scholarly journals Fine Mapping of Intracranial Aneurysm Susceptibility Based on a Genome-wide Association Study

2021 ◽  
Author(s):  
Eun Pyo Hong ◽  
Dong Hyuk Youn ◽  
Bong Jun Kim ◽  
Jun Hyong Ahn ◽  
Jeong Jin Park ◽  
...  
Keyword(s):  
Intracranial Aneurysm ◽  
Fine Mapping ◽  
Bayes Factor ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Network Analyses ◽  
Genome Wide ◽  
A Genome

Abstract In addition to conventional genome-wide association studies (GWAS), a fine-mapping is increasingly used to identify the genetic function of variants associated with disease susceptibilities. Here, we used a fine-mapping approach to evaluate the casual variants based on a previous GWAS involving patients with intracranial aneurysm (IA). Fine-mapping analysis was conducted based on the chromosomal data provided by GWAS consisting 250 patients diagnosed with IA and 296 controls using posterior inclusion probability (PIP) and log10 transformed Bayes factor (log10BF). The narrow sense of heritability (h2) explained by each casual variant was estimated. Subsequent gene expression and functional network analyses were used to calculate the transcripts per million (TPM) values. Twenty causal candidate single nucleotide polymorphisms (SNPs) surpassed a genome-wide significance threshold for creditable evidence (log10BF > 6.1). Four SNPs including rs75822236 (R535H, GBA; log10BF = 15.06), rs112859779 (G141S, TCF24; log10BF = 12.12), rs79134766 (A208T, OLFML2A; log10BF = 14.92), and rs371331393 (Q1932X, ARHGAP32; log10BF = 20.88) showed a completed PIP value in each chromosomal region, suggesting a high probability of variant causality associated with IA. Expression in GBA was highly enriched in the whole blood (TPM = 33.13), while TCF24 were rarely expressed in all tissues and cells. No direct interaction was observed between the four casual genes; however, PSAP appeared to be particularly important via indirect correlation between other genes. Our results suggested that four mutations of GBA, TCF24, OLFML2A, and ARHGAP32 were linked to IA susceptibility and pathogenesis. Our approach may promise more informative mutations in the following GWAS.

scholarly journals Prioritization of genes associated with the pathogenesis of leukosis in cattle

2019 ◽  
Vol 22 (8) ◽  
pp. 1063-1069 ◽  
Author(s):  
N. S. Yudin ◽  
N. L. Podkolodnyy ◽  
T. A. Agarkova ◽  
E. V. Ignatieva
Keyword(s):  
Protein Interactions ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Mammalian Species ◽  
Genome Wide Association ◽  
Farm Animals ◽  
Genome Wide Association Studies ◽  
Protein Protein Interactions ◽  
Genome Wide ◽  
A Genome

Selection by means of genetic markers is a promising approach to the eradication of infectious diseases in farm animals, especially in the absence of effective methods of treatment and prevention. Bovine leukemia virus (BLV) is spread throughout the world and represents one of the biggest problems for the livestock production and food security in Russia. However, recent genome-wide association studies have shown that sensitivity/resistance to BLV is polygenic. The aim of this study was to create a catalog of cattle genes and genes of other mammalian species involved in the pathogenesis of BLV-induced infection and to perform gene prioritization using bioinformatics methods. Based on manually collected information from a range of open sources, a total of 446 genes were included in the catalog of cattle genes and genes of other mammals involved in the pathogenesis of BLV-induced infection. The following criteria were used to prioritize 446 genes from the catalog: (1) the gene is associated with leukemia according to a genome-wide association study; (2) the gene is associated with leukemia according to a case-control study; (3) the role of the gene in leukemia development has been studied using knockout mice; (4) protein-protein interactions exist between the gene-encoded protein and either viral particles or individual viral proteins; (5) the gene is annotated with Gene Ontology terms that are overrepresented for a given list of genes; (6) the gene participates in biological pathways from the KEGG or REACTOME databases, which are over-represented for a given list of genes; (7) the protein encoded by the gene has a high number of protein-protein interactions with proteins encoded by other genes from the catalog. Based on each criterion, a rank was assigned to each gene. Then the ranks were summarized and an overall rank was determined. Prioritization of 446 candidate genes allowed us to identify 5 genes of interest (TNF,LTB,BOLA-DQA1,BOLA-DRB3,ATF2), which can affect the sensitivity/resistance of cattle to leukemia.

scholarly journals Genomic Variations in Susceptibility to Intracranial Aneurysm in the Korean Population

2019 ◽  
Vol 8 (2) ◽  
pp. 275 ◽  
Author(s):  
Eun Hong ◽  
Bong Kim ◽  
Steve Cho ◽  
Jin Yang ◽  
Hyuk Choi ◽  
...  
Keyword(s):  
Intracranial Aneurysm ◽  
Association Studies ◽  
Large Population ◽  
Genome Wide Association ◽  
Korean Population ◽  
Genome Wide Association Studies ◽  
Medicine Research ◽  
Genome Wide ◽  
A Genome ◽  
Significant Difference

