Biology subjects

Curtis, D.

Publications and source records attributed to Curtis, D..

9 recordsLinked to original sources

bioRxiv2018

In silico investigation of coding variants potentially affecting the functioning of the glutamatergic N-methyl-D-aspartate receptor in schizophrenia

BackgroundSeveral lines of evidence support the hypothesis that impaired function of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) might be involved in the aetiology of schizophrenia. NMDAR is activated by phosphorylation by Fyn and there is also some evidence to suggest that abnormalities in Fyn functionality could also be involved in susceptibility to schizophrenia. In a recent weighted burden analysis of exome sequenced schizophrenia cases and controls we noted modest statistical evidence for an enrichment of rare, functional variants in FYN, GRIN1 and GRIN2B in schizophrenia cases.\n\nAimsTo test the plausibility of the hypothesis that schizophrenia susceptibility might be associated with genetic variants predicted to cause impaired functioning of NMDAR, either directly or indirectly through impairment of the kinases which phosphorylate it.\n\nMethodIn an exome sequenced sample of 4225 schizophrenia cases and 5834 controls rare variants occurring in genes for the NMDAR subunits and for the kinases acting on it were annotated. The counts of disruptive and damaging variants were compared between cases and controls and the distribution of amino acids affected by damaging variants were visualised in ProteinPaint and the RCSB Protein Data Bank. Special attention was paid to tyrosine residues subject to phosphorylation.\n\nResultsThere was no suggestion that abnormalities of the serine-threonine kinases or of Src were associated with schizophrenia. 3 cases and no controls had a disruptive variant in GRIN2A and 2 cases and no controls had a disruptive variant in FYN. 14 cases and 3 controls had damaging variants in FYN and all the variants in controls affected amino acid residues in the N-terminal region outside of any known functional domains. By contrast, 10 variants in cases affected amino acids in functional domains and in the 3D structure of Fyn two of the amino acid substitions, A376T and Q517E, were adjacent to each other. 8 cases and 1 control had damaging variants in GRIN1 but there was no obvious pattern with respect to particular functional domains being affected in this or other genes. A single case had a variant in GRIN2A affecting a well-supported phosphorylation site, Y943C, and three cases had a variant which produce an amino acid change, T216S, which lies two residues away from two well-supported phosphorylation sites. Aside from this, there was no suggestion that tyrosine phosphorylation sites in Fyn or NMDAR were affected.\n\nConclusionsThe numbers of variants involved are too small for firm conclusions to be drawn. The results are consistent with the hypothesis that about 0.5% of subjects with schizophrenia have disruptive or damaging genetic variants which could plausibly impair functioning of NMDAR directly or indirectly through impairing Fyn function.

genetics↗

bioRxiv2018

A weighted burden test using logistic regression for integrated analysis of sequence variants, copy number variants and polygenic risk score

Previously described methods of analysis allow variants in a gene to be weighted more highly according to rarity and/or predicted function and then for the variant contributions to be summed into a gene-wise risk score which can be compared between cases and controls using a t test. However this does not allow incorporating covariates into the analysis. Schizophrenia is an example of an illness where there is evidence that different kinds of genetic variation can contribute to risk, including common variants contributing to a polygenic risk score (PRS), very rare copy number variants (CNVs) and sequence variants. A logistic regression approach has been implemented to compare the gene-wise risk scores between cases and controls while incorporating as covariates population principal components, the PRS and the presence of pathogenic CNVs and sequence variants. A likelihood ratio test is performed comparing the likelihoods of logistic regression models with and without this score. The method was applied to an ethnically heterogeneous exome-sequenced sample of 6000 controls and 5000 schizophrenia cases. In the raw analysis the test statistic is inflated but inclusion of principal components satisfactorily controls for this. In this dataset the inclusion of the PRS and effect from CNVs and sequence variants had only small effects. The set of genes which are FMRP targets showed some evidence for enrichment of rare, functional variants among cases (p=0.0005). This approach can be applied to any disease in which different kinds of genetic and non-genetic risk factors make contributions to risk.

genetics↗

bioRxiv2018

Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia

BackgroundThe polygenic risk score (PRS) for schizophrenia, derived from very large numbers of weakly associated genetic markers, has been repeatedly shown to be robustly associated with schizophrenia in independent samples and also with other diseases and traits.\n\nAimsTo explore the distribution of the schizophrenia PRS in subjects of different ancestry.\n\nMethodThe schizophrenia PRS derived from the large genome-wide association study carried out by the Psychiatric Genetics Consortium was calculated using the downloaded genotypes of HapMap subjects from eleven different ancestral groups. It was also calculated using downloaded genotypes of European schizophrenia cases and controls from the CommonMind Consortium.\n\nResultsThe PRS for schizophrenia varied significantly between ancestral groups (p < 2*10-16) and was much higher in African than European HapMap subjects. The mean difference between these groups was ten times as high as the mean difference between European schizophrenia cases and controls. The distributions of scores for African and European subjects hardly overlapped.\n\nConclusionsThe PRS cannot be regarded as simply a measure of the polygenic contribution to risk of schizophrenia and clearly contains a strong ancestry component. It is possible that this could be controlled for to some extent by incorporating principal components as covariates but doubts remain as to how it should be interpreted. The PRS derived from European subjects cannot be applied to non-Europeans, limiting its potential usefulness and raising issues of inequity. Previous studies which have used the PRS should be re-examined in the light of these findings.\n\nDeclaration of interestThe author declares he has no conflict of interest.

genetics↗

bioRxiv2017

Polygenic risk score for schizophrenia is not strongly associated with the expression of specific genes or gene sets

