scholarly journals HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bettina Konte ◽  
James T. R. Walters ◽  
Dan Rujescu ◽  
Sophie E. Legge ◽  
Antonio F. Pardiñas ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Risk Allele ◽  
Effect Sizes ◽  
European Ancestry ◽  
Treatment Resistant ◽  
Allele Distribution ◽  
Association Analyses ◽  
Local Ancestry ◽  
Risk Variants ◽  
Effective Medication

AbstractThe atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.

scholarly journals Vaginal microbiome Lactobacillus crispatus is heritable among European American women

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Michelle L. Wright ◽  
Jennifer M. Fettweis ◽  
Lindon J. Eaves ◽  
Judy L. Silberg ◽  
Michael C. Neale ◽  
...  
Keyword(s):  
Genetic Factors ◽  
European Ancestry ◽  
P Value ◽  
European American ◽  
Extrinsic Factors ◽  
American Women ◽  
Lactobacillus Crispatus ◽  
Host Genetic ◽  
Host Genetic Factors ◽  
European American Women

AbstractThe diversity and dominant bacterial taxa in the vagina are reported to be influenced by multiple intrinsic and extrinsic factors, including but not limited to pregnancy, contraceptive use, pathogenic states, socioeconomic status, and ancestry. However, the extent to which host genetic factors influence variation in the vaginal microbiota is unclear. We used a biometrical genetic approach to determine whether host genetic factors contribute to inter-individual differences in taxa from a sample of 332 twins who self-identified as being of African (44 pairs) or European ancestry (122 pairs). Lactobacillus crispatus, a major determinant of vaginal health, was identified as heritable among European American women (narrow-sense heritability = 34.7%, P-value = 0.018). Heritability of L. crispatus is consistent with the reduced prevalence of adverse reproductive disorders, including bacterial vaginosis and preterm birth, among women of European ancestry.

scholarly journals Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans

Leukemia ◽  
2021 ◽  
Author(s):  
Geffen Kleinstern ◽  
J. Brice Weinberg ◽  
Sameer A. Parikh ◽  
Esteban Braggio ◽  
Sara J. Achenbach ◽  
...  
Keyword(s):  
Environmental Factors ◽  
B Cell ◽  
Risk Score ◽  
Genetic Factors ◽  
Strong Predictor ◽  
Lymphocytic Leukemia ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
C Statistic

AbstractMonoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10−29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10−63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10−5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

scholarly journals Putting RFMix and ADMIXTURE to the test in a complex admixed population

2020 ◽  
Author(s):  
Caitlin Uren ◽  
Eileen G. Hoal ◽  
Marlo Möller
Keyword(s):  
World Wide ◽  
Association Studies ◽  
Structured Populations ◽  
Human Populations ◽  
Computational Tools ◽  
Association Analyses ◽  
Local Ancestry ◽  
Diverse World ◽  
Admixed Population ◽  
Global And Local

Abstract Background Global and local ancestry inference in admixed human populations can be performed using computational tools implementing distinct algorithms. The development and resulting accuracy of these tools has been tested largely on populations with relatively straightforward admixture histories but little is known about how well they perform in more complex admixture scenarios. Results Using simulations, we show that RFMix outperforms ADMIXTURE in determining global ancestry proportions even in a complex 5-way admixed population, in addition to assigning local ancestry with an accuracy of 89%. The ability of RFMix to determine global and local ancestry to a high degree of accuracy, particularly in admixed populations provides the opportunity for more accurate association analyses. Conclusion This study highlights the utility of the extension of computational tools to become more compatible to genetically structured populations, as well as the need to expand the sampling of diverse world-wide populations. This is particularly noteworthy as modern-day societies are becoming increasingly genetically complex and some genetic tools and commonly used ancestral populations are less appropriate. Based on these caveats and the results presented here, we suggest that RFMix be used for both global and local ancestry estimation in world-wide complex admixture scenarios particularly when including these estimates in association studies.

scholarly journals Genome-wide study on the polysomic genetic factors conferring plasticity of flower sexuality in hexaploid persimmon

DNA Research ◽  
2020 ◽  
Vol 27 (3) ◽  
Author(s):  
Kanae Masuda ◽  
Eiji Yamamoto ◽  
Kenta Shirasawa ◽  
Noriyuki Onoue ◽  
Atsushi Kono ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Diospyros Kaki ◽  
Dependent Manner ◽  
Male And Female ◽  
Association Analyses ◽  
Genome Wide ◽  
Allele Dosage ◽  
Partial Inactivation ◽  
In Cis ◽  
Segregating Population

Abstract Sexuality is one of the fundamental mechanisms that work towards maintaining genetic diversity within a species. In diploid persimmons (Diospyros spp.), separated sexuality, the presence of separate male and female individuals (dioecy), is controlled by the Y chromosome-encoded small-RNA gene, OGI. On the other hand, sexuality in hexaploid Oriental persimmon (Diospyros kaki) is more plastic, with OGI-bearing genetically male individuals, able to produce both male and female flowers (monoecy). This is thought to be linked to the partial inactivation of OGI by a retrotransposon insertion, resulting in DNA methylation of the OGI promoter region. To identify the genetic factors regulating branch sexual conversion, genome-wide correlation/association analyses were conducted using ddRAD-Seq data from an F1 segregating population, and using both quantitative and diploidized genotypes, respectively. We found that allelic ratio at the Y-chromosomal region, including OGI, was correlated with male conversion based on quantitative genotypes, suggesting that OGI can be activated in cis in a dosage-dependent manner. Genome-wide association analysis based on diploidized genotypes, normalized for the effect of OGI allele dosage, detected three fundamental loci associated with male conversion. These loci underlie candidate genes, which could potentially act epigenetically for the activation of OGI expression.

