scholarly journals Genome-wide analyses reveal a strong association between LEPR gene variants and body fat reserves in ewes

2021 ◽  
Author(s):  
Tiphaine Macé ◽  
Eliel Gonzalez-Garcia ◽  
Didier Foulquié ◽  
Fabien Carrière ◽  
Julien Pradel ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Body Condition Score ◽  
Receptor Gene ◽  
Strong Association ◽  
Significant Snps ◽  
Chromosome 1 ◽  
Nucleotide Polymorphisms ◽  
Fat Reserves ◽  
Genome Wide ◽  
Pregnancy And Lactation

Among the adaptive capacities of animals, the management of energetic body reserves (BR) through the BR mobilization and accretion processes (BR dynamics, BRD) has become an increasingly valuable attribute for livestock sustainability, allowing animals to cope with more variable environments. BRD has previously been reported to be heritable in ruminants. In the present study, we conducted genome-wide studies (GWAS) in sheep to determine genetic variants associated with BRD. BR levels and BR changes over time were obtained through body condition score measurements at eight physiological stages throughout each productive cycle in Romane ewes (n=1034) and were used as phenotypes for GWAS. After quality controls and imputation, 48,513 single nucleotide polymorphisms (SNP) were included in the GWAS. Among the QTLs identified, a major QTL associated with BR levels during pregnancy and lactation was identified on chromosome 1. In this region, several significant SNPs mapped to the leptin receptor gene (LEPR), among which one SNP mapped to the coding sequence. The point mutation induces the p.P1019S substitution in the cytoplasmic domain, close to tyrosine phosphorylation sites. The frequency of the SNP associated with increased BR levels was 32%, and the LEPR genotype explained up to 5% of the variance of the trait. These results provide strong evidence for involvement of LEPR in the regulation of BRD in sheep and highlight it as a major candidate for improving adaptive capacities.

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 Genome-Wide Association Studies for the Concentration of Albumin in Colostrum and Serum in Chinese Holstein

Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2211
Author(s):  
Shan Lin ◽  
Zihui Wan ◽  
Junnan Zhang ◽  
Lingna Xu ◽  
Bo Han ◽  
...  
Keyword(s):  
Association Studies ◽  
Significant Snps ◽  
Albumin Concentration ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Chinese Holstein ◽  
Genome Wide ◽  
Chinese Holstein Cows ◽  
Newborn Calves

Albumin can be of particular benefit in fighting infections for newborn calves due to its anti-inflammatory and anti-oxidative stress properties. To identify the candidate genes related to the concentration of albumin in colostrum and serum, we collected the colostrum and blood samples from 572 Chinese Holstein cows within 24 h after calving and measured the concentration of albumin in the colostrum and serum using the ELISA methods. The cows were genotyped with GeneSeek 150 K chips (containing 140,668 single nucleotide polymorphisms; SNPs). After quality control, we performed GWASs via GCTA software with 91,620 SNPs and 563 cows. Consequently, 9 and 7 genome-wide significant SNPs (false discovery rate (FDR) at 1%) were identified. Correspondingly, 42 and 206 functional genes that contained or were approximate to (±1 Mbp) the significant SNPs were acquired. Integrating the biological process of these genes and the reported QTLs for immune and inflammation traits in cattle, 3 and 12 genes were identified as candidates for the concentration of colostrum and serum albumin, respectively; these are RUNX1, CBR1, OTULIN,CDK6, SHARPIN, CYC1, EXOSC4, PARP10, NRBP2, GFUS, PYCR3, EEF1D, GSDMD, PYCR2 and CXCL12. Our findings provide important information for revealing the genetic mechanism behind albumin concentration and for molecular breeding of disease-resistance traits in dairy cattle.

