https://nova.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:40457 Wed 27 Jul 2022 11:14:03 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:20566 Wed 11 Apr 2018 10:41:17 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:38872 1, whereas schizophrenia affects men with greater frequency and severity relative to women². All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus^3,4,5,6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia⁷, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma^8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.]]> Tue 22 Feb 2022 16:36:25 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:44746 Tue 21 Mar 2023 16:53:58 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:44630 Tue 18 Oct 2022 12:11:18 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:21465 DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.]]> Sat 24 Mar 2018 07:52:31 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:18570 Sat 24 Mar 2018 07:50:10 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:29641 Sat 24 Mar 2018 07:41:54 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:42338 N = 29,125 cases and 34,836 controls), a robust polygenic signal was observed from gene sets based on TCF4, FMR1, upregulation from MIR137 and downregulation from CHD8. Additional analyses revealed a constant floor effect in the amount of variance explained, consistent with the omnigenic model. Thus, we report that putative core gene sets showed a significant effect above and beyond the floor effect that might be linked with the underlying omnigenic background. In addition, we demonstrate a method to quantify the contribution of specific gene sets within the omnigenic context.]]> Mon 22 Aug 2022 14:00:20 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:43035 Mon 12 Sep 2022 11:49:25 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:42814 Mon 05 Sep 2022 14:06:54 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:42186 n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.]]> Fri 26 Aug 2022 10:49:17 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:49142 Fri 05 May 2023 12:07:01 AEST ]]>