Genetic risk of clozapine-induced leukopenia and neutropenia: a genome-wide association study

Abstract Background Clozapine 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). Methods A 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). Results The 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. Conclusions The 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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Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-215521 ◽

2019 ◽

Vol 78 (10) ◽

pp. 1430-1437 ◽

Cited By ~ 14

Author(s):

Yusuke Kawamura ◽

Hirofumi Nakaoka ◽

Akiyoshi Nakayama ◽

Yukinori Okada ◽

Ken Yamamoto ◽

...

Keyword(s):

Association Study ◽

Molecular Mechanisms ◽

Genome Wide Association Study ◽

Serum Uric Acid Level ◽

Meta Analysis ◽

Genome Wide Association ◽

Significance Level ◽

Replication Studies ◽

Genome Wide ◽

First Time

ObjectiveThe first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout.MethodsWe carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia).ResultsThis new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10–8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three ‘gout vs AHUA GWAS’-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level.ConclusionsThis meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

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Genome wide association study of plant height and tiller number in hulless barley

PLoS ONE ◽

10.1371/journal.pone.0260723 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0260723

Author(s):

Yixiong Bai ◽

Xiaohong Zhao ◽

Xiaohua Yao ◽

Youhua Yao ◽

Likun An ◽

...

Keyword(s):

Association Study ◽

Plant Height ◽

Molecular Mechanisms ◽

Genome Wide Association Study ◽

Tiller Number ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Hulless Barley ◽

Genome Wide ◽

A Genome

Hulless barley (Hordeum vulgare L. var. nudum), also called naked barley, is a unique variety of cultivated barley. The genome-wide specific length amplified fragment sequencing (SLAF-seq) method is a rapid deep sequencing technology that is used for the selection and identification of genetic loci or markers. In this study, we collected 300 hulless barley accessions and used the SLAF-seq method to identify candidate genes involved in plant height (PH) and tiller number (TN). We obtained a total of 1407 M paired-end reads, and 228,227 SLAF tags were developed. After filtering using an integrity threshold of >0.8 and a minor allele frequency of >0.05, 14,504,892 single-nucleotide polymorphisms (SNP) loci were screened out. The remaining SNPs were used for the construction of a neighbour-joining phylogenetic tree, and the three subcluster members showed no obvious differentiation among regional varieties. We used a genome wide association study approach to identify 1006 and 113 SNPs associated with TN and PH, respectively. Based on best linear unbiased predictors (BLUP), 41 and 29 SNPs associated with TN and PH, respectively. Thus, several of genes, including Hd3a and CKX5, may be useful candidates for the future genetic breeding of hulless barley. Taken together, our results provide insight into the molecular mechanisms controlling barley architecture, which is important for breeding and yield.

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A genome-wide association study of reproduction traits in four pig populations with different genetic backgrounds

Asian-Australasian Journal of Animal Sciences ◽

10.5713/ajas.19.0411 ◽

2020 ◽

Vol 33 (9) ◽

pp. 1400-1410

Author(s):

Yao Jiang ◽

Shaoqing Tang ◽

Wei Xiao ◽

Peng Yun ◽

Xiangdong Ding

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Multiple Trait ◽

Multiple Populations ◽

Genome Wide ◽

A Genome ◽

Reproduction Traits

Objective: Genome-wide association study and two meta-analysis based on GWAS performed to explore the genetic mechanism underlying variation in pig number born alive (NBA) and total number born (TNB).Methods: Single trait GWAS and two meta-analysis (single-trait meta analysis and multitrait meta analysis) were used in our study for NBA and TNB on 3,121 Yorkshires from 4 populations, including three different American Yorkshire populations (n = 2,247) and one British Yorkshire populations (n = 874).Results: The result of single trait GWAS showed that no significant associated single nucleotide polymorphisms (SNPs) were identified. Using single-trait meta analysis and multi-trait meta analysis within populations, 11 significant loci were identified associated with target traits. Spindlin 1, vascular endothelial growth factor A, forkhead box Q1, msh homeobox 1, and LHFPL tetraspan submily member 3 are five functionally plausible candidate genes for NBA and TNB. Compared to the single population GWAS, single-trait Meta analysis can improve the detection power to identify SNPs by integrating information of multiple populations. The multiple-trait analysis reduced the power to detect trait-specific loci but enhanced the power to identify the common loci across traits.Conclusion: In total, our findings identified novel genes to be validated as candidates for NBA and TNB in pigs. Also, it enabled us to enlarge population size by including multiple populations with different genetic backgrounds and increase the power of GWAS by using meta analysis.

