Lack of association of HLA-DRA polymorphisms with aspirin exacerbated respiratory disease in a Korean population

The human HLA class II histocompatibility antigen, DR alpha chain (HLA-DRA) is a member of the MHC class II gene family that activates T cells allowing secretion in various cytokines to immune responses. Thus, we explored whether the genetic variations in HLA-DRA gene can influence susceptibility for aspirin exacerbated respiratory disease (AERD). To carry out the investigation, 22 single nucleotide polymorphisms (SNPs) in HLA-DRA were genotyped in 592 Korean asthma patients. Logistic and regression analyseis wereas used to evaluate the P-values for associations of HLA-DRA polymorphisms with AERD and a relevant phenotype, the fall rate of forced expiratory volume in the 1^st second (FEV₁). Logistic analyses revealed that two variants, rs6911777 and HLA_DRA_BL1_ht3 were initially associated with AERD via dominant and recessive models (P = 0.05 and 0.01, respectively), however, the signals did not reach the threshold of significance after multiple corrections. Furthermore, we observed that fall rate of FEV1 by aspirin provocation was marginally different between AERD cases and aspirin-tolerant asthma (ATA) controls (mean = 24.63 vs 3.54, respectively). This study provides result of first association analysis between the variants of HLA-DRA and the risk of AERD, and conclusions derived from the study do not support significant roles of polymorphisms in HLA-DRA with AERD.     

Genome-wide association study of idiopathic hypersomnia in a Japanese population

Sleep and Biological Rhythms - Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In...     

Genome-wide association study of schizophrenia in Japanese population

Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p = 0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology.     

Genome-wide association study for longevity in the Holstein cattle population

Longevity is one of the most important traits determining dairy cow profitability. In the last decades dairy cows suffered a lowering in the age at culling. With the aim to identify the genes involved in longevity, dates of birth, yields, dates of calving during lifespan and culling dates were collected for 946 culled cows which had been genotyped with the Bovine High Density panel. Using the GenABEL package in R, genome-wide association analysis was performed on three potential traits of longevity: (1) ‘days in production,’ (2) ‘days in herd,’ (3) number of calvings over lifespan.’ Five genome-wide significant single nucleotide polymorphisms (SNPs) associated with all three longevity traits were detected. Several consecutive SNPs identified on chromosomes 16 and 30 indicated the presence of two suggestive quantitative trait loci (QTL). The genes comprised in the QTL regions had biological functions related to fertility, reproductive disorders, heat stress and welfare of cows. These findings might contribute to improving breeding strategies to improve longevity.     

Genome-wide association study on bipolar disorder in the Bulgarian population

Bipolar disorder is a severe psychiatric disorder influenced by environmental and genetic factors. Genetic studies have implicated many variants in the disease's etiology but only few have been successfully replicated. We conducted a genome-wide association study (GWAS) on bipolar disorder in the Bulgarian population followed by a replication study of the top 100 single nucleotide polymorphisms (SNPs) showing the smallest P values. The GWAS was performed on 188 bipolar disorder patients and 376 control subjects genotyped on the Illumina 550 platform. The replication study was conducted on 122 patients and 328 controls. Although our study did not show any association P value that achieved genome-wide significance, and none of the top 100 SNPs reached the Bonferroni-corrected P value in the replication study, the plausible involvement of some variants cannot be entirely discarded. Three polymorphisms, rs8099939 [P = 2.12 × 10(-6), odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.43-2.67] in GRIK5, rs6122972 (P = 3.11 × 10(-6), OR = 2.02, 95% CI = 1.46-2.80) in PARD6B and rs2289700 (P = 9.14 × 10(-6), OR = 2.13, 95% CI = 1.53-2.95) in CTSH remained associated at a similar level after Mantel-Haenszel test for combining the results from the genome-wide and replication studies. A modest association was also detected for SNP rs1012053 (GWAS P = 4.50 × 10(-2)) in DGKH, which has already been reported as the most significant variant in a previous genome-wide scan on bipolar disorder. However, further studies using larger datasets are needed to identify variants with smaller effects that contribute to the risk of bipolar disorder.     

