GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy

2019 ◽  
Vol 40 (5) ◽  
pp. 661-668 ◽  
Author(s):  
Asahi Hishida ◽  
Tomotaka Ugai ◽  
Ryosuke Fujii ◽  
Masahiro Nakatochi ◽  
Michael C Wu ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Gastric Atrophy ◽  
Stage I ◽  
Cancer Center ◽  
Genome Wide Association Studies ◽  
Genetic Traits ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

Abstract Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel [false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10−7, respectively]. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10−8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10−27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.

GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications

2019 ◽  
Vol 20 (10) ◽  
pp. 765-780 ◽  
Author(s):  
Diana Cruz ◽  
Ricardo Pinto ◽  
Margarida Freitas-Silva ◽  
José Pedro Nunes ◽  
Rui Medeiros
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Variants ◽  
Complex Traits ◽  
Association Studies ◽  
Cardioembolic Stroke ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Genome Wide Significance

Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.

scholarly journals A Genome-Wide Association Study Identifies the Association between the 12q24 Locus and Black Tea Consumption in Japanese Populations

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3182
Author(s):  
Kyohei Furukawa ◽  
Maki Igarashi ◽  
Huijuan Jia ◽  
Shun Nogawa ◽  
Kaoru Kawafune ◽  
...  
Keyword(s):  
Alcohol Drinking ◽  
Genetic Variants ◽  
Association Studies ◽  
Black Tea ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Tea Consumption ◽  
Genome Wide ◽  
A Genome ◽  
Drinking Frequency

Several genome-wide association studies (GWASs) have reported the association between genetic variants and the habitual consumption of foods and drinks; however, no association data are available regarding the consumption of black tea. The present study aimed to identify genetic variants associated with black tea consumption in 12,258 Japanese participants. Data on black tea consumption were collected by a self-administered questionnaire, and genotype data were obtained from a single nucleotide polymorphism array. In the discovery GWAS, two loci met suggestive significance (p < 1.0 × 10−6). Three genetic variants (rs2074356, rs144504271, and rs12231737) at 12q24 locus were also significantly associated with black tea consumption in the replication stage (p < 0.05) and during the meta-analysis (p < 5.0 × 10−8). The association of rs2074356 with black tea consumption was slightly attenuated by the additional adjustment for alcohol drinking frequency. In conclusion, genetic variants at the 12q24 locus were associated with black tea consumption in Japanese populations, and the association is at least partly mediated by alcohol drinking frequency.

scholarly journals A Genome-Wide Association Study of Novel Genetic Variants Associated With Anthropometric Traits in Koreans

2021 ◽  
Vol 12 ◽  
Author(s):  
Hye-Won Cho ◽  
Hyun-Seok Jin ◽  
Yong-Bin Eom
Keyword(s):  
Genetic Variants ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Fat Distribution ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
A Genome

Most previous genome-wide association studies (GWAS) have identified genetic variants associated with anthropometric traits. However, most of the evidence were reported in European populations. Anthropometric traits such as height and body fat distribution are significantly affected by gender and genetic factors. Here we performed GWAS involving 64,193 Koreans to identify the genetic factors associated with anthropometric phenotypes including height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip ratio. We found nine novel single-nucleotide polymorphisms (SNPs) and 59 independent genetic signals in genomic regions that were reported previously. Of the 19 SNPs reported previously, eight genetic variants at RP11-513I15.6 and one genetic variant at the RP11-977G19.10 region and six Asian-specific genetic variants were newly found. We compared our findings with those of previous studies in other populations. Five overlapping genetic regions (PAN2, ANKRD52, RNF41, HGMA1, and C6orf106) had been reported previously but none of the SNPs were independently identified in the current study. Seven of the nine newly found novel loci associated with height in women revealed a statistically significant skeletal expression of quantitative trait loci. Our study provides additional insight into the genetic effects of anthropometric phenotypes in East Asians.

scholarly journals A Genome-Wide Association Study of spontaneous preterm birth in a European population