Response to Intravenous Cyclophosphamide Treatment for Lupus Nephritis Associated with Polymorphisms in the FCGR2B-FCRLA Locus

2016 ◽  
Vol 43 (6) ◽  
pp. 1045-1049 ◽  
Author(s):  
Kwangwoo Kim ◽  
So-Young Bang ◽  
Young Bin Joo ◽  
Taehyeung Kim ◽  
Hye-Soon Lee ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Receptor Gene ◽  
Genotype Imputation ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Cyclophosphamide Treatment

Objective.Cyclophosphamide (CYC) is an immunosuppressant drug widely used to treat various diseases including lupus nephritis, but its efficacy highly varies from individual to individual. This pharmacogenomics association study searched for genetic variations associated with CYC efficacy.Methods.Genome-wide association scan was performed for 109 Korean patients with systemic lupus erythematosus with lupus nephritis (classes III–V) who received intravenous CYC induction therapy. Genetic differences between responders and nonresponders were examined using Cochran–Armitage trend tests, and genotype imputation was used for defining the association locus.Results.Genetic polymorphisms in the Fcγ receptor gene (FCGR) cluster at human chromosome 1q23, previously associated with lupus nephritis susceptibility, were associated with the response to CYC treatment for lupus nephritis. Significant response association was found for 3 perfectly correlated (r2 = 1) single-nucleotide polymorphisms (SNP): rs6697139, rs10917686, and rs10917688, located between the FCGR2B and FCRLA genes (p = 3.4 × 10−8). Carriage of the minor alleles in these SNP was found only in nonresponders (31%) and none in responders (0%).Conclusion.This first genome-wide association approach for CYC response yielded a robust profile of genetic associations including large-effect SNP in the FCGR2B-FCRLA locus, which may provide better insights to CYC metabolism and efficacy.

Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort

2019 ◽  
Vol 54 (9) ◽  
pp. 902-908 ◽  
Author(s):  
Xiaoman Liu ◽  
Siew-Kee Low ◽  
Joshua R Atkins ◽  
Jing Qin Wu ◽  
William R Reay ◽  
...  
Keyword(s):  
Association Study ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Receptor Gene ◽  
Genome Wide Association ◽  
Polymorphism Analysis ◽  
Snp Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide

Objectives: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories. Methods: We performed a case–control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome. Results: The strongest finding ( p = 2.01 × 10−6, odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance ( p = 2.78 × 10−6). Conclusion: The identification of FZD1, as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.

Using hapmap tools to predict oncology-related phenotypes: TPMT activity vs hapmap SNPs

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13035-13035
Author(s):  
T. Jones ◽  
W. Yang ◽  
W. Evans ◽  
M. Relling
Keyword(s):  
Cell Lines ◽  
Association Studies ◽  
Rank Correlation ◽  
Significant Snps ◽  
Positive Control ◽  
Tpmt Activity ◽  
International Hapmap Project ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Thiopurine Therapy

13035 Background: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme responsible for the S-methylation of thiopurines. There are several functional genetic polymorphisms in TPMT activity, which can lead to drug toxicities; however, among individuals with high TPMT activity, a substantial portion of enzymatic variability remains unexplained. B-lymphoblastoid CEPH cell lines have been genotyped at over 2 million single nucleotide polymorphisms (SNPs) as part of the International HapMap project. Therefore, extensive phenotype-genotype association studies can be conducted in these cell lines by systematic determination of cancer-related phenotypes. Methods: We measured the phenotype of TPMT activity in 82 CEPH cell lines. Of these, 53 had expression data available on over 8000 genes from Affymetrix Focus Array technology. We evaluated whether TPMT activity was associated with HapMap SNPs in TPMT (cis SNPs), genome-wide HapMap SNPs (trans SNPs), and level of gene expression using Kruskal-Wallis test and Spearmans rank correlation. Results: We found associations of TPMT activity with four SNPs (p < 0.05) in TPMT (± 100K bp), one of which (rs1142345, p = 0.009) is a known functional SNP responsible for TPMT deficiency. Two other significant SNPs are in linkage disequilibrium with rs1142345. Associations were also found with 1598 trans SNPs across the genome (p < 0.001). TPMT activity was associated with the expression of eight genes (p < 0.0001, FDR <20%). The only overlapping trans gene is PACSIN2, whose expression most significantly correlated with TPMT activity and also contains two significantly predictive trans SNPs. Conclusions: The CEPH cell lines were useful in that a known functional variant, rs1142345, (serving as a positive control) was associated with TPMT activity, and that additional polymorphisms in TPMT and in potentially important trans-acting factors have been identified as possible additional genomic determinants of TPMT activity. Similar experiments with other phenotypes can likewise capitalize on this publicly available resource. With further validation, these studies may lead to discovery of additional candidate polymorphisms that can lead to further optimization of thiopurine therapy in the clinic. No significant financial relationships to disclose.