Genome-wide association studies found genetic variations with modulatory effects for intracranial aneurysm (IA) formations in European and Japanese populations. We aimed to identify the susceptibility of single nucleotide polymorphisms (SNPs) to IA in a Korean population consisting of 250 patients, and 294 controls using the Asian-specific Axiom Precision Medicine Research Array. Twenty-nine SNPs reached a genome-wide significance threshold (5 × 10−8). The rs371331393 SNP, with a stop-gain function of ARHGAP32 (11q24.3), showed the most significant association with the risk of IA (OR = 43.57, 95% CI: 21.84–86.95; p = 9.3 × 10−27). Eight out of 29 SNPs—GBA (rs75822236), TCF24 (rs112859779), OLFML2A (rs79134766), ARHGAP32 (rs371331393), CD163L1 (rs138525217), CUL4A (rs74115822), LOC102724084 (rs75861150), and LRRC3 (rs116969723)—demonstrated sufficient statistical power greater than or equal to 0.8. Two previously reported SNPs, rs700651 (BOLL, 2q33.1) and rs6841581 (EDNRA, 4q31.22), were validated in our GWAS (Genome-wide association study). In a subsequent analysis, three SNPs showed a significant difference in expressions: the rs6741819 (RNF144A, 2p25.1) was down-regulated in the adrenal gland tissue (p = 1.5 × 10−6), the rs1052270 (TMOD1. 9q22.33) was up-regulated in the testis tissue (p = 8.6 × 10−10), and rs6841581 (EDNRA, 4q31.22) was up-regulated in both the esophagus (p = 5.2 × 10−12) and skin tissues (1.2 × 10−6). Our GWAS showed novel candidate genes with Korean-specific variations in IA formations. Large population based studies are thus warranted.

scholarly journals Bacterial Genome wide association studies (bGWAS) and transcriptomics identifies cryptic antimicrobial resistance mechanisms in Acinetobacter baumannii

2019 ◽  
Author(s):  
Chandler Roe ◽  
Charles H.D. Williamson ◽  
Adam J. Vazquez ◽  
Kristen Kyger ◽  
Michael Valentine ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Acinetobacter Baumannii ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Bacterial Genome ◽  
Genome Wide Association ◽  
Multiple Drug ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

AbstractAntimicrobial resistance (AMR) in the nosocomial pathogen, Acinetobacter baumannii, is becoming a serious public health threat. While some mechanisms of AMR have been reported, understanding novel mechanisms of resistance is critical for identifying emerging resistance. One of the first steps in identifying novel AMR mechanisms is performing genotype/phenotype association studies. However, performing genotype/phenotype association studies is complicated by the plastic nature of the A. baumannii pan-genome. In this study, we compared the antibiograms of 12 antimicrobials associated with multiple drug families for 84 A. baumannii isolates, many isolated in Arizona, USA. in silico screening of these genomes for known AMR mechanisms failed to identify clear correlations for most drugs. We then performed a genome wide association study (GWAS) looking for associations between all possible 21-mers; this approach generally failed to identify mechanisms that explained the resistance phenotype. In order to decrease the genomic noise associated with population stratification, we compared four phylogenetically-related pairs of isolates with differing susceptibility profiles. RNA-Sequencing (RNA-Seq) was performed on paired isolates and differentially expressed genes were identified. In these isolate pairs, we identified four different potential mechanisms, highlighting the difficulty of broad AMR surveillance in this species. To verify and validate differential expression, amplicon sequencing was performed. These results suggest that a diagnostic platform based on gene expression rather than genomics alone may be beneficial in certain surveillance efforts. The implementation of such advanced diagnostics coupled with increased AMR surveillance will potentially improve A. baumannii infection treatment and patient outcomes.

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 Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

2020 ◽  
Author(s):  
Segun Fatumo ◽  
Tinashe Chikowore ◽  
Robert Kalyesubula ◽  
Rebecca N Nsubuga ◽  
Gershim Asiki ◽  
...  
Keyword(s):  
Kidney Function ◽  
Fine Mapping ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Causal Variant ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractGenome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288 Ugandans and replicated the findings in 8224 African Americans. We identified two loci associated with eGFR at genome-wide significance (p<5×10−8). The most significantly associated variant (rs2433603, p=2.4×10−9) in GATM was distinct from previously reported signals. A second association signal mapping near HBB (rs141845179, p=3.0×10−8) was not significant after conditioning on a previously reported SNP (rs334) for eGFR. However, fine-mapping analyses highlighted rs141845179 to be the most likely causal variant at the HBB locus (posterior probability of 0.61). A trans-ethnic GRS of eGFR constructed from previously reported lead SNPs was not predictive into the Ugandan population, indicating that additional large-scale efforts in Africa are necessary to gain further insight into the genetic architecture of kidney disease.

scholarly journals Genome-Wide Association Studies of Somatic Cell Count in the Assaf Breed

Animals ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1531
Author(s):  
Yasemin Öner ◽  
Malena Serrano ◽  
Pilar Sarto ◽  
Laura Pilar Iguácel ◽  
María Piquer-Sabanza ◽  
...  
Keyword(s):  
Somatic Cell ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Significant Snps ◽  
Genome Wide Association ◽  
System Response ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
A Genome