The polygenic risk score (PRS) is derived from SNPs including both those which are genome-wide significant and also a large number of others more weakly associated with schizophrenia. Such variants are widely dispersed, though concentrated near genes expressed in the brain, and it has been proposed that these SNP associations result from impacts on cell regulatory networks which ultimately affect the expression or function of a modest number of \"core\" genes. A previous study demonstrated association of some GWAS-significant variants with expression of a number of genes, by examining pair-wise correlations of gene expression with SNP genotypes. The present study used data downloaded from the CommonMind Consortium site, consisting of SNP genotypes and RNAseq expression data from the dorsolateral prefrontal cortex, to examine whether the expression of individual genes or sets of genes correlated with PRS in 207 controls and 209 schizophrenia cases. Although the PRS was significantly associated with phenotype, the correlations with genes and genes sets followed distributions expected by chance. Thus, this analysis failed to demonstrate that the PRS captures a cumulative effect of multiple variants impacting the expression of a small number of genes and it failed to focus attention on a small number of genes of biological relevance. The multiple SNP associations observed in schizophrenia may result from other mechanisms, including effects mediated indirectly through environmental risk factors.

genetics↗

bioRxiv2017

Weighted burden analysis of exome-sequenced case-control sample implicates synaptic genes in schizophrenia aetiology

A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non-singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls. No individual variants or genes were significantly enriched in cases but 13 out of the 31 gene sets were significant after Bonferroni correction and the \"FMRP targets\" set produced a signed log p value (SLP) of 7.1. The gene within this set with the highest SLP, equal to 3.4, was FYN, which codes for a tyrosine kinase which phosphorylates glutamate metabotropic receptors and ionotropic NMDA receptors, thus modulating their trafficking, subcellular distribution and function. In the most recent GWAS of schizophrenia it was identified as a \"prioritized candidate gene\". Two of the subunits of the NMDA receptor which are substrates of FYN are coded for by GRIN1 (SLP=1.7) and GRIN2B (SLP=2.1). Of note, for some sets there was a substantial enrichment of non-singleton variants. Of 1454 GO gene sets, 3 were significant after Bonferroni correction. Identifying specific genes and variants will depend on genotyping them in larger samples and/or demonstrating that they cosegregate with illness within pedigrees.

genetics↗

bioRxiv2017

KCC1 Activation protects Mice from the Development of Experimental Cerebral Malaria.

Plasmodium falciparum malaria causes half a million deaths per year, with up to 9% of this mortality caused by cerebral malaria (CM). One of the major processes contributing to the development of CM is an excess of host inflammatory cytokines. Recently K+ signaling has emerged as an important mediator of the inflammatory response to infection; we therefore investigated whether mice carrying an ENU induced activation of the electroneutral K+ channel KCC1 had an altered response to Plasmodium berghei. Here we show that Kcc1M935K/M935K mice are protected from the development of experimental cerebral malaria, and that this protection is associated with an increased CD4+ T cells and TNF- response. This is the first description of a K+ channel affecting the development of experimental cerebral malaria.

microbiology↗

bioRxiv2017

Common variants of NRXN1, LRP1B and RORA are associated with increased ventricular volumes in psychosis - GWAS findings from the B-SNIP deep phenotyping study

Schizophrenia, Schizoaffective, and Bipolar Disorders share common illness traits, intermediate phenotypes and a partially overlapping polygenic basis. We performed GWAS on deep phenotyping data, including structural MRI and DTI, clinical, and behavioral scales from 1,115 cases and controls. Significant associations were observed with two cerebrospinal fluid volumes: the temporal horn of left lateral ventricle was associated with NRXN1, and the volume of the cavum septum pellucidum was associated with LRP1B and RORA. Both volumes were associated with illness. Suggestive associations were observed with local gyrification indices, fractional anisotropy and age at onset. The deep phenotyping approach allowed unexpected genetic sharing to be found between phenotypes, including temporal horn of left lateral ventricle and age at onset.

genetics↗

bioRxiv2017

Association study of schizophrenia with variants in miR-137 binding sites

There is strong cumulative evidence for the involvement of miR-137 and its targets in the aetiology of schizophrenia. Here we test whether variants, especially rare variants, in miR137 binding sites are associated with schizophrenia in an exome-sequenced sample of 4225 cases and 5834 controls. A weighted burden test using 372 variants was significant at p=0.024. The sample size is too small to implicate individual variants or genes but overall this finding provides further support for the hypothesis that disruption of miR-137 binding sites can increase the risk of schizophrenia, perhaps by leading to over-expression of the target gene. These findings could be followed up by genotyping these variants in larger samples and by experimentally testing whether they do indeed effect expression. When carrying out exome sequencing it is important to include UTRs so that disruption of microRNA bindings sites can be detected.

genetics↗

bioRxiv2017

Construction of an exome-wide risk score for schizophrenia based on a weighted burden test

Polygenic risk scores obtained as a weighted sum of associated variants can be used to explore association in additional data sets and to assign risk scores to individuals. The methods used to derive polygenic risk scores from common SNPs are not suitable for variants detected in whole exome sequencing studies. Rare variants which may have major effects are seen too infrequently to judge whether they are associated and may not be shared between training and test subjects. A method is proposed whereby variants are weighted according to their frequency, their annotations and to the genes they affect. A weighted sum across all variants provides an individual risk score. Scores constructed in this way are used in a weighted burden test and are shown to be significantly different between schizophrenia cases and controls using a five-way cross validation procedure. This approach represents a first attempt to summarise exome sequence variation into a summary risk score, which could be combined with risk scores from common variants and from environmental factors. It is hoped that the method could be developed further.

genetics↗