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Faculty Opinions recommendation of Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718310292.793531798 ◽

2017 ◽

Author(s):

Erik Melen

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Association Study ◽

Pulmonary Disease ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Genome Wide ◽

A Genome

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Genome-Wide Association Study (GWAS) for Examining the Genomics Controlling Prickle Production in Red Raspberry (Rubus idaeus L.)

Agronomy ◽

10.3390/agronomy11010027 ◽

2020 ◽

Vol 11 (1) ◽

pp. 27

Author(s):

Archana Khadgi ◽

Courtney A. Weber

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genomic Region ◽

Rubus Idaeus ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Red Raspberry ◽

Genome Wide ◽

A Genome ◽

Genotype By Sequencing

Red raspberry (Rubus idaeus L.) is an expanding high-value berry crop worldwide. The presence of prickles, outgrowths of epidermal tissues lacking vasculature, on the canes, petioles, and undersides of leaves complicates both field management and harvest. The utilization of cultivars with fewer prickles or prickle-free canes simplifies production. A previously generated population segregating for prickles utilizing the s locus between the prickle-free cultivar Joan J (ss) and the prickled cultivar Caroline (Ss) was analyzed to identify the genomic region associated with prickle development in red raspberry. Genotype by sequencing (GBS) was combined with a genome-wide association study (GWAS) using fixed and random model circulating probability unification (FarmCPU) to analyze 8474 single nucleotide polymorphisms (SNPs) and identify significant markers associated with the prickle-free trait. A total of four SNPs were identified on chromosome 4 that were associated with the phenotype and were located near or in annotated genes. This study demonstrates how association genetics can be used to decipher the genetic control of important horticultural traits in Rubus, and provides valuable information about the genomic region and potential genes underlying the prickle-free trait.

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Three New Single Nucleotide Polymorphisms Identified by a Genome-Wide Association Study in Korean Patients with Vitiligo

Journal of Korean Medical Science ◽

10.3346/jkms.2013.28.5.775 ◽

2013 ◽

Vol 28 (5) ◽

pp. 775 ◽

Cited By ~ 11

Author(s):

Kyung Ah Cheong ◽

Nan-Hyung Kim ◽

Minsoo Noh ◽

Ai-Young Lee

Keyword(s):

Single Nucleotide Polymorphisms ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Korean Patients ◽

Genome Wide ◽

A Genome

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Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies

Placenta ◽

10.1016/j.placenta.2018.04.008 ◽

2018 ◽

Vol 66 ◽

pp. 8-16 ◽

Cited By ~ 2

Author(s):

Tsegaselassie Workalemahu ◽

Daniel A. Enquobahrie ◽

Bizu Gelaye ◽

Sixto E. Sanchez ◽

Pedro J. Garcia ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Placental Abruption ◽

Association Studies ◽

Meta Analysis ◽

Genetic Variations ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

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Abstract 4437: Genome-Wide Association Study for the Response to Antihypertensive Medication: HOMED-BP-GENE Study

Circulation ◽

10.1161/circ.118.suppl_18.s_890 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Tomohiro Katsuya ◽

Kei Asayama ◽

Ryusuke Inoue ◽

Ken Sugimoto ◽

Takayoshi Ohkubo ◽

...