Genome-wide association study identifies genetic risk loci for adiposity in a Taiwanese population

Overweight and obese are risk factors for various diseases. In Taiwan, the combined prevalence of overweight and obesity has increased dramatically. Here, we conducted a genome-wide association study (GWAS) on four adiposity traits, including body-mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-hip ratio (WHR), using the data for more than 21,000 subjects in Taiwan Biobank. Associations were evaluated between 6,546,460 single-nucleotide polymorphisms (SNPs) and adiposity traits, yielding 13 genome-wide significant (GWS) adiposity-associated trait-loci pairs. A known gene, FTO, as well as two BF%-associated loci (GNPDA2-GABRG1 [4p12] and RNU6-2-PIAS1 [15q23]) were identified as pleiotropic effects. Moreover, RALGAPA1 was found as a specific genetic predisposing factor to high BMI in a Taiwanese population. Compared to other populations, a slightly lower heritability of the four adiposity traits was found in our cohort. Surprisingly, we uncovered the importance of neural pathways that might influence BF%, WC and WHR in the Taiwanese (East Asian) population. Additionally, a moderate genetic correlation between the WHR and BMI (γ_g = 0.52; p = 2.37×10⁻⁹) was detected, suggesting different genetic determinants exist for abdominal adiposity and overall adiposity. In conclusion, the obesity-related genetic loci identified here provide new insights into the genetic underpinnings of adiposity in the Taiwanese population.     

Genome-wide association study for atopy and allergic rhinitis in a Singapore Chinese population

Allergic rhinitis (AR) is an atopic disease which affects about 600 million people worldwide and results from a complex interplay between genetic and environmental factors. However genetic association studies on known candidate genes yielded variable results. The aim of this study is to identify the genetic variants that influence predisposition towards allergic rhinitis in an ethnic Chinese population in Singapore using a genome-wide association study (GWAS) approach. A total of 4461 ethnic Chinese volunteers were recruited in Singapore and classified according to their allergic disease status. The GWAS included a discovery stage comparing 515 atopic cases (including 456 AR cases) and 486 non-allergic non-rhinitis (NANR) controls. The top SNPs were then validated in a replication cohort consisting of a separate 2323 atopic cases (including 676 AR cases) and 511 NANR controls. Two SNPs showed consistent association in both discovery and replication phases; MRPL4 SNP rs8111930 on 19q13.2 (OR = 0.69, P_combined = 4.46×10⁻⁰⁵) and BCAP SNP rs505010 on chromosome 10q24.1 (OR = 0.64, P_combined = 1.10×10⁻⁰⁴). In addition, we also replicated multiple associations within known candidates regions such as HLA-DQ and NPSR1 locus in the discovery phase. Our study suggests that MRPL4 and BCAP, key components of the HIF-1α and PI3K/Akt signaling pathways respectively, are two novel candidate genes for atopy and allergic rhinitis. Further study on these molecules and their signaling pathways would help in understanding of the pathogenesis of allergic rhinitis and identification of targets for new therapeutic intervention.     

Genome-wide association study of body weight in chicken F2 resource population

Chicken body weight is an economically important trait and great genetic progress has been accomplished in genetic selective for body weight. To identify genes and chromosome regions associated with body weight, we performed a genome-wide association study using the chicken 60 k SNP panel in a chicken F2 resource population derived from the cross between Silky Fowl and White Plymouth Rock. A total of 26 SNP effects involving 9 different SNP markers reached 5% Bonferroni genome-wide significance. A chicken chromosome 4 (GGA4) region approximately 8.6 Mb in length (71.6-80.2 Mb) had a large number of significant SNP effects for late growth during weeks 7-12. The LIM domain-binding factor 2 (LDB2) gene in this region had the strongest association with body weight for weeks 7-12 and with average daily gain for weeks 6-12. This GGA4 region was previously reported to contain body weight QTL. GGA1 and GGA18 had three SNP effects on body weight with genome-wide significance. Some of the SNP effects with the significance of "suggestive linkage" overlapped with previously reported results.     

Genetic analysis between FGD6 and aspirin exacerbated respiratory disease in a Korean population

The human FYVE, RhoGEF and PH domain containing 6 (FGD6) gene regulates mechanisms that are implicated in airway bronchospasm, and therefore, may be a risk factor for aspirin exacerbated respiratory disease (AERD). This study aims to investigate the association between FGD6 variations and AERD in a Korean asthma cohort. A total of 34 single nucleotide polymorphisms (SNPs) were selected for genotyping based on previously reported polymorphisms in the HapMap database. Genotyping was carried out using TaqMan assay and nine major haplotypes from two haplotype blocks were obtained in 163 AERD cases and 429 aspirin-tolerant asthma (ATA) controls. Genotype frequency distributions of FGD6 polymorphisms and haplotypes were analyzed using logistic and regression models. Findings from logistic and regression analyses revealed a lack of association of FGD6 genetic variations with AERD and fall rate of FEV₁ (P > 0.05 in co-dominant, dominant and recessive models). This preliminary report provides evidences that variations in the FGD6 gene do not influence the risk of AERD and its relevant phenotype in a Korean population. This report may contribute to the etiology of aspirin hypersensitivity in Korean asthma patients.     