Genetic Variations in GRIA1 On Chromosome 5q33 Related to Asparaginase Hypersensitivity in Childhood Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 112-112
Author(s):  
Shih-Hsiang Chen ◽  
Deqing Pei ◽  
Wenjian Yang ◽  
Cheng Cheng ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Validation Cohort ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Nucleotide Polymorphisms ◽  
Discovery Cohort ◽  
Genomic Variations ◽  
Genome Wide ◽  
Antileukemic Effect ◽  
Bacterial Sources

Abstract Abstract 112 Asparaginase, an important antileukemic agent for ALL, is isolated from bacterial sources, and hence hypersensitivity reactions frequently occur; these reactions may attenuate its enzymatic activity and thus its antileukemic effect. Inherited genomic variations are known to affect the risk of hypersensitivity to some medications, but those that affect the risk of asparaginase allergy are not known. We interrogated 500,000 single nucleotide polymorphisms (SNPs) in 485 children with ALL treated on a single clinical trial to identify SNPs associated with allergy to native E. Coli (Elspar) asparaginase. A total of 204 (41%) patients developed an allergic reaction, most of which were NCI grade 2. We divided the patients into a discovery (n = 322) and a validation (n = 163) cohort, balancing for age, sex, treatment arm, race, and the occurrence of asparaginase allergy. Among the top 100 SNPs significantly associated with allergy in the discovery cohort, SNPs on chromosomes 5 and 19 were overrepresented, hosting 12 SNPs annotated to genes. Among these 12 SNPs, only one SNP (rs4958381 in GRIA1 on chromosome 5q33) replicated in the validation cohort (p = 2.8 ′ 10−5 and 2.0 ′ 10−3 in the discovery and validation cohorts, respectively). This locus has been associated with asthma or atopy. We further found that an additional 11 SNPs annotated to GRIA1 (a glutamate receptor gene) associated with asparaginase allergy at p < 0.05 in the discovery cohort, 4 of which replicated in the validation cohort (rs10070447, rs6890057, rs4958676, and rs6889909) at p < 0.05. Based on GRIA1 SNP rs4958381, the cumulative incidence of asparaginase allergy (Figure) was 74%, 44%, and 32% for those with the AA, AG, and GG genotypes, respectively (n = 485, p = 4.2 ′ 10−8). The 5q33 region hosts several cytokine and immunomodulatory genes, with multiple genome-wide studies implicating this locus in asthma and atopy. An agnostic genome-wide approach implicates genomic variations in GRIA1 on chromosome 5q33 as predisposing to the risk of asparaginase allergy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Fine mapping of porcine chromosome 6 QTL and LEPR effects on body composition in multiple generations of an Iberian by Landrace intercross

2005 ◽  
Vol 85 (1) ◽  
pp. 57-67 ◽  
Author(s):  
C. ÓVILO ◽  
A. FERNÁNDEZ ◽  
J. L. NOGUERA ◽  
C. BARRAGÁN ◽  
R. LETÓN ◽  
...  
Keyword(s):  
Body Composition ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Chromosome 6 ◽  
Nucleotide Polymorphisms ◽  
Fat Percentage ◽  
Muscle Area ◽  
Eye Muscle ◽  
Coding Regions ◽  
Narrow Region