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 255 ◽  
Author(s):  
Wilfred Wu ◽  
Erin A S Clark ◽  
Tracy A Manuck ◽  
M Sean Esplin ◽  
Michael W Varner ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Genetic Variants ◽  
Association Studies ◽  
European Population ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Spontaneous Preterm Birth ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Background: Preterm birth is defined as a birth prior to 37 completed weeks’ gestation. It affects more than 10% of all births worldwide, and is the leading cause of neonatal mortality in non-anomalous newborns. Even if the preterm newborn survives, there is an increased risk of lifelong morbidity. Despite the magnitude of this public health problem, the etiology of spontaneous preterm birth is not well understood. Previous studies suggest that genetics is an important contributing factor. We therefore employed a genome-wide association approach to explore possible fetal genetic variants that may be associated with spontaneous preterm birth.Methods: We obtained preterm birth phenotype and genotype data from the National Center for Biotechnology Information Genotypes and Phenotypes Database (study accession phs000103.v1.p1). This dataset contains participants collected by the Danish National Birth Cohort and includes 1000 preterm births and 1000 term births as controls. Whole genomes were genotyped on the Illumina Human660W-Quad_v1_A platform, which contains more than 500,000 markers. After data quality control, we performed genome-wide association studies for the 22 autosomal chromosomes.Results: No single nucleotide polymorphism reached genome-wide significance after Bonferroni correction for multiple testing.Conclusion: We found no evidence of genetic association with spontaneous preterm birth in this European population. Approaches that facilitate detection of both common and rare genetic variants, such as evaluation of high-risk pedigrees and genome sequencing, may be more successful in identifying genes associated with spontaneous preterm birth.

scholarly journals Identifying novel genetic variants for brain amyloid deposition: a genome-wide association study in the Korean population

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hang-Rai Kim ◽  
Sang-Hyuk Jung ◽  
Jaeho Kim ◽  
Hyemin Jang ◽  
Sung Hoon Kang ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Prediction Models ◽  
Association Studies ◽  
Genome Wide Association ◽  
Korean Population ◽  
European Ancestry ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract Background Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer’s disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid β (Aβ) positivity using a large sample of Korean population. Methods One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aβ positivity (measured by amyloid positron emission tomography). Aβ prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. Results In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aβ positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aβ positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10−8). Prediction performance for Aβ positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74–0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. Conclusion The novel genetic variants associated with FGL2 decreased risk of Aβ positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations.

scholarly journals The multiple testing burden in sequencing-based disease studies of global populations

2016 ◽  
Author(s):  
Sara L. Pulit ◽  
Sera A.J. de With ◽  
Paul I.W. de Bakker
Keyword(s):  
Disease Risk ◽  
Association Studies ◽  
Statistical Tests ◽  
Whole Genome Sequence ◽  
Common Disease ◽  
Genome Wide Association Studies ◽  
Sequencing Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

AbstractGenome-wide association studies (GWAS) of common disease have been hugely successful in implicating loci that modify disease risk. The bulk of these associations have proven robust and reproducible, in part due to community adoption of statistical criteria for claiming significant genotype-phenotype associations. Currently, studies of common disease are rapidly shifting towards the use of sequencing technologies. As the cost of sequencing drops, assembling large samples in global populations is becoming increasingly feasible. Sequencing studies interrogate not only common variants, as was true for genotyping-based GWAS, but variation across the full allele frequency spectrum, yielding many more (independent) statistical tests. We sought to empirically determine genome-wide significance for various analysis scenarios. Using whole-genome sequence data, we simulated sequencing-based disease studies of varying sample size and ancestry. We determined that future sequencing efforts in >2,000 samples should practically employ a genome-wide significance threshold of of p <5 ×10−9, though the threshold does vary with ancestry. Studies of European or East Asian ancestry should set genome-wide significance at approximately p <5×10−9, but similar studies of African or South Asian samples should be more stringent (p <1×10−9). Because sequencing analysis brings with it many challenges (especially for rare variants), appropriate adoption of a revised multiple test correction will be crucial to avoid irreproducible claims of association.

scholarly journals Genome-wide association studies reveal candidate genes associated to bacteraemia caused by ST93-IV CA-MRSA

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Stanley Pang ◽  
Denise A Daley ◽  
Shafi Sahibzada ◽  
Shakeel Mowlaboccus ◽  
Marc Stegger ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Virulence Genes ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genetic Traits ◽  
Genome Wide ◽  
A Genome ◽  
Northern Regions

