scholarly journals Hearing Function: Identification of New Candidate Genes Further Explaining the Complexity of This Sensory Ability

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1228
Author(s):  
Maria Pina Concas ◽  
Anna Morgan ◽  
Fabrizio Serra ◽  
Andries Paul Nagtegaal ◽  
Berthe C. Oosterloo ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Expression Patterns ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Hearing Ability ◽  
Significance Threshold ◽  
Nominal Significance ◽  
Hearing Function ◽  
Eastern Usa

To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and pure-tone averages of thresholds at low, medium, and high frequencies) collected in nine cohorts from Europe, South-Eastern USA, Caucasus, and Central Asia, for an overall number of ~9000 subjects. Three hundred seventy-five genes across all nine analyses were tagged by single nucleotide polymorphisms (SNPs) reaching a suggestive p-value (p < 10−5). Amongst these, 15 were successfully replicated using a gene-based approach in the independent Italian Salus in the Apulia cohort (n = 1774) at the nominal significance threshold (p < 0.05). In addition, the expression level of the replicated genes was assessed in published human and mouse inner ear datasets. Considering expression patterns in humans and mice, eleven genes were considered particularly promising candidates for the hearing function: BNIP3L, ELP5, MAP3K20, MATN2, MTMR7, MYO1E, PCNT, R3HDM1, SLC9A9, TGFB2, and YTHDC2. These findings represent a further contribution to our understanding of the genetic basis of hearing function and its related diseases.

DCC and RET pathway analysis to identify factors associated with advanced colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 457-457
Author(s):  
Stacey Shiovitz ◽  
Li Hsu ◽  
Conghui Qu ◽  
Tabitha A. Harrison ◽  
Sonja Berndt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Genome Project ◽  
P Value ◽  
Candidate Snps ◽  
Nucleotide Polymorphisms ◽  
Dependence Receptor

457 Background: DCC (deleted in colon cancer; 18q21.3) is frequently lost in colorectal cancers (CRC), but few mutations in DCC have been discovered, even in tumors with 18q loss of heterozygosity. DCC has been shown to be a dependence receptor, with differential signaling depending on the presence (proliferative) or absence (pro-apoptotic) of the netrin-1 ligand (NTN1). DCC-mutated CRC tend to present at advanced stage and have a poor prognosis. RET, another dependence receptor, is a possible tumor suppressor gene in CRC and associates with CRC progression. Given the apparent role of DCC and RET in CRC progression, we carried out a genetic association study to determine if specific genetic variants in these pathways associate with advanced vs. early CRC. Methods: Imputed HapMap genome-wide association study (GWAS) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), a collection of 19 international case-control and cohort studies, was used to identify single nucleotide polymorphisms (SNPs) in DCC, NTN1, RET and interacting genes within 5kb upstream to 500mb downstream of each of the 54 genes. With the resultant 10,102 SNPs, we performed a stage-stratified analysis, comparing advanced (AJCC stage III-IV, n = 3500) to early CRC (I-II, n = 5300). An inverse-variance weighted fixed effect meta-analysis was performed with significance set at p=0.05/10102 SNPs=5x10-6 for multiple test correction. Results: Of the examined SNPs within DCC, the lowest p-value comparing advanced vs. early CRC was 3.6x10-3. SNPs in DOCK1 (dedicator of cytokinesis 1), which complexes with DCC and netrin-1, were associated with advanced CRC at p=1.11x10-3. SNPs in NTN1 and RET reached significance only at p = 1.73x10-2 and 1.53x10-2, respectively. No SNPs reached the pre-determined level of statistical significance. Conclusions: Our current analysis does not provide clear evidence for candidate SNPs associated with advanced CRC. Further approaches include expanding the analysis to include 1,000 Genome Project and ExomeChip data (~30,000 added SNPs), comparison of cases and controls, and evaluating candidate SNP-SNP interactions to better evaluate pathway pathogenesis. We plan to present an updated analysis at the symposium.