The leptin receptor gene (LEPR) is a candidate for traits related to growth and body composition, and is located on SSC6 in a region where fatness and meat composition quantitative trait loci (QTL) have previously been detected in several F2 experimental designs. The aims of this work were: (i) to fine map these QTL on a larger sample of animals and generations (F3 and backcross) of an Iberian×Landrace intercross and (ii) to examine the effects of LEPR alleles on body composition traits. Eleven single nucleotide polymorphisms (SNPs) were detected by sequencing LEPR coding regions in Iberian and Landrace pig samples. Three missense polymorphisms were genotyped by pyrosequencing in 33 F0, 70 F1, 418 F2, 86 F3 and 128 individuals coming from the backcross of four F2 males with 24 Landrace females. Thirteen microsatellites and one SNP were also genotyped. Traits analysed were: backfat thickness at different locations (BFT), intramuscular fat percentage (IMFP), eye muscle area (EMA), loin depth (LOD), weight of shoulder (SHW), weight of ribs (RIBW) and weight of belly bacon (BBW). Different statistical models were applied in order to evaluate the number and effects of QTL on chromosome 6 and the possible causality of the LEPR gene variants with respect to the QTL. The results support the presence of two QTL on SSC6. One, at position 60–100 cM, affects BFT and RIBW. The other and more significant maps in a narrow region (130–132 cM) and affects BFT, IMFP, EMA, LOD, SHW, RIBW and BBW. Results also support the association between LEPR alleles and BFT traits. The possible functional implications of the analysed polymorphisms are considered.

scholarly journals Genetics of Arthrogryposis and Macroglossia in Piemontese Cattle Breed

Animals ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1732
Author(s):  
Liliana Di Stasio ◽  
Andrea Albera ◽  
Alfredo Pauciullo ◽  
Alberto Cesarani ◽  
Nicolò P. P. Macciotta ◽  
...  
Keyword(s):  
Genetic Background ◽  
Nervous Tissue ◽  
Genome Wide Association Study ◽  
Strong Association ◽  
Cattle Breed ◽  
Significant Snps ◽  
Canonical Discriminant Analysis ◽  
Genome Wide Association ◽  
Genetic Studies ◽  
Genome Wide

Arthrogryposis and macroglossia are congenital pathologies known in several cattle breeds, including Piemontese. As variations in single genes were identified as responsible for arthrogryposis in some breeds, we decided: (i) to test the hypothesis of a similar genetic determinism for arthrogryposis in the Piemontese breed by genotyping affected and healthy animals with a high-density chip and applying genome-wide association study (GWAS), FST and canonical discriminant analysis (CDA) procedures, and (ii) to investigate with the same approach the genetic background of macroglossia, for which no genetic studies exist so far. The study included 125 animals (63 healthy, 30 with arthrogryposis, and 32 with macroglossia). Differently from what reported for other breeds, the analysis did not evidence a single strong association with the two pathologies. Rather, 23 significant markers on different chromosomes were found (7 associated to arthrogryposis, 11 to macroglossia, and 5 to both pathologies), suggesting a multifactorial genetic mechanism underlying both diseases in the Piemontese breed. In the 100-kb interval surrounding the significant SNPs, 20 and 26 genes were identified for arthrogryposis and macroglossia, respectively, with 12 genes in common to both diseases. For some genes (NTN3, KCNH1, KCNH2, and KANK3), a possible role in the pathologies can be hypothesized, being involved in processes related to muscular or nervous tissue development. The real involvement of these genes needs to be further investigated and validated.