Abstract Background The global emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has seen the dominance of specific clones in different regions around the world with the PVL-positive ST93-IV as the predominant CA-MRSA clone in Australia. In this study we applied a genome-wide association study (GWAS) approach on a collection of Australian ST93-IV MRSA genomes to screen for genetic traits that might have assisted the ongoing transmission of ST93-IV in Australia. We also compared the genomes of ST93-IV bacteraemia and non-bacteraemia isolates to search for potential virulence genes associated with bacteraemia. Results Based on single nucleotide polymorphism phylogenetics we revealed two distinct ST93-IV clades circulating concurrently in Australia. One of the clades contained isolates primarily isolated in the northern regions of Australia whilst isolates in the second clade were distributed across the country. Analyses of the ST93-IV genome plasticity over a 15-year period (2002–2017) revealed an observed gain in accessory genes amongst the clone’s population. GWAS analysis on the bacteraemia isolates identified two gene candidates that have previously been associated to this kind of infection. Conclusions Although this hypothesis was not tested here, it is possible that the emergence of a ST93-IV clade containing additional virulence genes might be related to the high prevalence of ST93-IV infections amongst the indigenous population living in the northern regions of Australia. More importantly, our data also demonstrated that GWAS can reveal candidate genes for further investigations on the pathogenesis and evolution of MRSA strains within a same lineage.

scholarly journals Analysis of multiple related phenotypes in genome-wide association studies

2016 ◽  
Vol 14 (05) ◽  
pp. 1644005 ◽  
Author(s):  
Sohee Oh ◽  
Iksoo Huh ◽  
Seung Yeoun Lee ◽  
Taesung Park
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Multivariate Approach ◽  
Complex Phenotypes ◽  
Genome Wide ◽  
Related Phenotype ◽  
Univariate Approach ◽  
Genome Wide Significance

Most genome-wide association studies (GWAS) have been conducted by focusing on one phenotype of interest for identifying genetic variants associated with common complex phenotypes. However, despite many successful results from GWAS, only a small number of genetic variants tend to be identified and replicated given a very stringent genome-wide significance criterion, and explain only a small fraction of phenotype heritability. In order to improve power by using more information from data, we propose an alternative multivariate approach, which considers multiple related phenotypes simultaneously. We demonstrate through computer simulation that the multivariate approach can improve power for detecting disease-predisposing genetic variants and pleiotropic variants that have simultaneous effects on multiple related phenotypes. We apply the multivariate approach to a GWA dataset of 8,842 Korean individuals genotyped for 327,872 SNPs, and detect novel genetic variants associated with metabolic syndrome related phenotypes. Considering several related phenotype simultaneously, the multivariate approach provides not only more powerful results than the conventional univariate approach but also clue to identify pleiotropic genes that are important to the pathogenesis of many related complex phenotypes.

Migraine: Genetic Variants and Clinical Phenotypes

2019 ◽  
Vol 26 (34) ◽  
pp. 6207-6221 ◽  
Author(s):  
Innocenzo Rainero ◽  
Alessandro Vacca ◽  
Flora Govone ◽  
Annalisa Gai ◽  
Lorenzo Pinessi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Mthfr Gene ◽  
Genome Wide Association Studies ◽  
Clinical Phenotypes ◽  
Network Analyses ◽  
Genome Wide ◽  
Genomic Studies ◽  
The Common ◽  
The Relationship

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

scholarly journals Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Shuquan Rao ◽  
Yao Yao ◽  
Daniel E. Bauer
Keyword(s):  
Genome Editing ◽  
Genetic Variants ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Functional Genetics ◽  
Genome Wide ◽  
Causal Variants ◽  
Experimental Approaches

AbstractGenome-wide association studies (GWAS) have uncovered thousands of genetic variants that influence risk for human diseases and traits. Yet understanding the mechanisms by which these genetic variants, mainly noncoding, have an impact on associated diseases and traits remains a significant hurdle. In this review, we discuss emerging experimental approaches that are being applied for functional studies of causal variants and translational advances from GWAS findings to disease prevention and treatment. We highlight the use of genome editing technologies in GWAS functional studies to modify genomic sequences, with proof-of-principle examples. We discuss the challenges in interrogating causal variants, points for consideration in experimental design and interpretation of GWAS locus mechanisms, and the potential for novel therapeutic opportunities. With the accumulation of knowledge of functional genetics, therapeutic genome editing based on GWAS discoveries will become increasingly feasible.

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