scholarly journals Genetics and epigenetics of syntropic diseases

2010 ◽  
Vol 8 (4) ◽  
pp. 39-43 ◽  
Author(s):  
Viktoriya N Gorbunova
Keyword(s):  
Association Studies ◽  
Structural Features ◽  
Human Diseases ◽  
Functional Polymorphisms ◽  
Genetic Components ◽  
Expression Control ◽  
Candidate Gene Association ◽  
Genome Wide ◽  
The Common ◽  
The Many

 The genetic components are involved in aetiology of the common human diseases. For most of them it is significant the phenomenon of syntropies — nonrandom combination of different diseases in the same patients. Three methodic approaches have been successfully used for the identification of genetic factors predisposed to the common human diseases: linkage analysis, candidate gene association studies (GASs) and genome-wide association scans (GWASs). The structural features of the many genes make a small but significant contribution to the overall risk of common diseases. Syntropy of related diseases is determined of having of share in disease pathogenesis the functional polymorphisms of genes controlling the same metabolic pathways. Nonrandom combination of different diseases in the same patients is determined of common epigenetic mechanisms involved in expression control of different «gene nets» disorder.

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 Estimating Effect Sizes and Expected Replication Probabilities from GWAS Summary Statistics

2015 ◽  
Author(s):  
Dominic Holland ◽  
Yunpeng Wang ◽  
Wesley K Thompson ◽  
Andrew Schork ◽  
Chi-Hua Chen ◽  
...  
Keyword(s):  
Association Studies ◽  
Significant Snps ◽  
Effect Sizes ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Sample Sizes ◽  
Genetic Components ◽  
Complex Phenotypes ◽  
Genome Wide ◽  
Z Scores

Genome-wide Association Studies (GWAS) result in millions of summary statistics (``z-scores'') for single nucleotide polymorphism (SNP) associations with phenotypes. These rich datasets afford deep insights into the nature and extent of genetic contributions to complex phenotypes such as psychiatric disorders, which are understood to have substantial genetic components that arise from very large numbers of SNPs. The complexity of the datasets, however, poses a significant challenge to maximizing their utility. This is reflected in a need for better understanding the landscape of z-scores, as such knowledge would enhance causal SNP and gene discovery, help elucidate mechanistic pathways, and inform future study design. Here we present a parsimonious methodology for modeling effect sizes and replication probabilities that does not require raw genotype data, relying only on summary statistics from GWAS substudies, and a scheme allowing for direct empirical validation. We show that modeling z-scores as a mixture of Gaussians is conceptually appropriate, in particular taking into account ubiquitous non-null effects that are likely in the datasets due to weak linkage disequilibrium with causal SNPs. The four-parameter model allows for estimating the degree of polygenicity of the phenotype -- the proportion of SNPs (after uniform pruning, so that large LD blocks are not over-represented) likely to be in strong LD with causal/mechanistically associated SNPs -- and predicting the proportion of chip heritability explainable by genome wide significant SNPs in future studies with larger sample sizes. We apply the model to recent GWAS of schizophrenia (N=82,315) and additionally, for purposes of illustration, putamen volume (N=12,596), with approximately 9.3 million SNP z-scores in both cases. We show that, over a broad range of z-scores and sample sizes, the model accurately predicts expectation estimates of true effect sizes and replication probabilities in multistage GWAS designs. We estimate the degree to which effect sizes are over-estimated when based on linear regression association coefficients. We estimate the polygenicity of schizophrenia to be 0.037 and the putamen to be 0.001, while the respective sample sizes required to approach fully explaining the chip heritability are 106and 105. The model can be extended to incorporate prior knowledge such as pleiotropy and SNP annotation. The current findings suggest that the model is applicable to a broad array of complex phenotypes and will enhance understanding of their genetic architectures.

Abstract 18836: Integrative Pathway Analysis of Genome-wide Association Studies of Carotid Plaque Phenotypes

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yuqi Zhao ◽  
Sander M van der Laan ◽  
Hester M den Ruijter ◽  
Saskia Haitjema ◽  
Gerard Pasterkamp ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cardiovascular Events ◽  
Association Studies ◽  
Genome Wide Association ◽  
Sphingolipid Metabolism ◽  
Genome Wide Association Studies ◽  
Plaque Composition ◽  
Genetic Loci ◽  
Genetic Components ◽  
Genome Wide

Introduction: The composition of atherosclerotic plaques differs between individuals and contributes to the incidence of cardiovascular events. A better understanding of the biology underlying variability in plaque composition will provide insights into the progression of cardiovascular diseases. We carried out genome-wide association studies (GWAS) to investigate the genetic underpinnings of the plaque. Methods: We included carotid endarterectomy patients from the Athero-Express Biobank Study (n = 1,439). We quantified the percentage of macrophages and smooth muscle cells, the number of intraplaque vessels, the amount of collagen and calcification, the atheroma size, and the presence of plaque hemorrhage. GWAS was performed for all 9 plaque traits, and combined with summary level from GWAS consortia data on coronary artery disease (CAD), and ischemic stroke. Next, these data were integrated with data from human expression quantitative trait loci analyses, and pathway analyses of the plaque traits. Results: No individual locus reached genome-wide significance, likely due to the moderate sample size involved. However, it is plausible that perturbations of diverse pathways by a large number of genetic loci with small effects together contribute to the regulation of plaque composition. We identified 42-97 pathways significantly associated with each plaque phenotype, with many specific to each trait, supporting the presence of unique genetic components of individual plaque phenotypes. We also detected 39 pathways associated with at least four plaque phenotypes, among which were CAD-associated processes such as “extracellular matrix”, “complement and coagulation cascades” and stroke-associated pathways such as “Toll-like receptor signaling”. Interestingly, we found that smooth muscle cell percentage and atheroma size shared more genetic loci and pathways with intraplaque hemorrhage (such as “Sphingolipid metabolism”); the latter trait is associated with secondary cardiovascular events. Conclusion: There are genetic correlations among plaque phenotypes as well as between plaque phenotypes that provide mechanistic insight into the composition of the plaque and progression to secondary events.

