RAI1-PEMT-RASD1 (P_LAS=2.69x10^-5), EDNRA (P_LAS=7.29x10^-4), and CYP17A1-CNNM2-NT5C2 (P_LAS=4.9x10^-4). Conclusions-Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.]]> Sat 24 Mar 2018 08:05:46 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:19050 2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. Conclusions - A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.]]> Sat 24 Mar 2018 08:05:17 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21387 Catechol-O-methyltransferase (COMT) Val¹⁵⁸Met polymorphism, a common genetic variant known to affect cognition and prefrontal dopamine levels. Participants were 429 schizophrenia/schizoaffective cases from the Australian Schizophrenia Research Bank (ASRB). Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Controlled Oral Word Association Test (COWAT), Letter Number Sequencing (LNS) test, and the Wechsler Test of Adult Reading (WTAR). Hierarchical regression was used to test the main effects and additive interaction effects of genotype and childhood trauma in the domains of physical abuse, emotional abuse, and emotional neglect, on cognition and symptom profiles of clinical cases. Consistent with previous findings, COMT Val homozygotes performed worse on cognitive measures in the absence of childhood adversity. In addition, a significant interaction between COMT genotype and physical abuse was associated with better executive function in Val homozygotes, relative to those of the same genotype with no history of abuse. Finally, the severity of positive symptoms was greater in Met carriers who had experienced physical abuse, and the severity of negative symptoms in Met carriers was greater in the presence of emotional neglect. These results suggest that the possible epigenetic modulation of the expression of the COMT Val¹⁵⁸Met polymorphism and consequent effects on cognition and symptoms in schizophrenia, with worse outcomes associated with adverse childhood experiences in Met carriers.]]> Sat 24 Mar 2018 08:05:04 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:17291 Sat 24 Mar 2018 08:01:50 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:17373 Sat 24 Mar 2018 08:01:32 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21864 Sat 24 Mar 2018 07:59:11 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:16210 Sat 24 Mar 2018 07:56:04 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:20141 Sat 24 Mar 2018 07:51:38 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:19980 Sat 24 Mar 2018 07:50:58 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21021 N = 2088) and the Sydney Memory and Ageing Study (Sydney MAS, N = 541). Genotyping was undertaken using Affymetrix microarrays with imputation to HapMap2. Analyses were performed using linear regression. No genome-wide significant results were observed in HCS nor were any of the top signals replicated in Sydney MAS. Gene-based analyses in HCS identified two significant genes (ZNF295, C2CD2), but these results were not replicated in Sydney MAS. One out of eight SNPs previously associated with GS, rs550942, located near the CNTF gene, was significantly associated with GS (p = 0.005) in the HCS cohort only. Study differences may explain the lack of consistent results between the studies, including the smaller sample size of the Sydney MAS cohort. Our modest sample size also had limited power to identify variants of small effect. Our results suggest that similar to various other complex traits, many genetic variants of small effect size may influence GS. Future GWAS using larger samples and consistent measures may prove more fruitful at identifying genetic contributors for GS in middle-aged to older adults.]]> Sat 24 Mar 2018 07:50:32 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:6124 Sat 24 Mar 2018 07:44:37 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:29000 Sat 24 Mar 2018 07:41:17 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:25277 −11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28–1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.]]> Sat 24 Mar 2018 07:38:17 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27385 -6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. Results: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 x 10^-10) and replication cohorts (p = 5.65 x 10^-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 x 10^-8, and rs6813517 [SPOCK3], p = 2.58 x 10^-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. Conclusions: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.]]> Sat 24 Mar 2018 07:34:11 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27383 -16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 x 10^-7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 x 10^-37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 x 10^-22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 x 10^-6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.]]> Sat 24 Mar 2018 07:34:11 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:27208 Sat 24 Mar 2018 07:32:26 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:30050 Sat 24 Mar 2018 07:31:15 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:26934 KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10^-6 in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. Conclusions: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.]]> Sat 24 Mar 2018 07:27:31 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:22288 Sat 24 Mar 2018 07:17:30 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:25211 Sat 24 Mar 2018 07:14:02 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:23064 combined=3.32 x 10(^-15), OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.]]> Sat 24 Mar 2018 07:12:28 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:34360 Mon 24 Feb 2020 11:21:38 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:38229 Mon 16 Aug 2021 17:39:39 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:50980 Mon 14 Aug 2023 15:24:38 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:46738 Mon 10 Jul 2023 13:53:20 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:40845 Mon 08 Aug 2022 15:39:55 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:55070 Mon 08 Apr 2024 13:27:57 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:48305 Mon 01 May 2023 15:23:00 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:49398 Fri 30 Jun 2023 10:10:23 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:42223 P=0.0007; odds ratio=0.89; 95% CI, 0.82–0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91–0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80–0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89–0.98) whereas imbalance without ohnologs lacked such an association. Conclusions: Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.]]> Fri 26 Aug 2022 09:34:08 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:53849 Fri 19 Jan 2024 10:25:16 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:53055 Fri 17 Nov 2023 11:47:02 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:51705 Fri 15 Sep 2023 14:03:12 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:51706 Fri 15 Sep 2023 14:02:18 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:46943 METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.]]> Fri 09 Dec 2022 14:01:32 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:55053 Fri 05 Apr 2024 09:56:04 AEDT ]]>