A multi-locus genetic association test for a dichotomous trait and its secondary phenotype

Genetic association studies often collect information on secondary phenotypes related to the primary disease status. In many situations, the secondary phenotypes are only measured in subjects with the disease condition. It would be advantageous to model the primary trait and the secondary phenotype together if they share certain level of genetic heritability. We propose a family of multi-locus testing procedures to detect the composite association between a set of genetic markers and two traits (the primary trait and a secondary phenotype), in order to identify genes influencing both traits. The proposed test is derived from a random effect model with two variance components, with each presenting the genetic effect on one trait, and incorporates a model selection procedure for seeking the optimal model to represent the two sources of genetic effects. We conduct simulation studies to evaluate performance of the proposed procedure and apply the method to a genome-wide association study of prostate cancer with the Gleason score as the secondary phenotype.

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Identification of SNPs and Candidate Genes for Milk Produce Ability in Yorkshire Pig

10.21203/rs.3.rs-585023/v1 ◽

2021 ◽

Author(s):

Lijun Shi ◽

Yang Li ◽

Qian Liu ◽

Longchao Zhang ◽

Ligang Wang ◽

...

Keyword(s):

Candidate Genes ◽

Milk Fat ◽

Genome Wide Association Study ◽

Random Effect ◽

Random Effect Model ◽

Significant Snps ◽

Limiting Factor ◽

Lactation Performance ◽

Genome Wide ◽

A Genome

Abstract Background: Sow milk produce ability is an important limiting factor impacting suboptimal growth and survival of piglets. By pig genetic improvement, the litter size has been increased, and larger litters need more suckled mammary glands, that results in increased milk from lactating sow. Hence, it has much significance to explore the sow lactation performance. The aim of this study was to estimate genetic parameters and screen single nucleotide polymorphisms (SNPs) for milk produce ability trait in 985 Yorkshire pigs by a genome-wide association study (GWAS), and to further identify the candidate genes.Results: By ASReml, we estimated the heritability of sow milk produce ability: 0.18 ± 0.07. With the Fixed and random effect model Circulating Probability Unification (FarmCPU), we performed a GWAS, and detected seven genome-wide significant SNPs, namely, Sus scrofa Chromosome (SSC) 2: ASGA0010040 (P = 7.73E-11); SSC2:MARC0029355 (P = 1.30E-08), SSC6: WU_10.2_6_65751151 (P = 1.32E-10), SSC7: MARC0058875 (P = 4.99E-09), SSC10: WU_10.2_10_49571394 (P = 6.79E-08), SSC11: M1GA0014659 (P = 1.19E-07), and SSC15: MARC0042106 (P = 1.16E-07). We performed the distribution of phenotypes corresponding to genotypes of the seven SNPs, and showed that ASGA0010040, MARC0029355, MARC0058875, WU_10.2_10_49571394, M1GA0014659, and MARC0042106 have extreme phenotypic values corresponded to the homozygous genotypes, while the intermediate values corresponded to the heterozygous genotypes. Further, we screened for flanking regions ± 200 kb nearby seven significant SNPs, and identified 30 genes. Among of them, 24 as the candidates were involved in lactose metabolism, colostrum immunity, milk protein, and milk fat by the gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis. Through the combined analysis between 24 candidate genes and differently expressed genes (DEGs) detected in transcriptome data (GSE101983), we found 11 commons (NAV2, ANO3, MUC15, DISP3, FBXO6, CLCN6, SLA-DQB1, PSMB8, PSMB9, TAP1, and KIF5C). Further, by comparing the chromosome positions of the candidate genes with the quantitative trait locus (QTLs) previously reported, a total of 13 genes were found to be within 0.86 Mb to 93.92 Mb of the reported QTLs for sow milk yield, in which, NAV2 was found to be located with 0.86 Mb of the QTL region ssc2: 40936355.Conclusions: In conclusion, we identified seven significant SNPs located on SSC2, 6, 7, 10, 11, and 15, and proposed 24 candidate genes for milk produce ability trait in Yorkshire pig. Among of them, 11 were the key candidates. These results contribute to the identification of variants and candidate genes for sow milk produce ability.

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A genome-wide association study of serum proteins reveals shared loci with common diseases

10.1101/2021.07.02.450858 ◽

2021 ◽

Author(s):

Alexander Gudjonsson ◽

Valborg Gudmundsdottir ◽

Gisli T Axelsson ◽

Elias F Gudmundsson ◽

Brynjolfur G Jonsson ◽

...

Keyword(s):

Genetic Association ◽

Genetic Variants ◽

Large Scale ◽

Complex Disease ◽

Genome Wide Association Study ◽

Serum Proteins ◽

Association Studies ◽

Loss Of Function ◽

Protein Levels ◽

A Genome

With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,113 independent associations between genetic variants and 2,099 serum proteins, of which 37% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a proteins genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.