Genome-wide association studies of Ca and Mn in the seeds of the common bean (Phaseolus vulgaris L.)

Genomics ◽  
2020 ◽  
Vol 112 (6) ◽  
pp. 4536-4546
Author(s):  
Semih Erdogmus ◽  
Duygu Ates ◽  
Seda Nemli ◽  
Bulent Yagmur ◽  
Tansel Kaygisiz Asciogul ◽  
...  
Keyword(s):  
Phaseolus Vulgaris ◽  
Common Bean ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Phaseolus Vulgaris L ◽  
Genome Wide ◽  
The Common

scholarly journals Common and Rare Variants in Genes Associated with von Willebrand Factor Level Variation: No Accumulation of Rare Variants in Swedish von Willebrand Disease Patients

TH Open ◽  
2020 ◽  
Vol 04 (04) ◽  
pp. e322-e331
Author(s):  
Eric Manderstedt ◽  
Christina Lind-Halldén ◽  
Stefan Lethagen ◽  
Christer Halldén
Keyword(s):  
Von Willebrand Factor ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Von Willebrand Disease ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Common ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractGenome-wide association studies (GWASs) have identified genes that affect plasma von Willebrand factor (VWF) levels. ABO showed a strong effect, whereas smaller effects were seen for VWF, STXBP5, STAB2, SCARA5, STX2, TC2N, and CLEC4M. This study screened comprehensively for both common and rare variants in these eight genes by resequencing their coding sequences in 104 Swedish von Willebrand disease (VWD) patients. The common variants previously associated with the VWF level were all accumulated in the VWD patients compared to three control populations. The strongest effect was detected for blood group O coded for by the ABO gene (71 vs. 38% of genotypes). The other seven VWF level associated alleles were enriched in the VWD population compared to control populations, but the differences were small and not significant. The sequencing detected a total of 146 variants in the eight genes. Excluding 70 variants in VWF, 76 variants remained. Of the 76 variants, 54 had allele frequencies > 0.5% and have therefore been investigated for their association with the VWF level in previous GWAS. The remaining 22 variants with frequencies < 0.5% are less likely to have been evaluated previously. PolyPhen2 classified 3 out of the 22 variants as probably or possibly damaging (two in STAB2 and one in STX2); the others were either synonymous or benign. No accumulation of low frequency (0.05–0.5%) or rare variants (<0.05%) in the VWD population compared to the gnomAD (Genome Aggregation Database) population was detected. Thus, rare variants in these genes do not contribute to the low VWF levels observed in VWD patients.

scholarly journals Independent Replication and Meta-Analysis for Endometriosis Risk Loci

2015 ◽  
Vol 18 (5) ◽  
pp. 518-525 ◽  
Author(s):  
Yadav Sapkota ◽  
Amelie Fassbender ◽  
Lisa Bowdler ◽  
Jenny N. Fung ◽  
Daniëlle Peterse ◽  
...  
Keyword(s):  
Complex Disease ◽  
Association Studies ◽  
Meta Analysis ◽  
Candidate Gene Association ◽  
Genome Wide ◽  
Independent Population ◽  
Original Genome ◽  
Independent Replication ◽  
Successful Replication ◽  
Coding Variants

Endometriosis is a complex disease that affects 6–10% of women in their reproductive years and 20–50% of women with infertility. Genome-wide and candidate-gene association studies for endometriosis have identified 10 independent risk loci, and of these, nine (rs7521902, rs13394619, rs4141819, rs6542095, rs1519761, rs7739264, rs12700667, rs1537377, and rs10859871) are polymorphic in European populations. Here we investigate the replication of nine SNP loci in 998 laparoscopically and histologically confirmed endometriosis cases and 783 disease-free controls from Belgium. SNPs rs7521902, rs13394619, and rs6542095 show nominally significant (p < .05) associations with endometriosis, while the directions of effect for seven SNPs are consistent with the original reports. Association of rs6542095 at the IL1A locus with ‘All’ (p = .066) and ‘Grade_B’ (p = .01) endometriosis is noteworthy because this is the first successful replication in an independent population. Meta-analysis with the published results yields genome-wide significant evidence for rs7521902, rs13394619, rs6542095, rs12700667, rs7739264, and rs1537377. Notably, three coding variants in GREB1 (near rs13394619) and CDKN2B-AS1 (near rs1537377) also showed nominally significant associations with endometriosis. Overall, this study provides important replication in a uniquely characterized independent population, and indicates that the majority of the original genome-wide association findings are not due to chance alone.

scholarly journals What is Next for the Genetics of Multiple Sclerosis?

2011 ◽  
Vol 2011 ◽  
pp. 1-3 ◽  
Author(s):  
Sreeram V. Ramagopalan ◽  
David A. Dyment
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Risk ◽  
Neurological Disease ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
New Genes ◽  
Histocompatibility Complex ◽  
Genome Wide ◽  
The Common

We review here our current understanding of the genetic aetiology of the common complex neurological disease multiple sclerosis (MS). The strongest genetic risk factor for MS is the major histocompatibility complex which was identified in the 1970s. In 2011, after a number of genome-wide association studies have been completed and have identified approximately 20 new genes for MS, we ask the question—what is next for the genetics of MS?

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