Queensland Institute of Medical Research Berghofer Medical Research Institute
Queensland Institute of Medical Research Berghofer Medical Research Institute
PubMed | University of Groningen, Queensland Institute of Medical Research Berghofer Medical Research Institute and University of Queensland
Type: | Journal: Human molecular genetics | Year: 2016
The mitochondrial and nuclear genomes coordinate and co-evolve in eukaryotes in order to adapt to environmental changes. Variation in the mitochondrial genome is capable of affecting expression of genes on the nuclear genome. Sex-specific mitochondrial genetic control of gene expression has been demonstrated in Drosophila melanogaster, where males were found to drive most of the total variation in gene expression. This has potential implications for male-related health and disease resulting from variation in mtDNA solely inherited from the mother. We used a family-based study comprised of 47,323 gene expression probes and 78 mitochondrial SNPs (mtSNPs) from n = 846 individuals to examine the extent of mitochondrial genetic control of gene expression in humans. This identified 15 significant probe-mtSNP associations (P < 10
PubMed | University of Turku, Key Laboratory of Metabolism and Molecular Medicine, Finnish Institute of Occupational Health, St George's, University of London and 43 more.
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2016
Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified -Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 10
Markey K.A.,Queensland Institute of Medical Research Berghofer Medical Research Institute |
Markey K.A.,Royal Brisbane and Womens Hospital |
MacDonald K.P.A.,Queensland Institute of Medical Research Berghofer Medical Research Institute |
Hill G.R.,Queensland Institute of Medical Research Berghofer Medical Research Institute |
Hill G.R.,Royal Brisbane and Womens Hospital
Blood | Year: 2014
The last 6 decades have seen major advances in the understanding of immunologic diseases, driven by preclinical animal models. Indeed, bone marrow transplantation (BMT) has its genesis in rodentmodels dating back to the 1950s. Allogeneic BMT and its major complication, graft-versushostdisease (GVHD), representaparadigm for the translation of preclinical concepts into clinical practice. The appreciation that GVHD can be thought of as a stepwise escalation in immune activation characterized by eventual massive target tissue apoptosis has allowed the design of rational approaches to better manage patients. Here, we describe the pathophysiology of GVHD as defined in preclinical models, focusing on the successes and failures of this research to instruct and translate clinical practice. We also provide a commentary on the limitations of these models so that they may be better appreciated and addressed in future studies. Notable preclinical successes include the definition of modern immune suppression, reductions in conditioning intensity, posttransplant cyclophosphamide, and the promotion of regulatory T-cell reconstitution. New strategies including naïve T-cell depletion, focused cytokine and chemokine inhibition, and the blockade of costimulation now also appear highly promising and very likely to translate into patients in the near future. © 2014 by The American Society of Hematology.
PubMed | Stockholm School of Economics, Karolinska Institutet, Queensland Institute of Medical Research Berghofer Medical Research Institute, University of Queensland and 10 more.
Type: Journal Article | Journal: Psychological science | Year: 2014
A recent genome-wide-association study of educational attainment identified three single-nucleotide polymorphisms (SNPs) whose associations, despite their small effect sizes (each R (2) 0.02%), reached genome-wide significance (p < 5 10(-8)) in a large discovery sample and were replicated in an independent sample (p < .05). The study also reported associations between educational attainment and indices of SNPs called polygenic scores. In three studies, we evaluated the robustness of these findings. Study 1 showed that the associations with all three SNPs were replicated in another large (N = 34,428) independent sample. We also found that the scores remained predictive (R (2) 2%) in regressions with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered genome-wide-association studies can identify replicable genetic associations with behavioral traits. The small effect sizes of individual SNPs are likely to be a major contributing factor explaining the striking contrast between our results and the disappointing replication record of most candidate-gene studies.
PubMed | Queensland Institute of Medical Research Berghofer Medical Research Institute, Walter and Eliza Hall Institute of Medical Research, Leiden University, Queensland University of Technology and 3 more.
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2015
Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic repressor with described roles in X inactivation and genomic imprinting, but Smchd1 is also critically involved in the pathogenesis of facioscapulohumeral dystrophy. The underlying molecular mechanism by which Smchd1 functions in these instances remains unknown. Our genome-wide transcriptional and epigenetic analyses show that Smchd1 binds cis-regulatory elements, many of which coincide with CCCTC-binding factor (Ctcf) binding sites, for example, the clustered protocadherin (Pcdh) genes, where we show Smchd1 and Ctcf act in opposing ways. We provide biochemical and biophysical evidence that Smchd1-chromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. Our results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonize Ctcf-facilitated chromatin interactions, resulting in coordinated transcriptional control.
PubMed | Washington University in St. Louis, Queensland Institute of Medical Research Berghofer Medical Research Institute, University of New South Wales, University of Western Australia and 3 more.
Type: Journal Article | Journal: Biological psychiatry | Year: 2015
No opioid receptor, mu 1 (OPRM1) gene polymorphisms, including the functional single nucleotide polymorphism (SNP) rs1799971, have been conclusively associated with heroin/other opioid addiction, despite their biological plausibility. We used evidence of polymorphisms altering OPRM1 expression in normal human brain tissue to nominate and then test associations with heroin addiction.We tested 103 OPRM1 SNPs for association with OPRM1 messenger RNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-expression quantitative trait loci (cis-eQTL) SNPs for association with heroin addiction in the Urban Health Study and two replication cohorts, totaling 16,729 European Americans, African Americans, and Australians of European ancestry.Four putative cis-eQTL SNPs were significantly associated with heroin addiction in the Urban Health Study (smallest p = 8.9 10(-5)): rs9478495, rs3778150, rs9384169, and rs562859. Rs3778150, located in OPRM1 intron 1, was significantly replicated (p = 6.3 10(-5)). Meta-analysis across all case-control cohorts resulted in p = 4.3 10(-8): the rs3778150-C allele (frequency = 16%-19%) being associated with increased heroin addiction risk. Importantly, the functional SNP allele rs1799971-A was associated with heroin addiction only in the presence of rs3778150-C (p = 1.48 10(-6) for rs1799971-A/rs3778150-C and p = .79 for rs1799971-A/rs3778150-T haplotypes). Lastly, replication was observed for six other intron 1 SNPs that had prior suggestive associations with heroin addiction (smallest p = 2.7 10(-8) for rs3823010).Our findings show that common OPRM1 intron 1 SNPs have replicable associations with heroin addiction. The haplotype structure of rs3778150 and nearby SNPs may underlie the inconsistent associations between rs1799971 and heroin addiction.