Association analysis of ILVBL gene polymorphisms with aspirin-exacerbated respiratory disease in asthma

Background

We previously reported that the ILVBL gene on chromosome 19p13.1 was associated with the risk for aspirin-exacerbated respiratory disease (AERD) and the percent decline of forced expired volume in one second (FEV1) after an oral aspirin challenge test. In this study, we confirmed the association between polymorphisms and haplotypes of the ILVBL gene and the risk for AERD and its phenotype.

Methods

We recruited 141 AERD and 995 aspirin-tolerant asthmatic (ATA) subjects. All study subjects underwent an oral aspirin challenge (OAC). Nine single nucleotide polymorphisms (SNPs) with minor allele frequencies above 0.05, which were present in the region from 2 kb upstream to 0.5 kb downstream of ILVBL in Asian populations, were selected and genotyped.

Results

In an allelic association analysis, seven of nine SNPs were significantly associated with the risk for AERD after correction for multiple comparisons. In a codominant model, the five SNPs making up block2 (rs2240299, rs7507755, rs1468198, rs2074261, and rs13301) showed significant associations with the risk for AERD (corrected P?=?0.001–0.004, OR?=?0.59–0.64). Rs1468198 was also significantly associated with the percent decline in FEV1 in OAC tests after correction for multiple comparisons in the codominant model (corrected P?=?0.033), but the other four SNPs in hapblock2 were not.

Conclusion

To the best of our knowledge, this is the first report of an association between SNPs on ILVBL and AERD. SNPs on ILVBL could be promising genetic markers of this condition.

     

Genome-wide association studies and Crohn's disease

The development of genome-wide association scanning (GWAS) has revolutionized the search for genetic loci associated with complex diseases. Crohn's disease (CD), together with ulcerative colitis, has been a principal beneficiary of this technology with a recent meta-analysis from the International IBD Genetics Consortium increasing the number of confirmed CD susceptibility loci to 71. When one considers that prior to the development of GWAS only three susceptibility loci had been identified, the degree of progress becomes obvious. In this article we will summarize the principal discoveries that have been made in CD genetics and explain how these have contributed to our improved understanding of disease pathogenesis.     

Genome-wide association study reveals the genetic determinism of growth traits in a Gushi-Anka F2 chicken population

Chicken growth traits are economically important, but the relevant genetic mechanisms have not yet been elucidated. Herein, we performed a genome-wide association study to identify the variants associated with growth traits. In total, 860 chickens from a Gushi-Anka F₂ resource population were phenotyped for 68 growth and carcass traits, and 768 samples were genotyped based on the genotyping-by-sequencing (GBS) method. Finally, 734 chickens and 321,314 SNPs remained after quality control and removal of the sex chromosomes, and these data were used to carry out a GWAS analysis. A total of 470 significant single-nucleotide polymorphisms (SNPs) for 43 of the 68 traits were detected and mapped on chromosomes (Chr) 1–6, -9, -10, -16, -18, -23, and -27. Of these, the significant SNPs in Chr1, -4, and -27 were found to be associated with more than 10 traits. Multiple traits shared significant SNPs, indicating that the same mutation in the region might have a large effect on multiple growth or carcass traits. Haplotype analysis revealed that SNPs within the candidate region of Chr1 presented a mosaic pattern. The significant SNPs and pathway enrichment analysis revealed that the MLNR, MED4, CAB39L, LDB2, and IGF2BP1 genes could be putative candidate genes for growth and carcass traits. The findings of this study improve our understanding of the genetic mechanisms regulating chicken growth and carcass traits and provide a theoretical basis for chicken breeding programs.Subject terms: Genome-wide association studies, Genetic linkage study, Development, DNA sequencing, Animal breeding     

Genome-wide association study of milk production traits in a crossbred dairy sheep population using three statistical models

Milk production is one of the most important characteristics of dairy sheep, and the identification of genes affecting milk production traits is critical to understanding the genetics and improve milk production in future generations. Three statistical techniques, namely GWAS, ridge-regression BLUP and BayesC , were used to identify SNPs in significant association with three milk production traits (milk yield, fat yield and protein yield) in a crossbred dairy sheep population. The results suggested that chromosomes 1, 3, 4, 5, 7 and 11 were likely to harbor genes important to milk production because these chromosomes had the greatest top-100-SNP variance contributions on the three milk production traits. The GWAS analysis identified between 74 and 288 genome-wide significant SNP (P < 0.05) whereas the BayesCπ model revealed between six and 63 SNPs, each with >95% posterior probability of inclusion as having a non-zero association effect on at least one of the three milk production traits. Positional candidate genes for milk production in sheep were searched, based on the sheep genomic assembly OAR version 3.1, such as those which map position coincided with or was located within 0.1 Mbp of a genome-wide suggestive or significant SNP. These identified SNPs and candidate genes supported some previous findings and also added new information about genetic markers for genetic improvement of lactation in dairy sheep, but keeping in mind that the majority of these positional candidate genes are not necessarily true causative loci for these traits and future validations are thus necessary.     

Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean

Hepatitis B virus (HBV) infection can lead to serious liver diseases, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC); however, about 85-90% of infected individuals become inactive carriers with sustained biochemical remission and very low risk of LC or HCC. To identify host genetic factors contributing to HBV clearance, we conducted genome-wide association studies (GWAS) and replication analysis using samples from HBV carriers and spontaneously HBV-resolved Japanese and Korean individuals. Association analysis in the Japanese and Korean data identified the HLA-DPA1 and HLA-DPB1 genes with P(meta)?=?1.89×10?12 for rs3077 and P(meta)?=?9.69×10?1? for rs9277542. We also found that the HLA-DPA1 and HLA-DPB1 genes were significantly associated with protective effects against chronic hepatitis B (CHB) in Japanese, Korean and other Asian populations, including Chinese and Thai individuals (P(meta)?=?4.40×10?1? for rs3077 and P(meta)?=?1.28×10?1? for rs9277542). These results suggest that the associations between the HLA-DP locus and the protective effects against persistent HBV infection and with clearance of HBV were replicated widely in East Asian populations; however, there are no reports of GWAS in Caucasian or African populations. Based on the GWAS in this study, there were no significant SNPs associated with HCC development. To clarify the pathogenesis of CHB and the mechanisms of HBV clearance, further studies are necessary, including functional analyses of the HLA-DP molecule.     

Genome-wide association study identifies TNFSF13 as a susceptibility gene for IgA in a South Chinese population in smokers

IgA is an important factor in our immune system. There are many diseases associated with it, such as IgA nephropathy, IgA deficiency, and so on. In order to describe the relationship between the genes and the IgA level, we performed a genome-wide association study of serum IgA with 1,999 healthy Chinese men in the first stage and replicated on an independent Chinese sample with 1,496 subjects in the second stage. Association between each SNP with IgA was estimated by multivariate linear regression analysis conditioned on age and smoke. Haplotype analysis for the block around the top SNP was performed. In the first stage, one genomic locus was identified to be significantly associated with IgA. The loci is TNFSF13 (17p13.1; rs3803800; P?=?6.26?×?10(-8)). In smoke-specific analysis, rs3803800 was approximately significantly associated with IgA levels in smokers (P?=?3.96?×?10(-7)), while no association was observed in nonsmokers (P?=?2.28?×?10(-1)). In addition, we performed the haplotype analysis on chromosome 17 with the SNPs around rs3803800. Although the total P value for the haplotype did not acquire significant difference, three haplotypes (TGAG, CACG, and CACA) reached significant (P?相似文献   

Genome-wide association study of footrot in Texel sheep

Background

This is the first study based on a genome-wide association approach that investigates the links between ovine footrot scores and molecular polymorphisms in Texel sheep using the ovine 50 K SNP array (42 883 SNPs (single nucleotide polymorphisms) after quality control). Our aim was to identify molecular predictors of footrot resistance.

Methods

This study used data from animals selected from a footrot-phenotyped Texel sheep population of 2229 sheep with an average of 1.60 scoring records per animal. From these, a subset of 336 animals with extreme trait values for footrot was selected for genotyping based on their phenotypic records. De-regressed estimated breeding values (EBV) for footrot were used as pseudo-phenotypes in the genome-wide association analysis.

Results

Seven SNPs were significant on a chromosome-wise level but the association analysis did not reveal any genome-wise significant SNPs associated with footrot. Based on the current state of knowledge of the ovine genome, it is difficult to clearly link the function of the genes that contain these significant SNPs with a potential role in resistance/susceptibility to footrot. Linkage disequilibrium (LD) was analysed as one of the factors that influence the power of detecting QTL (quantitative trait loci). A mean LD of 0.20 (r² at a distance of 50 kb between two SNPs) in the population analysed was estimated. LD declined from 0.15 to 0.07 and to 0.04 at distances between two SNPs of 100, 1000 and 2000 kb, respectively.