Mutations in the leptin receptor gene associated with delayed onset of puberty are also associated with decreased ovulation and lambing rates in prolific Davisdale sheep

2016 ◽  
Vol 28 (9) ◽  
pp. 1318 ◽  
Author(s):  
Jennifer L. Juengel ◽  
Michelle C. French ◽  
Anne R. O'Connell ◽  
Sara J. Edwards ◽  
Avijit Haldar ◽  
...  
Keyword(s):  
Reproductive Performance ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Reproductive Traits ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Partial Failure ◽  
Delayed Onset ◽  
Service Conception

The aim of this study was to determine if single nucleotide polymorphisms (SNPs) in the leptin receptor (LEPR) gene associated with delayed onset of puberty are associated with changes in other reproductive traits in adult ewes. The ovulation rate of ewes homozygous for the SNPs was ~15% lower (P < 0.001) than either wild-type or heterozygous ewes. First-service conception rate was also affected, being ~12% lower (P < 0. 01) in ewes homozygous for the LEPR SNPs than their wild-type or heterozygous contemporaries. Partial failure of multiple ovulations was also increased (P < 0.01) in ewes that ovulated three ova that were either heterozygous or homozygous for the mutations. Ewes homozygous for the mutations in LEPR had on average 0.2 fewer lambs at mid-pregnancy and at birth compared with the wild-type or heterozygous ewes (P < 0.01). Thus, mutations in LEPR were strongly associated with poorer reproductive performance in Davisdale ewes, which is likely to be linked to both a reduced number of ova available for fertilisation and an increased number of ewes failing to become pregnant. Increased partial failure of multiple ovulations in ewes with high ovulation rates (i.e. 3 or greater) may also contribute to the poor reproductive performance.

scholarly journals Obesity in Children with Leptin Receptor Gene Polymorphisms

2021 ◽  
Vol 64 (3) ◽  
pp. 158-164
Author(s):  
Aleksandr Abaturov ◽  
Anna Nikulina
Keyword(s):  
Discriminant Analysis ◽  
Sequential Analysis ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Bioinformatic Analysis ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Multiple Discriminant Analysis ◽  
Obese Children ◽  
Nominal Data

Introduction: The study of single nucleotide polymorphisms (SNPs) of the leptin receptor gene (LEPR) based on next generation genomic sequencing (NGS) data is becoming an increasingly important aspect of diagnosis, treatment and prevention of both metabolically healthy (MHO) and metabolically unhealthy obesity (MUO) phenotypes. Material and methods: 35 obese children 6-18 years old were examined by the NGS method with bioinformatic analysis. The main group (n = 18) was formed by children with MUO, according to the recommendations of the expert group of the National Heart, Lung, and Blood Institute. The control group (n = 17) was represented by children with MHO. Statistical methods were used: analysis of variance, Wald’s sequential analysis, Spearman’s correlation analysis, analysis of nominal data and multiple discriminant analysis. Results: 10 types of non-synonymous SNPs (rs3790435, rs1137100, rs2186248, rs70940803, rs79639154, rs1359482195, rs1137101, rs1805094, rs13306520, rs13306522) of the LEPR gene in obese children have been identified. Multiple discriminant analysis demonstrated that the following LEPR SNPs are of greatest importance in the development of MUO: rs3790435, rs13306522, rs13306520. Analysis of nominal data revealed significant differences in the groups for Copy number variation (CNV) rs3790435 of the LEPR gene. Wald’s analysis allowed us to identify 6 important predictors of MUO (І ≥ 0.5): 2 CNV rs3790435 (Relative Risk, RR = 2, Prognostic coefficient, PC = +2.76); male gender of the child (RR = 1.3, PC = +1.35); rs3790435 (RR = 1.9, PC = +2.76); hyperleptinemia more than 40.56 ng/ml (RR = 2, PC = +3); CNV rs1359482195 ≥ 3 (RR = 1.9, PC = +5.8); SNP of the LEPR gene ≥4 (RR = 3.8, PC = +5.8). Conclusion: Children with the genotype rs3790435 gene LEPR had signs of MUO more often.

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