scholarly journals Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jaakko Laaksonen ◽  
Pashupati P. Mishra ◽  
Ilkka Seppälä ◽  
Leo-Pekka Lyytikäinen ◽  
Emma Raitoharju ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mitochondrial Dna ◽  
Genome Wide Association Study ◽  
Rare Variants ◽  
Meta Analysis ◽  
Noncommunicable Diseases ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Mitochondrial Dna Variants

AbstractHigh blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

scholarly journals Genome-Wide Association study Identifies a Novel Association Between a Cardiovascular Gene Polymorphism and Superior Athletic Performance

2020 ◽  
Author(s):  
Mohamed Elrayess ◽  
Fatima Al-Khelaifi ◽  
Noha Yousri ◽  
Omar Al-Bagha
Keyword(s):  
Athletic Performance ◽  
Genome Wide Association Study ◽  
Endurance Athlete ◽  
Meta Analysis ◽  
Significant Snps ◽  
Nucleotide Polymorphisms ◽  
Replication Studies ◽  
Genome Wide ◽  
Small Effect Size ◽  
Metabolomics Analysis

Research into the genetic predisposition to superior athletic performance has been a hindered by the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis. Results: The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high (n=662) and low/moderate (n=134) aerobic component. Validation of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (MYBPC3; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status (P=1.43E-08, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO2max than carriers of the AA+AG (P = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82x10-05) including the testosterone precursor androstenediol (3beta, 17beta) disulfate. Conclusion: This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted.

scholarly journals RAPID COMMUNICATION: Multi-breed validation study unraveled genomic regions associated with puberty traits segregating across tropically adapted breeds1

2019 ◽  
Vol 97 (7) ◽  
pp. 3027-3033 ◽  
Author(s):  
Thaise P Melo ◽  
Marina R S Fortes ◽  
Gerardo A Fernandes Junior ◽  
Lucia G Albuquerque ◽  
Roberto Carvalheiro
Keyword(s):  
Candidate Genes ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Reference Population ◽  
High Linkage Disequilibrium ◽  
P Value ◽  
Early Puberty ◽  
Sexual Precocity ◽  
Tropical Conditions ◽  
Genomic Regions

Abstract An efficient strategy to improve QTL detection power is performing across-breed validation studies. Variants segregating across breeds are expected to be in high linkage disequilibrium (LD) with causal mutations affecting economically important traits. The aim of this study was to validate, in a Tropical Composite cattle (TC) population, QTL associations identified for sexual precocity traits in a Nellore and Brahman meta-analysis genome-wide association study. In total, 2,816 TC, 8,001 Nellore, and 2,210 Brahman animals were available for the analysis. For that, genomic regions significantly associated with puberty traits in the meta-analysis study were validated for the following sexual precocity traits in TC: age at first corpus luteum (AGECL), first postpartum anestrus interval (PPAI), and scrotal circumference at 18 months of age (SC). We considered validated QTL those underpinned by significant markers from the Nellore and Brahman meta-analysis (P ≤ 10–4) that were also significant for a TC trait, i.e., presenting a P-value of ≤10–3 for AGECL, PPAI, or SC. We also considered as validated QTL those regions where significant markers in the reference population were at ±250 kb from significant markers in the validation population. Using this criteria, 49 SNP were validated for AGECL, 4 for PPAI, and 14 for SC, from which 5 were in common with AGECL, totaling 62 validated SNP for these traits and 30 candidate genes surrounding them. Considering just candidate genes closest to the top SNP of each chromosome, for AGECL 8 candidate genes were identified: COL8A1, PENK, ENSBTAG00000047425, BPNT1, ADAMTS17, CCHCR1, SUFU, and ENSBTAG00000046374. For PPAI, 3 genes emerged as candidates (PCBP3, KCNK10, and MRPS5), and for SC 8 candidate genes were identified (SNORA70, TRAC, ASS1, BPNT1, LRRK1, PKHD1, PTPRM, and ENSBTAG00000045690). Several candidate regions presented here were previously associated with puberty traits in cattle. The majority of emerging candidate genes are related to biological processes involved in reproductive events, such as maintenance of gestation, and some are known to be expressed in reproductive tissues. Our results suggested that some QTL controlling early puberty seem to be segregating across cattle breeds adapted to tropical conditions.

