Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.
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ABSTRACT:
SUBMITTER: Legge SE
PROVIDER: S-EPMC5754465 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.
| S-EPMC5065090 | biostudies-literature
Project description:BackgroundClozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN).MethodsA total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC).ResultsThe authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10-8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10-8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis.ConclusionsThe associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.
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Project description:BackgroundColorectal cancer has significant impact on individuals and healthcare systems. Many genes have been identified to influence its pathogenesis. However, the genetic basis of mucinous tumor histology, an aggressive subtype of colorectal cancer, is currently not well-known. This study aimed to identify common and rare genetic variations that are associated with the mucinous tumor phenotype.MethodsGenome-wide single nucleotide polymorphism (SNP) data was investigated in a colorectal cancer patient cohort (n = 505). Association analyses were performed for 729,373 common SNPs and 275,645 rare SNPs. Common SNP association analysis was performed using univariable and multivariable logistic regression under different genetic models. Rare-variant association analysis was performed using a multi-marker test.ResultsNo associations reached the traditional genome-wide significance. However, promising genetic associations were identified. The identified common SNPs significantly improved the discriminatory accuracy of the model for mucinous tumor phenotype. Specifically, the area under the receiver operating characteristic curve increased from 0.703 (95% CI: 0.634-0.773) to 0.916 (95% CI: 0.873-0.960) when considering the most significant SNPs. Additionally, the rare variant analysis identified a number of genetic regions that potentially contain causal rare variants associated with the mucinous tumor phenotype.ConclusionsThis is the first study applying both common and rare variant analyses to identify genetic associations with mucinous tumor phenotype using a genome-wide genotype data. Our results suggested novel associations with mucinous tumors. Once confirmed, these results will not only help us understand the biological basis of mucinous histology, but may also help develop targeted treatment options for mucinous tumors.
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Project description:Excessive fat deposition is a negative factor for poultry production because it reduces feed efficiency, increases the cost of meat production and is a health concern for consumers. We genotyped 497 birds from a Brazilian F2 Chicken Resource Population, using a high-density SNP array (600?K), to estimate the genomic heritability of fat deposition related traits and to identify genomic regions and positional candidate genes (PCGs) associated with these traits. Selection signature regions, haplotype blocks and SNP data from a previous whole genome sequencing study in the founders of this chicken F2 population were used to refine the list of PCGs and to identify potential causative SNPs. We obtained high genomic heritabilities (0.43-0.56) and identified 22 unique QTLs for abdominal fat and carcass fat content traits. These QTLs harbored 26 PCGs involved in biological processes such as fat cell differentiation, insulin and triglyceride levels, and lipid biosynthetic process. Three of these 26 PCGs were located within haplotype blocks there were associated with fat traits, five overlapped with selection signature regions, and 12 contained predicted deleterious variants. The identified QTLs, PCGs and potentially causative SNPs provide new insights into the genetic control of fat deposition and can lead to improved accuracy of selection to reduce excessive fat deposition in chickens.
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Project description:Infectious diseases still threaten global human health, and host genetic factors have been indicated as determining risk factors for observed variations in disease susceptibility, severity, and outcome. We performed a genome-wide meta-analysis on 4624 subjects from the 10,001 Dalmatians cohort, with 14 infection-related traits. Despite a rather small number of cases in some instances, we detected 29 infection-related genetic associations, mostly belonging to rare variants. Notably, the list included the genes CD28, INPP5D, ITPKB, MACROD2, and RSF1, all of which have known roles in the immune response. Expanding our knowledge on rare variants could contribute to the development of genetic panels that could assist in predicting an individual's life-long susceptibility to major infectious diseases. In addition, longitudinal biobanks are an interesting source of information for identifying the host genetic variants involved in infectious disease susceptibility and severity. Since infectious diseases continue to act as a selective pressure on our genomes, there is a constant need for a large consortium of biobanks with access to genetic and environmental data to further elucidate the complex mechanisms behind host-pathogen interactions and infectious disease susceptibility.