scholarly journals Genome-wide association analyses identify two susceptibility loci for pachychoroid disease central serous chorioretinopathy

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Yoshikatsu Hosoda ◽  
Masahiro Miyake ◽  
Rosa L. Schellevis ◽  
Camiel J. F. Boon ◽  
Carel B. Hoyng ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Central Serous Chorioretinopathy ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association ◽  
Susceptibility Loci ◽  
Association Analyses ◽  
Age Related ◽  
Genome Wide

AbstractThe recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13,029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10−13; rs6061548, odds ratio = 1.63, P = 5.36 × 10−15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD.

scholarly journals Germline Genetic Factors Influence Outcome of Interferon Alpha Therapy in Polycythemia Vera

Blood ◽  
2020 ◽  
Author(s):  
Roland Jäger ◽  
Heinz Gisslinger ◽  
Elisabeth Fuchs ◽  
Edith Bogner ◽  
Jelena D. Milosevic Feenstra ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Interferon Alpha ◽  
Genetic Factors ◽  
Myeloproliferative Neoplasms ◽  
Association Studies ◽  
Study Cohort ◽  
Molecular Response ◽  
Genome Wide Association Studies ◽  
Association Analyses ◽  
Genome Wide

Interferon alpha (IFNα) based therapies can induce hematologic and molecular responses in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have previously been implicated in differential drug response. We addressed the effect of common germline polymorphisms on hematologic and molecular response (HR/MR) in PV therapy within the PROUD-PV and CONTINUATION-PV studies including 122 patients with PV receiving ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over 36 months follow-up did not reveal any associations at genome-wide significance. Further, we performed targeted association analyses at the interferon lambda 4 (IFNL4) locus, well known for its role in hepatitis C viral clearance and recently reported to influence HR during therapy of myeloproliferative neoplasms. While we did not observe any association of IFNL4 polymorphisms with HR in our study cohort, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair including the protein-coding variants rs368234815/rs117648444) on MR (p=3.91x10-4; OR=10.80; 95%CI:[2.39-69.97]) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of PV patients based on IFNL4 functionality may allow for optimizing patient management during IFNα treatment.

scholarly journals Clinical and Genetic Factors Associated with Resistance to Treatment in Patients with Schizophrenia: A Case-Control Study

2019 ◽  
Vol 20 (19) ◽  
pp. 4753 ◽  
Author(s):  
Aline Hajj ◽  
Sahar Obeid ◽  
Saria Sahyoun ◽  
Chadia Haddad ◽  
Jocelyne Azar ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Case Control Study ◽  
Rating Scale ◽  
Multivariable Analysis ◽  
Case Control ◽  
Response To Treatment ◽  
Treatment Resistant ◽  
Factors Associated ◽  
Resistance To Treatment ◽  
Control Study

Objectives: To assess clinical and genetic factors affecting response to treatment in a sample of patients with schizophrenia (treatment-resistant patients versus treatment responders). We also aimed at examining if these factors are different when we consider two different resistance classifications (the positive and negative syndrome scale, PANSS and the brief psychiatric rating scale, BPRS). Material and Methods: A case-control study included treatment-resistant patients and good responders. Patients were stratified in two groups based on the established criteria for treatment-resistant schizophrenia using BPRS and PANSS. The study was approved by the ethical committees (references: CEHDF1017; HPC-017-2017) and all patients/legal representatives gave their written consent. Clinical factors were assessed. DNA was obtained using a buccal swab and genotyping for OPRM1, COMT, DRD2 et MTHFR genes using the Lightcycler® (Roche). Results: Some discrepancies between the BPRS and PANSS definitions were noted in our study when assessing the patients’ psychopathological symptoms and response to treatment. The multivariable analysis, taking the presence versus absence of treatment resistance as the dependent variable, showed that that family history of schizophrenia, university studies, time since the beginning of treatment and chlorpromazine equivalent dose as well as the COMT gene are associated with resistance to treatment. In addition, a gender-related difference was noted for COMT SNP; men with at least one Met allele were more prone to be resistant to treatment than Val/Val patients. Conclusion: Uncovering the clinical and genetic factors associated with resistance to treatment could help us better treat our schizophrenic patients in a concept of personalized medicine.

scholarly journals Genetic Analysis of LRRK2 R1628P in Parkinson’s Disease in Asian Populations

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Yuan Zhang ◽  
Qiying Sun ◽  
Minhan Yi ◽  
Xun Zhou ◽  
Jifeng Guo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Chinese Population ◽  
Genetic Factors ◽  
Meta Analysis ◽  
Asian Population ◽  
High Quality ◽  
Asian Populations ◽  
Risk Variants

Although the etiology of Parkinson’s disease (PD) remains unclear, there is increasing evidence of genetic factors contributing to the onset of PD. Various mutations and risk variants of the gene LRRK2 have been reported, but the association between LRRK2 R1628P and PD is still inconsistent. Thus, we conducted a meta-analysis to determine the potential relationship between R1628P and PD. Our study sample was an aggregate of 17 publications, which in total consisted of 9,275 PD patients and 8,114 controls. All of these articles are of high quality according to NOS, and there was no obvious reporting bias or heterogeneity. In a general Asian population, the pooled OR of the risk genotype contrasts was 1.83 (95% CI: 1.57, 2.13). When stratified by ethnicity, the pooled ORs were 1.84 (95% CI: 1.56, 2.18) in a Chinese population and 1.79 (95% CI: 1.27, 2.52) in a non-Chinese population. Our study suggests that LRRK2 R1628P appears to be a risk factor for PD in Asian populations, both Chinese and non-Chinese.

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