Conclusions

Based on a relatively small number of genotyped animals, this study is a first step to search for genomic regions that are involved in resistance to footrot using the ovine 50 K SNP array. Seven SNPs were found to be significant on a chromosome-wise level. No major genome-wise significant QTL were identified.     

Genome-wide association study of birth weight in sheep

Birth weight is the earliest available growth trait with considerable impacts on lamb survivability and growth performance traits. This study was conducted to perform a genome-wide association study of birth weight in a meat-type sheep. A total of 132 Lori-Bakhtiari sheep were selected based on estimated of breeding values (EBVs) for BW analyses. The selected animals were genotyped using Illumina Ovine SNP50 Bead Chip. After quality control, a total of 41 323 single-nucleotide polymorphisms (SNPs) and 130 sheep were used for subsequent analyses. Plink 1.90 beta software was used for the analyses. Seven SNPs on chromosomes 1, 16, 19 and 22 were detected based on genome-wide unadjusted P-values (P <10⁻⁶), which jointly accounted for 1.2% of total genetic variation. However, based on Bonferroni-adjusted P-values, only three SNPs on chromosome 1 had significant associations with EBVs for birth weight (P <0.05), which jointly explained 0.8% of total genetic variation. A total of seven genes were found in 50 kb intervals from the three significant SNPs on chromosome 1, but only three genes, including RAB6B (a member of RAS oncogene family), Tf serotransferrin and GIGYF2 (a GRB10 interacting GYF protein 2), could be considered as candidate genes for birth weight in future studies. The results of this study may facilitate potential use of the genes involving in growth and production traits for genetic improvement of productivity in sheep.     

Fatty acid binding protein 1 is related with development of aspirin-exacerbated respiratory disease

Background

Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the ingestion of aspirin. Although alterations in eicosanoid metabolites play a role in AERD, other immune or inflammatory mechanisms may be involved. We aimed to identify proteins that were differentially expressed in nasal polyps between patients with AERD and aspirin-tolerant asthma (ATA).

Methodology/Principal Findings

Two-dimensional electrophoresis was adopted for differential display proteomics. Proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS). Western blotting and immunohistochemical staining were performed to compare the amount of fatty acid-binding protein 1 (FABP1) in the nasal polyps of patients with AERD and ATA. Fifteen proteins were significantly up- (seven spots) or down-regulated in the nasal polyps of patients with AERD (n = 5) compared to those with ATA (n = 8). LC-MS revealed an increase in seven proteins expression and a decrease in eight proteins expression in patients with AERD compared to those with ATA (P = 0.003–0.045). FABP1-expression based on immunoblotting and immunohistochemical analysis was significantly higher in the nasal polyps of patients with AERD compared to that in patients with ATA. FABP1 was observed in epithelial, eosinophils, macrophages, and the smooth-muscle cells of blood vessels in the polyps.

Conclusions/Significance

Our results indicate that alterations in 15 proteins, including FABP1, may be related to the development of AERD.     

Contribution of the OBSCN nonsynonymous variants to aspirin exacerbated respiratory disease susceptibility in Korean population

Airway remodeling and exacerbated airway narrowing in asthma have been attributed to the regulation of intracellular Ca(2+) by sarcoplasmic reticulum (SR) of the airway smooth muscle cells. The protein encoded by obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF (OBSCN) is a crucial factor in determining the SR architecture in Obscn(-/-) mice. This study genotyped a total of 55 common single-nucleotide polymorphisms (SNPs) in 592 Korean asthmatics including 163 aspirin exacerbated respiratory disease (AERD) cases and 429 aspirin-tolerant asthma (ATA) controls. Eight SNPs, including two nonsynonymous polymorphisms rs1188722C>T (Leu2116Phe) and rs1188729G>C (Cys4642Ser), and one haplotype BL2_ht1 showed statistically significant associations with AERD development (p=0.003-0.03). Two variants, rs1188722C>T (Leu2116Phe) and rs369252C>A, also revealed nominal association with FEV1 decline by aspirin provocation in asthmatics (p=0.03-0.04). Intriguingly, rs1188722C>T (Leu2116Phe) is a highly conserved amino acid residue among species, suggesting its functional relevance to AERD. In addition, the A allele of rs369252C>A, which was more prevalent in AERD than in ATA, was predicted as a potential branch point (BP) site for alternative splicing (BP score=4.29). Although further functional evaluation is required, our findings suggest that OBSCN polymorphisms, in particular, highly conserved nonsynonymous Leu2116Phe variant, might contribute to aspirin hypersensitivity in asthmatics.