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Project description:Anthracnose, caused by the hemibiotrophic fungus Colletotrichum lindemuthianum, is a damaging disease of common beans that can drastically reduce crop yield. The most effective strategy to manage anthracnose is the use of resistant cultivars. There are many resistance loci that have been identified, mapped and associated with markers in common bean chromosomes. The Leucine-rich repeat kinase receptor protein (LRR-RLK) family is a diverse group of transmembrane receptors, which potentially recognizes pathogen-associated molecular patterns and activates an immune response. In this study, we performed in silico analyses to identify, classify, and characterize common bean LRR-RLKs, also evaluating their expression profile in response to the infection by C. lindemuthianum. By analyzing the entire genome of Phaseolus vulgaris, we could identify and classify 230 LRR-RLKs into 15 different subfamilies. The analyses of gene structures, conserved domains and motifs suggest that LRR-RLKs from the same subfamily are consistent in their exon/intron organization and composition. LRR-RLK genes were found along the 11 chromosomes of the species, including regions of proximity with anthracnose resistance markers. By investigating the duplication events within the LRR-RLK family, we associated the importance of such a family with an expansion resulting from a strong stabilizing selection. Promoter analysis was also performed, highlighting cis-elements associated with the plant response to biotic stress. With regard to the expression pattern of LRR-RLKs in response to the infection by C. lindemuthianum, we could point out several differentially expressed genes in this subfamily, which were associated to specific molecular patterns of LRR-RLKs. Our work provides a broad analysis of the LRR-RLK family in P. vulgaris, allowing an in-depth structural and functional characterization of genes and proteins of this family. From specific expression patterns related to anthracnose response, we could infer a direct participation of RLK-LRR genes in the mechanisms of resistance to anthracnose, highlighting important subfamilies for further investigations.
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Project description:We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
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Project description:Over the last decade, GWAS meta-analyses have used a strict P-value threshold of 5 × 10-8 to classify associations as significant. Here, we use our current understanding of frequently studied traits including lipid levels, height, and BMI to revisit this genome-wide significance threshold. We compare the performance of studies using the P = 5 × 10-8 threshold in terms of true and false positive rate to other multiple testing strategies: (1) less stringent P-value thresholds, (2) controlling the FDR with the Benjamini-Hochberg and Benjamini-Yekutieli procedure, and (3) controlling the Bayesian FDR with posterior probabilities. We applied these procedures to re-analyze results from the Global Lipids and GIANT GWAS meta-analysis consortia and supported them with extensive simulation that mimics the empirical data. We observe in simulated studies with sample sizes ∼20,000 and >120,000 that relaxing the P-value threshold to 5 × 10-7 increased discovery at the cost of 18% and 8% of additional loci being false positive results, respectively. FDR and Bayesian FDR are well controlled for both sample sizes with a few exceptions that disappear under a less stringent definition of true positives and the two approaches yield similar results. Our work quantifies the value of using a relaxed P-value threshold in large studies to increase their true positive discovery but also show the excess false positive rates due to such actions in modest-sized studies. These results may guide investigators considering different thresholds in replication studies and downstream work such as gene-set enrichment or pathway analysis. Finally, we demonstrate the viability of FDR-controlling procedures in GWAS.
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Project description:Transporter proteins play an essential role in the uptake, trafficking and storage of metals in plant tissues. The Natural Resistance-Associated Macrophage Protein (NRAMP) family plays an essential role in divalent metal transport. We conducted bioinformatics approaches to identify seven NRAMP genes in the Phaseolus vulgaris genome, investigated their phylogenetic relation, and performed transmembrane domain and gene/protein structure analyses. We found that the NRAMP gene family forms two distinct groups. One group included the PvNRAMP1, -6, and -7 genes that share a fragmented structure with a numerous exon/intron organization and encode proteins with mitochondrial or plastidial localization. The other group is characterized by few exons that encode cytoplasmic proteins. In addition, our data indicated that PvNRAMP6 and -7 may be involved in mineral uptake and mobilization in nodule tissues, while the genes PvNRAMP1, -2, -3, -4 and -5 are potentially recruited during plant development. This data provided a more comprehensive understanding of the role of NRAMP transporters in metal homeostasis in P. vulgaris.
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Project description:Multiple endocrine neoplasia type I (MEN1) is a familial cancer syndrome characterized primarily by tumors of multiple endocrine glands. The gene for MEN1 encodes a ubiquitously expressed tumor suppressor protein called menin. Menin was recently shown to interact with several components of a trithorax family histone methyltransferase complex including ASH2, Rbbp5, WDR5, and the leukemia proto-oncoprotein MLL. To elucidate menin's role as a tumor suppressor and gain insights into the endocrine-specific tumor phenotype in MEN1, we mapped the genomic binding sites of menin, MLL1, and Rbbp5, to approximately 20,000 promoters in HeLa S3, HepG2, and pancreatic islet cells using the strategy of chromatin-immunoprecipitation coupled with microarray analysis. We found that menin, MLL1, and Rbbp5 localize to the promoters of thousands of human genes but do not always bind together. These data suggest that menin functions as a general regulator of transcription. We also found that factor occupancy generally correlates with high gene expression but that the loss of menin does not result in significant changes in most transcript levels. One exception is the developmentally programmed transcription factor, HLXB9, which is overexpressed in islets in the absence of menin. Our findings expand the realm of menin-targeted genes several hundred-fold beyond that previously described and provide potential insights to the endocrine tumor bias observed in MEN1 patients.
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