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Association of FOXP3 Polymorphisms with Susceptibility to Multiple Sclerosis: A Meta-Analysis on Genetic Association Studies

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692118666200122163559 ◽

2020 ◽

Vol 17 (2) ◽

pp. 94-103

Author(s):

Nazanin Mousavi ◽

Seyyed Amir Yasin Ahmadi ◽

Zahra Mahmoudi ◽

Reza Nekouian ◽

Bijan Ansari-moghaddam ◽

...

Keyword(s):

Multiple Sclerosis ◽

Risk Factor ◽

Genetic Association ◽

Association Studies ◽

Meta Analysis ◽

Random Effect ◽

Random Effect Model ◽

Genetic Association Studies ◽

Genotype Frequencies ◽

Effect Model

Objectives: OXP3 is a gene related to regulatory T cells existing on chromosome X. This meta-analysis, based on genetic association studies, was conducted to investigate the association of FOXP3 polymorphisms with susceptibility to multiple sclerosis (MS). Methods: All genetic association studies covering both FOXP3 and multiple sclerosis terms were searched in PubMed, Web of Science and Google Scholar. The information of genotype frequencies was summarized and results were synthesized through odds ratio (OR). Heterogeneity and publication bias were investigated using I2 scale and Begg's funnel plot, respectively. Results: For rs3761548 -3279 C/A polymorphism, AA/AY genotypes were a risk factor in comparison to CC/CY genotypes (P =0.022; OR =1.752; 95% confidence interval [CI] =1.084-2.830; random). AC genotype was a risk factor in comparison to CC/CY genotypes (P =0.004; OR =1.537; 95% CI =1.145-2.062; random) and homozygote genotypes (P =0.016; OR =1.216; 95% CI =1.038-1.426; fixed). For rs2232365 -924 G/A polymorphism, 2 significant associations were found according to a fixed effect model; of course, they did not remain significant in the random effect model. Conclusion: According to the collected populations, susceptibility to and protection from MS are associated with rs3761548 -3279 C/A upstream polymorphism. However, it should be regarded that this association is ethnicity dependent with low effect size.

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Prioritization of genes associated with the pathogenesis of leukosis in cattle

Vavilov Journal of Genetics and Breeding ◽

10.18699/vj18.451 ◽

2019 ◽

Vol 22 (8) ◽

pp. 1063-1069 ◽

Cited By ~ 1

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.

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Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies

Placenta ◽

10.1016/j.placenta.2018.04.008 ◽

2018 ◽

Vol 66 ◽

pp. 8-16 ◽

Cited By ~ 2

Author(s):

Tsegaselassie Workalemahu ◽

Daniel A. Enquobahrie ◽

Bizu Gelaye ◽

Sixto E. Sanchez ◽

Pedro J. Garcia ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Placental Abruption ◽

Association Studies ◽

Meta Analysis ◽

Genetic Variations ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

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The Genetic Basis of Natural Variation in Drosophila melanogaster Immune Defense against Enterococcus faecalis

Genes ◽

10.3390/genes11020234 ◽

2020 ◽

Vol 11 (2) ◽

pp. 234 ◽

Cited By ~ 2

Author(s):

Joanne R Chapman ◽

Maureen A Dowell ◽

Rosanna Chan ◽

Robert L Unckless

Keyword(s):

Drosophila Melanogaster ◽

Enterococcus Faecalis ◽

Natural Variation ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Association Studies ◽

Immune Defense ◽

Nucleotide Polymorphisms ◽

Disease Response ◽

A Genome

Dissecting the genetic basis of natural variation in disease response in hosts provides insights into the coevolutionary dynamics of host-pathogen interactions. Here, a genome-wide association study of Drosophila melanogaster survival after infection with the Gram-positive entomopathogenic bacterium Enterococcus faecalis is reported. There was considerable variation in defense against E. faecalis infection among inbred lines of the Drosophila Genetics Reference Panel. We identified single nucleotide polymorphisms associated with six genes with a significant (p < 10−08, corresponding to a false discovery rate of 2.4%) association with survival, none of which were canonical immune genes. To validate the role of these genes in immune defense, their expression was knocked-down using RNAi and survival of infected hosts was followed, which confirmed a role for the genes krishah and S6k in immune defense. We further identified a putative role for the Bomanin gene BomBc1 (also known as IM23), in E. faecalis infection response. This study adds to the growing set of association studies for infection in Drosophila melanogaster and suggests that the genetic causes of variation in immune defense differ for different pathogens.