scholarly journals Genetic variants in humanin nuclear isoform gene regions show no association with coronary artery disease

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Mall Eltermaa ◽  
Maili Jakobson ◽  
Meeme Utt ◽  
Sulev Kõks ◽  
Reedik Mägi ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Multiple Testing ◽  
Meta Analysis ◽  
Noncommunicable Disease ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Artery Disease ◽  
Preventive Methods

Abstract Objective Coronary artery disease contributes to noncommunicable disease deaths worldwide. In order to make preventive methods more accurate, we need to know more about the development and progress of this pathology, including the genetic aspects. Humanin is a small peptide known for its cytoprotective and anti-apoptotic properties. Our study looked for genomic associations between humanin-like nuclear isoform genes and coronary artery disease using CARDIoGRAMplusC4D Consortium data. Results Lookup from meta-analysis datasets gave single nucleotide polymorphisms in all 13 humanin-like nuclear isoform genes with the lowest P value for rs6151662 from the MTRNR2L2 gene including the 50 kb flanking region in both directions (P-value = 0.0037). Within the gene region alone the top variant was rs78083998 from the MTRNR2L13 region (meta-analysis P-value = 0.042). None of the found associations were statistically significant after correction for multiple testing. Lookup for expression trait loci in these gene regions gave no statistically significant variants.

Vegf and bFGF Single-Nucleotide Polymorphisms In Chronic Lymphocytic Leukemia: Impact On Susceptibility

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5287-5287
Author(s):  
Sandra Ballester ◽  
Begoña Pineda ◽  
Eduardo Tormo ◽  
Blanca Navarro ◽  
Ariadna Perez ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Expression Patterns ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Exact Test ◽  
Cd38 Expression ◽  
Mutational Status ◽  
The Individual

Abstract Background B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease with a highly variable clinical outcome. Recent studies have identified a number of different molecular prognostic markers (including mutational status of the IgVH gene, ZAP70 and CD38 expression) that allow to discriminate patients in prognostic subgroups. However, different expression patterns of angiogenic factors as VEGF, VEGFR1 and bFGF have been related with B-CLL susceptibility and treatment requirements. We have analyzed the polymorphisms: -710 C/T in VEGFR1, rs1109324, rs1547651, rs3025039 (936C/T) and rs833052 in VEGF and rs1449683 (223 C/T) in bFGF in order to determine the possible association with susceptibility in B-CLL. Methods Peripheral blood samples from 230 B-CLL patients and 476 healthy controls were genotyped using probes TaqMan SNP Genotyping Assays. Samples were providing from the Hospital Clinic of Valencia. Four SNPs in the VEGF gene, one SNP in the bFGF gene and one SNP in the VEGFR1 gene were evaluated. Statistical analysis was performed using SNPStats program (Catalan Institute of Oncology) and Fisher's exact test was applied to evaluate the significance. Results We have observed an increased frequency of the T allele in the rs1449683 SNP [OR 1.62 (95% CI: 0.98-2.66) p-value =0.063] and in the rs1547651 SNP [OR 0.72 (95% CI: 0.51-1.03), p-value=0.072] in our B-LLC patients when compared to control subjects. Moreover we observed that T allele carriers of rs3025039 (VEGF) have a significant protective effect concerning this disease [OR 0.59 (95% CI: 0.39-0.89) p-value=0.009]. Conclusion Our data indicate an increased frequency of the T allele in polymorphisms rs1449683 (bFGF) and rs1547651 (VEGF) in the group of patients, which possibly account for the individual susceptibility to develop B-CLL. On the other hand the data provided suggest that the T allele of VEGF rs3025039 is likely important genetic marker of susceptibility to B-CLL. Further studies regarding the role of pro-angiogenic markers in B-CLL would be beneficial to help elucidate pathogenic pathways in this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility

Blood ◽  
2009 ◽  
Vol 113 (22) ◽  
pp. 5575-5582 ◽  
Author(s):  
Jeffrey A. Knight ◽  
Andrew D. Skol ◽  
Abhijit Shinde ◽  
Darcie Hastings ◽  
Richard A. Walgren ◽  
...  
Keyword(s):  
Association Study ◽  
Myeloid Leukemia ◽  
Genome Wide Association Study ◽  
Nucleotide Polymorphisms ◽  
Significant Excess ◽  
Single Nucleotide ◽  
Sporadic Cancer ◽  
Genome Wide ◽  
Nominal Significance ◽  
Acquired Abnormalities

Abstract Therapy-related acute myeloid leukemia (t-AML) is a rare but fatal complication of cytotoxic therapy. Whereas sporadic cancer results from interactions between complex exposures and low-penetrance alleles, t-AML results from an acute exposure to a limited number of potent genotoxins. Consequently, we hypothesized that the effect sizes of variants associated with t-AML would be greater than in sporadic cancer, and, therefore, that these variants could be detected even in a modest-sized cohort. To test this, we undertook an association study in 80 cases and 150 controls using Affymetrix Mapping 10K arrays. Even at nominal significance thresholds, we found a significant excess of associations over chance; for example, although 6 associations were expected at P less than .001, we found 15 (Penrich = .002). To replicate our findings, we genotyped the 10 most significantly associated single nucleotide polymorphisms (SNPs) in an independent t-AML cohort (n = 70) and obtained evidence of association with t-AML for 3 SNPs in the subset of patients with loss of chromosomes 5 or 7 or both, acquired abnormalities associated with prior exposure to alkylator chemotherapy. Thus, we conclude that the effect of genetic factors contributing to cancer risk is potentiated and more readily discernable in t-AML compared with sporadic cancer.

scholarly journals Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Gut ◽  
2019 ◽  
Vol 68 (5) ◽  
pp. 854-865 ◽  
Author(s):  
Clemens Schafmayer ◽  
James William Harrison ◽  
Stephan Buch ◽  
Christina Lange ◽  
Matthias C Reichert ◽  
...  
Keyword(s):  
Diverticular Disease ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Population Based ◽  
Genome Wide Association ◽  
P Value ◽  
Risk Variant ◽  
Complex Disorder ◽  
Genome Wide ◽  
Epithelial Dysfunction

ObjectiveDiverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.DesignDiscovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.ResultsWe discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10−10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33).ConclusionIn silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

scholarly journals A regulatory variant of CHRM3 is associated with cannabis-induced hallucinations in European Americans

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhongshan Cheng ◽  
Chureerat Phokaew ◽  
Yi-Ling Chou ◽  
Dongbing Lai ◽  
Jacquelyn L. Meyers ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Collaborative Study ◽  
Risk Genes ◽  
European Americans ◽  
Genome Wide ◽  
Nominal Significance ◽  
A Genome ◽  
Regulatory Variant

AbstractCannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs (n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 (P = 1.66 × 10−10), rs74722579 (P = 2.81 × 10−9), and rs1938228 (P = 1.57 × 10−8); signals were GWS in Yale-Penn 1 EAs (n = 1092) and nominally significant in Yale-Penn 2 EAs (n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs’ association signals were increased (meta-P-values 1.32 × 10−10 and 2.60 × 10−9, respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis (n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes (GABAG2, CHRNA4, and HRH3) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait.

A family-based genome-wide association study reveals an association of spondyloarthritis with MAPK14

2016 ◽  
Vol 76 (1) ◽  
pp. 310-314 ◽  
Author(s):  
Félicie Costantino ◽  
Alice Talpin ◽  
Roula Said-Nahal ◽  
Ariane Leboime ◽  
Elena Zinovieva ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Gwas Study ◽  
Genome Wide ◽  
Multiplex Families ◽  
Family Based

ObjectiveMore than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA.Methods906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations.Results43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1×10−4). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5×10−7). Such association appeared to be independent of HLA-B27.ConclusionsWe report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.

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