A genome-wide association study (GWAS) was performed to identify new single nucleotide polymorphisms (SNPs) and genes associated with mastitis resistance in Assaf sheep by using the Illumina Ovine Infinium® HD SNP BeadChip (680K). In total, 6173 records from 1894 multiparous Assaf ewes with at least three test day records and aged between 2 and 7 years old were used to estimate a corrected phenotype for somatic cell score (SCS). Then, 192 ewes were selected from the top (n = 96) and bottom (n = 96) tails of the corrected SCS phenotype distribution to be used in a GWAS. Although no significant SNPs were found at the genome level, four SNPs (rs419096188, rs415580501, rs410336647, and rs424642424) were significant at the chromosome level (FDR 10%) in two different regions of OAR19. The SNP rs419096188 was located in intron 1 of the NUP210 and close to the HDAC11 genes (61 kb apart), while the other three SNPs were totally linked and located 171 kb apart from the ARPP21 gene. These three genes were related to the immune system response. These results were validated in two SNPs (rs419096188 and rs424642424) in the total population (n = 1894) by Kompetitive Allele-Specific PCR (KASP) genotyping. Furthermore, rs419096188 was also associated with lactose content.

A genome-wide association study of colorectal cancer in Mexican mestizos suggest novel common tumor-risk variants

2020 ◽  
Author(s):  
AUGUSTO Rojas-Martinez ◽  
Valentina Colistro ◽  
Raquel Cruz ◽  
Clara Ruiz ◽  
Inés Quintela ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Latin American ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Statistical Significance ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Autosomal Snps ◽  
Genome Wide ◽  
A Genome

Abstract Background: Genome-wide association studies (GWAS) for colorectal cancer (CRC) have detected high-risk genetic variants associated with CRC in several ethnic groups, but Latin American communities are still underrepresented. The aim was to identify variants related to CRC in an admixed Latin American population. Methods: The study was performed in 831 cases and 881 controls from Mexico, who were genotyped for 1,006,703 autosomal SNPs. Logistic regression was carried out including covariants, such as sex, age and genetic ancestry. Lastly, we performed a sequence-kernel association test (SKAT) to consider the joint effect of several SNPs lying in genes.Results: Eight chromosomal regions reached genome-wide significance level ( p < 5×10 -8 ): 1p36.22, 1p31.1, 1q42.13, 6p22, 7p14.1, 12q24.32, 16q12.2 and 21q22.2 and 63 variants reached borderline statistical significance ( p < 1×10 − 6 ). SKAT analysis detected 13 loci associated with CRC, none of them previously associated with CRC. Conclusions: We found 8 SNPs and 13 loci associated with CRC. These signals may contribute to enrich the panoply of genes involved with CRC. Further analyses remain to be done to validate the associations in other Latin American populations. This study highlights the importance of conducting GWAS in poorly explored admixed populations.

scholarly journals Rapid response to the alpha-1 adrenergic agent phenylephrine in the perioperative period is impacted by genomics and ancestry

2020 ◽  
Author(s):  
Stephane Wenric ◽  
Janina M. Jeff ◽  
Thomas Joseph ◽  
Muh-Ching Yee ◽  
Gillian M. Belbin ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Clinical Care ◽  
Low Frequency ◽  
Perioperative Period ◽  
Rapid Response ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes occurring during inpatient clinical care. Here we study the genetic underpinnings of the rapid response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. We quantified this response by extracting blood pressure (BP) measurements 5 min before and after the administration of phenylephrine. Based on this derived phenotype, we show that systematic differences exist between self-reported ancestry groups: European-Americans (EA; n = 1387) have a significantly higher systolic response to phenylephrine than African-Americans (AA; n = 1217) and Hispanic/Latinos (HA; n = 1713) (31.3% increase, p value < 6e−08 and 22.9% increase, p value < 5e−05 respectively), after adjusting for genetic ancestry, demographics, and relevant clinical covariates. We performed a genome-wide association study to investigate genetic factors underlying individual differences in this derived phenotype. We discovered genome-wide significant association signals in loci and genes previously associated with BP measured in ambulatory settings, and a general enrichment of association in these genes. Finally, we discovered two low frequency variants, present at ~1% in EAs and AAs, respectively, where patients carrying one copy of these variants show no phenylephrine response. This work demonstrates our ability to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from dense clinical and physiological measures captured for managing patients during surgery. We identify genetic variants underlying non response to phenylephrine, with implications for preemptive pharmacogenomic screening to improve safety during surgery.

scholarly journals Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

2021 ◽  
Author(s):  
Segun Fatumo ◽  
Tinashe Chikowore ◽  
Robert Kalyesubula ◽  
Rebecca N Nsubuga ◽  
Gershim Asiki ◽  
...  
Keyword(s):  
Kidney Function ◽  
Fine Mapping ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genetic Risk Score ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women’s Health Initiative. Loci attaining genome-wide significant evidence for association (P &lt; 5 × 10−8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10−8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10−8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.

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