https://nova.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:43392 Wed 22 Mar 2023 15:32:42 AEDT ]]> 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:44630 Tue 18 Oct 2022 12:11:18 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:20380 g) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of h²_g from imputed SNPs (5.1× enrichment; p = 3.7 × 10⁻¹⁷) and 38% (SE = 4%) of h²_g from genotyped SNPs (1.6× enrichment, p = 1.0 × 10⁻⁴). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of h²_g despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.]]> Sat 24 Mar 2018 07:58:12 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:23306 Sat 24 Mar 2018 07:16:19 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 ]]>