scholarly journals Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients—a genome-wide association study adjusting for smoking habits

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Robert Løvsletten Smith ◽  
Kevin O’Connell ◽  
Lavinia Athanasiu ◽  
Srdjan Djurovic ◽  
Marianne Kristiansen Kringen ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Smoking Habits ◽  
Serum Concentrations ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Novel Variant

Abstract Clozapine (CLZ) is the superior antipsychotic drug for treatment of schizophrenia, but exhibits an extensive interpatient pharmacokinetic variability. Here, we conducted a genome-wide association study (GWAS) of CLZ serum concentration adjusting for known smoking habits, which is a major nongenetic factor reducing CLZ levels. The study included 484 patients with 10,283 steady-state serum concentrations of CLZ and N-desmethylclozapine, prescribed dosing, co-medications and known smoking habits (n = 422; 9284 serum samples) from a therapeutic drug monitoring (TDM) service. The GWAS analyses were performed with and without smoking habits as covariate, where possible hits were assessed in relation to the target CLZ concentration range applied in the TDM service (300–2500 nmol/L). The smoking-independent analysis of N-desmethylclozapine serum concentration and the CLZ-to-N-desmethylclozapine ratio replicated the previously identified locus on chromosome 4. After adjusting for smoking habits in patients confirmed as ‘smokers’ (61%) or ‘nonsmokers’ (39%), a novel variant (rs28379954; minor T>C allele frequency 4.1%; 7.6% CT carriers in the population) within the gene encoding the nuclear factor 1 B-type (NFIB) was significantly associated with reduced CLZ serum concentration (p = 1.68 × 10−8, beta = −0.376; explained variance 7.63%). There was no significant association between rs28379954 and N-desmethylclozapine concentration in the GWAS analysis (p = 5.63 × 10−5). The fraction of CLZ TDM samples below 300 nmol/L was significantly higher in carriers vs. noncarriers of the rs28379954 minor C allele [12.0% (95% CI: 9.4–14.7) vs. 6.2% (95% CI: 5.7–6.8), p < 0.001]. We identified a novel variant in the NFIB gene associated with reduced CLZ levels and increased risk of subtherapeutic serum concentrations. This warrants testing of clinical relevance of screening for this gene variant, and also experimental studies to investigate the biological mechanisms of NFIB involvement in CLZ pharmacokinetics.

scholarly journals Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population

2021 ◽  
Vol 118 (11) ◽  
pp. e2004199118
Author(s):  
Marina Penova ◽  
Shuji Kawaguchi ◽  
Jun-ichirou Yasunaga ◽  
Takahisa Kawaguchi ◽  
Tomoo Sato ◽  
...  
Keyword(s):  
Amino Acid ◽  
Association Study ◽  
Proviral Load ◽  
Odds Ratio ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

HTLV-1–associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10−9) and class II (P = 1.21 × 10−8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C*07:02 (P = 2.61 × 10−5), HLA-B*07:02 (P = 4.97 × 10−10), HLA-DRB1*01:01 (P = 1.15 × 10−9) and HLA-DQB1*05:01 (P = 2.30 × 10−9) were associated with disease risk, while HLA-B*40:06 (P = 3.03 × 10−5), HLA-DRB1*15:01 (P = 1.06 × 10−5) and HLA-DQB1*06:02 (P = 1.78 × 10−6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10−10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.

scholarly journals The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response

2015 ◽  
Vol 5 (4) ◽  
pp. e553-e553 ◽  
Author(s):  
J M Biernacka ◽  
K Sangkuhl ◽  
G Jenkins ◽  
R M Whaley ◽  
P Barman ◽  
...  
Keyword(s):  
Association Study ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Genome Wide Association Study ◽  
Transmembrane Domain ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Research Network ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Abstract Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E−08) and SNPs 5’ upstream of the neuregulin-1 gene, NRG1 (P=1.20E−06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

scholarly journals Correction: Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients—a genome-wide association study adjusting for smoking habits

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Robert Løvsletten Smith ◽  
Kevin O’Connell ◽  
Lavinia Athanasiu ◽  
Srdjan Djurovic ◽  
Marianne Kristiansen Kringen ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Smoking Habits ◽  
Clozapine Concentration ◽  
Genome Wide ◽  
A Genome

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Correction: Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma: A Genome-Wide Association Study