Keyword(s):

Association Study ◽

Antihypertensive Medication ◽

Genome Wide Association Study ◽

Early Morning ◽

Home Blood Pressure ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

A Genome ◽

Drug Responsiveness

AAntihypertensive therapy is a powerful approach to prevent the cardiovascular disease. However, the responsiveness of the therapy is highly individual due to the variability of genetic or environmental factors. To elucidate the genetic background underlying antihypertensive drug responsiveness, we carried out a genome-wide association study (GWAS). The subjects studied were recruited from the participants of HOMED-BP study (UMIN Registered ID C000000137, http://www.cpt.med.tohoku.ac.jp/HOMED-BP/) after obtaining the informed consent for the genetic analysis. After DNA extraction from peripheral blood, about half million single nucleotide polymorphisms (SNPs) were examined using GeneChip Genome-Wide Human SNP5.0 Array (Affymetrix). Home blood pressure (HBP) was measured every day within 1 hour after wake-up and before going to bed using HEM747-IC-N (Omron). The study protocol was approved by the ethical committee of Osaka University. SNP5.0 Array analysis was demonstrated for 300 participants. Antihypertensive therapy for 4weeks decreased their average HBP from 149.9/88.8mmHg to 137.7/82.2mmHg in early morning and 142.6/82.3mmHg to 129.1/74.7mmHg before going to bed. We excluded the SNPs data that showed low call rate, lack of Hardy-Weinberg’s equilibrium and minor allele frequency less than 0.05. Eight SNPs were significantly (p<0.001) associated with mean HBP reduction both in the early morning and at bedtime. Nine SNPs were more significantly (p<0.0001) associated with morning HBP reduction and 3 SNPs were associated with bedtime HBP reduction. In conclusion, GWAS of antihypertensive medication revealed several candidate loci responsible for a month therapy with the difference between morning and evening.

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Genome-Wide Association Study of Metabolic Syndrome Reveals Primary Genetic Variants at CETP Locus in Indians

Biomolecules ◽

10.3390/biom9080321 ◽

2019 ◽

Vol 9 (8) ◽

pp. 321 ◽

Cited By ~ 3

Author(s):

Gauri Prasad ◽

Khushdeep Bandesh ◽

Anil Giri ◽

Yasmeen Kauser ◽

Prakriti Chanda ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Rapid Urbanization ◽

Significance Level ◽

Genome Wide ◽

A Genome ◽

Replication Phase

Indians, a rapidly growing population, constitute vast genetic heterogeneity to that of Western population; however they have become a sedentary population in past decades due to rapid urbanization ensuing in the amplified prevalence of metabolic syndrome (MetS). We performed a genome-wide association study (GWAS) of MetS in 10,093 Indian individuals (6617 MetS and 3476 controls) of Indo-European origin, that belong to our previous biorepository of The Indian Diabetes Consortium (INDICO). The study was conducted in two stages—discovery phase (N = 2158) and replication phase (N = 7935). We discovered two variants within/near the CETP gene—rs1800775 and rs3816117—associated with MetS at genome-wide significance level during replication phase in Indians. Additional CETP loci rs7205804, rs1532624, rs3764261, rs247617, and rs173539 also cropped up as modest signals in Indians. Haplotype association analysis revealed GCCCAGC as the strongest haplotype within the CETP locus constituting all seven CETP signals. In combined analysis, we perceived a novel and functionally relevant sub-GWAS significant locus—rs16890462 in the vicinity of SFRP1 gene. Overlaying gene regulatory data from ENCODE database revealed that single nucleotide polymorphism (SNP) rs16890462 resides in repressive chromatin in human subcutaneous adipose tissue as characterized by the enrichment of H3K27me3 and CTCF marks (repressive gene marks) and diminished H3K36me3 marks (activation gene marks). The variant displayed active DNA methylation marks in adipose tissue, suggesting its likely regulatory activity. Further, the variant also disrupts a potential binding site of a key transcription factor, NRF2, which is known for involvement in obesity and metabolic syndrome.

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