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Circulating antioxidants and Alzheimer disease prevention: a Mendelian randomization study

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy225 ◽

2018 ◽

Vol 109 (1) ◽

pp. 90-98 ◽

Cited By ~ 4

Author(s):

Dylan M Williams ◽

Sara Hägg ◽

Nancy L Pedersen

Keyword(s):

Alzheimer Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Disease Risk ◽

Late Onset ◽

Association Studies ◽

Nucleotide Polymorphisms ◽

Primary Methods ◽

A Genome ◽

Β Carotene

ABSTRACT Background Higher circulating antioxidant concentrations are associated with a lower risk of late-onset Alzheimer disease (AD) in observational studies, suggesting that diet-sourced antioxidants may be modifiable targets for reducing disease risk. However, observational evidence is prone to substantial biases that limit causal inference, including residual confounding and reverse causation. Objectives In order to infer whether long-term circulating antioxidant exposure plays a role in AD etiology, we tested the hypothesis that AD risk would be lower in individuals with lifelong, genetically predicted increases in concentrations of 4 circulating antioxidants that are modifiable by diet. Methods Two-sample Mendelian randomization analyses were conducted. First, published genetic association studies were used to identify single-nucleotide polymorphisms (SNPs) that determine variation in circulating ascorbate (vitamin C), β-carotene, retinol (vitamin A), and urate. Second, for each set of SNP data, statistics for genotype associations with AD risk were extracted from data of a genome-wide association study of late-onset AD cases and controls (n = 17,008 and 37,154, respectively). Ratio-of-coefficients and inverse-variance-weighted meta-analyses were the primary methods used to assess the 4 sets of SNP-exposure and SNP-AD associations. Additional analyses assessed the potential impact of bias from pleiotropy on estimates. Results The models suggested that genetically determined differences in circulating ascorbate, retinol, and urate are not associated with differences in AD risk. All estimates were close to the null, with all ORs for AD ≥1 per unit increase in antioxidant exposure (ranging from 1.00 for ascorbate to 1.05 for retinol). There was little evidence to imply that pleiotropy had biased results. Conclusions Our findings suggest that higher exposure to ascorbate, β-carotene, retinol, or urate does not lower the risk of AD. Replication Mendelian randomization studies could assess this further, providing larger AD case-control samples and, ideally, using additional variants to instrument each exposure.

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An integrated genomic-transcriptomic approach supports a role for the proto-oncogene BCL3 in atherosclerosis

Thrombosis and Haemostasis ◽

10.1160/th14-05-0466 ◽

2015 ◽

Vol 113 (03) ◽

pp. 655-663 ◽

Cited By ~ 7

Author(s):

Giovanna Marchetti ◽

Domenico Girelli ◽

Carlotta Zerbinati ◽

Barbara Lunghi ◽

Simonetta Friso ◽

...

Keyword(s):

Genome Wide Association Study ◽

Association Studies ◽

Integrated Approach ◽

Mrna Levels ◽

Nucleotide Polymorphisms ◽

Tissue Samples ◽

A Genome ◽

Artery Disease ◽

Genetic Signatures ◽

Adjusted Model

Summaryassociation studies of coronary artery disease (CAD), could include functionally relevant associations. We propose an integrated genomic and transcriptomic approach for unravelling new potential genetic signatures of atherosclerosis. Fifteen among 91 single nucleotide polymorphisms (SNPs) were first selected for association in a sex- and age-adjusted model by examining 510 patients with CAD and myocardial infarction and 388 subjects with normal coronary arteries (CAD-free) in the replication stages of a genome-wide association study. We investigated the expression of 71 genes proximal to the 15 tag-SNPs by two subsequent steps of microarray-based Mrna profiling, the former in vascular smooth muscle cell populations, isolated from non-atherosclerotic and atherosclerotic human carotid portions, and the latter in whole carotid specimens. BCL3 and PVRL2, contiguously located on chromosome 19, and ABCA1, extensively investigated before, were found to be differentially expressed. BCL3 and PVRL2 SNPs were genotyped within a second population of CAD patients (n=442) and compared with CAD-free subjects (n=393). The carriership of the BCL3 rs2965169 G allele was more represented among CAD patients and remained independently associated with CAD after adjustment for all the traditional cardiovascular risk factors (odds ratio=1.70 with 95% confidence interval 1.07–2.71), while the BCL3 rs8100239 A allele correlated with metabolic abnormalities. The upregulation of BCL3 mRNA levels in atherosclerotic tissue samples was consistent with BCL3 protein expression, which was detected by immunostaining in the intima-media of atherosclerotic specimens, but not within non-atherosclerotic ones. Our integrated approach suggests a role for BCL3 in cardiovascular diseases.

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