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0130109 ◽  
Author(s):  
Giuseppe Matullo ◽  
Simonetta Guarrera ◽  
Marta Betti ◽  
Giovanni Fiorito ◽  
Daniela Ferrante ◽  
...  
Keyword(s):  
Association Study ◽  
Malignant Pleural Mesothelioma ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Pleural Mesothelioma ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

scholarly journals Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma: A Genome-Wide Association Study

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e61253 ◽  
Author(s):  
Giuseppe Matullo ◽  
Simonetta Guarrera ◽  
Marta Betti ◽  
Giovanni Fiorito ◽  
Daniela Ferrante ◽  
...  
Keyword(s):  
Association Study ◽  
Malignant Pleural Mesothelioma ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Pleural Mesothelioma ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

PSIV-16 Genome-wide association study of Rambouillet rams with angular limb deformities

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 301-302
Author(s):  
Gabrielle M Becker ◽  
Morgan R Stegemiller ◽  
Christopher S S Schauer ◽  
Whit C C Stewart ◽  
Brenda M Murdoch
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Principal Component ◽  
Genome Wide Association ◽  
P Value ◽  
Genetic Associations ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Limb Deformities

Abstract Lameness and limb deformities can be detrimental to range and breeding sheep. Growing animals are at an increased risk of angular limb deformities (ALD) and lameness, which adversely affects their mobility, breeding soundness and ultimately longevity. Ram testing allows developing ram lambs from different farms to be evaluated together under a consistent nutritive and environment management system. The aim of this study is to investigate rams from four ram test cohorts (North Dakota State University and University of Wyoming in two consecutive years) for genetic associations with ALD occurrence. In total 131 Rambouillet rams, including 17 ALD-affected and 114 unaffected, were genotyped using AxiomTM Ovine Genotyping Array (50K). A genome-wide association study was conducted using a recessive chi-square model with correction by principal component analysis (eigenstrat). A marker on chromosome eight is significantly (unadjusted P-value= 1.74e-08) associated with the incidence of ALD. This marker is located within the gene; branched chain keto acid dehydrogenase E1 subunit beta (BCKDHB). BCKDHB is associated with mitochondrial membranes and metabolism which is required for effective bone (osteoblast and chondrocytes) formation. It is proposed that altered branched amino acid metabolism in rapidly growing sheep with this genotype may impart risk of limb deformities classified as ALD. Identifying genetic associations with ALD in sheep may help detect animals with a higher propensity for ALD, which would provide producers with additional tools to make informed management and breeding decisions.

scholarly journals CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children’s Oncology Group Genome-Wide Association Study

2016 ◽  
Vol 34 (8) ◽  
pp. 863-870 ◽  
Author(s):  
Xuexia Wang ◽  
Can-Lan Sun ◽  
Adolfo Quiñones-Lombraña ◽  
Purnima Singh ◽  
Wendy Landier ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Dose Dependent

Purpose Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests that genetic susceptibility could play a role. The current study uses an agnostic approach to identify genetic variants that could modify cardiomyopathy risk. Methods A genome-wide association study was conducted in childhood cancer survivors with and without cardiomyopathy (cases and controls, respectively). Single-nucleotide polymorphisms (SNPs) that surpassed a prespecified threshold for statistical significance were independently replicated. The possible mechanistic significance of validated SNP(s) was sought by using healthy heart samples. Results No SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10−5). Multivariable analyses adjusted for age at cancer diagnosis, sex, anthracycline dose, and chest radiation revealed that, among patients with the A allele, cardiomyopathy was infrequent and not dose related. However, among those exposed to greater than 300 mg/m2 of anthracyclines, the rs1786814 GG genotype conferred a 10.2-fold (95% CI, 3.8- to 27.3-fold; P < .001) increased risk of cardiomyopathy compared with those who had GA/AA genotypes and anthracycline exposure of 300 mg/m2 or less. This gene-environment interaction was successfully replicated in an independent set of anthracycline-related cardiomyopathy. CUG-BP and ETR-3-like factor proteins control developmentally regulated splicing of TNNT2, the gene that encodes for cardiac troponin T (cTnT), a biomarker of myocardial injury. Coexistence of more than one cTnT variant results in a temporally split myofilament response to calcium, which causes decreased contractility. Analysis of TNNT2 splicing variants in healthy human hearts suggested an association between the rs1786814 GG genotype and coexistence of more than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P = .005). Conclusion We report a modifying effect of a polymorphism of CELF4 (rs1786814) on the dose-dependent association between anthracyclines and cardiomyopathy, which possibly occurs through a pathway that involves the expression of abnormally spliced TNNT2 variants.

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