scholarly journals Systems biology analysis of human genomes points to key pathways conferring spina bifida risk

2021 ◽  
Vol 118 (51) ◽  
pp. e2106844118
Author(s):  
Vanessa Aguiar-Pulido ◽  
Paul Wolujewicz ◽  
Alexander Martinez-Fundichely ◽  
Eran Elhaik ◽  
Gaurav Thareja ◽  
...  
Keyword(s):  
Systems Biology ◽  
Spina Bifida ◽  
Association Studies ◽  
Mendelian Inheritance ◽  
Population Substructure ◽  
Whole Genome Sequence ◽  
Incomplete Penetrance ◽  
Sequence Variant ◽  
Genome Wide Association Studies ◽  
Genome Wide

Spina bifida (SB) is a debilitating birth defect caused by multiple gene and environment interactions. Though SB shows non-Mendelian inheritance, genetic factors contribute to an estimated 70% of cases. Nevertheless, identifying human mutations conferring SB risk is challenging due to its relative rarity, genetic heterogeneity, incomplete penetrance, and environmental influences that hamper genome-wide association studies approaches to untargeted discovery. Thus, SB genetic studies may suffer from population substructure and/or selection bias introduced by typical candidate gene searches. We report a population based, ancestry-matched whole-genome sequence analysis of SB genetic predisposition using a systems biology strategy to interrogate 298 case-control subject genomes (149 pairs). Genes that were enriched in likely gene disrupting (LGD), rare protein-coding variants were subjected to machine learning analysis to identify genes in which LGD variants occur with a different frequency in cases versus controls and so discriminate between these groups. Those genes with high discriminatory potential for SB significantly enriched pathways pertaining to carbon metabolism, inflammation, innate immunity, cytoskeletal regulation, and essential transcriptional regulation consistent with their having impact on the pathogenesis of human SB. Additionally, an interrogation of conserved noncoding sequences identified robust variant enrichment in regulatory regions of several transcription factors critical to embryonic development. This genome-wide perspective offers an effective approach to the interrogation of coding and noncoding sequence variant contributions to rare complex genetic disorders.

scholarly journals Systems Biology Analysis of Human Genomes Points to Key Pathways Conferring Spina Bifida Risk

2021 ◽  
Author(s):  
Vanessa Aguiar-Pulido ◽  
Paul Wolujewicz ◽  
Alexander Martinez-Fundichely ◽  
Eran Elhaik ◽  
Gaurav Thareja ◽  
...  
Keyword(s):  
Systems Biology ◽  
Spina Bifida ◽  
Genetic Disorders ◽  
Population Based ◽  
Mendelian Inheritance ◽  
Population Substructure ◽  
Whole Genome Sequence ◽  
Incomplete Penetrance ◽  
Sequence Variant ◽  
Protein Coding

Spina bifida (SB) is a debilitating birth defect caused by multiple gene and environment interactions. Though SB shows non-Mendelian inheritance, genetic factors contribute to an estimated 70% of cases. Nevertheless, identifying human mutations conferring SB risk is challenging due to its relative rarity, genetic heterogeneity, incomplete penetrance and environmental influences that hamper GWAS approaches to untargeted discovery. Thus, SB genetic studies may suffer from population substructure and/or selection bias introduced by typical candidate gene searches. We report a population based, ancestry-matched whole-genome sequence analysis of SB genetic predisposition using a systems biology strategy to interrogate 298 case-control subject genomes (149 pairs). Genes that were enriched in likely gene disrupting (LGD), rare protein-coding variants were subjected to machine learning analysis to identify genes in which LGD variants occur with a different frequency in cases vs. controls and so discriminate between these groups. Those genes with high discriminatory potential for SB significantly enriched pathways pertaining to carbon metabolism, inflammation, innate immunity, cytoskeletal regulation and essential transcriptional regulation, indicating their impact on the pathogenesis of human SB. Additionally, interrogation of conserved non-coding sequences identified robust variant enrichment in regulatory regions of several transcription factors critical to embryonic development. This genome-wide perspective offers an effective approach to interrogation of coding and non-coding sequence variant contributions to rare complex genetic disorders.

Pathophysiology and genetic factors in moyamoya disease

2009 ◽  
Vol 26 (4) ◽  
pp. E4 ◽  
Author(s):  
Achal S. Achrol ◽  
Raphael Guzman ◽  
Marco Lee ◽  
Gary K. Steinberg
Keyword(s):  
Moyamoya Disease ◽  
Genetic Factors ◽  
Association Studies ◽  
Vascular Anomalies ◽  
Future Research ◽  
Incomplete Penetrance ◽  
Genome Wide Association Studies ◽  
Research Directions ◽  
Genome Wide ◽  
Future Research Directions

Moyamoya disease is an uncommon cerebrovascular condition characterized by progressive stenosis of the bilateral internal carotid arteries with compensatory formation of an abnormal network of perforating blood vessels providing collateral circulation. The etiology and pathogenesis of moyamoya disease remain unclear. Evidence from histological studies, proteomics, and endothelial progenitor cell analyses suggests new theories underlying the cause of vascular anomalies, including moyamoya disease. Familial moyamoya disease has been noted in as many as 15% of patients, indicating an autosomal dominant inheritance pattern with incomplete penetrance. Genetic analyses in familial moyamoya disease and genome-wide association studies represent promising strategies for elucidating the pathophysiology of this condition. In this review, the authors discuss recent studies that have investigated possible mechanisms underlying the etiology of moyamoya disease, including stem cell involvement and genetic factors. They also discuss future research directions that promise not only to offer new insights into the origin of moyamoya disease but to enhance our understanding of new vessel formation in the CNS as it relates to stroke, vascular anomalies, and tumor growth.

scholarly journals Genome-wide Association Studies Identify Quantitative Trait Loci Affecting Cattle Temperament

2020 ◽  
Author(s):  
Jiafei Shen ◽  
Qiuming Chen ◽  
Fengwei Zhang ◽  
Quratulain Hanif ◽  
Bizhi Huang ◽  
...  
Keyword(s):  
Open Field ◽  
Association Studies ◽  
Productive Efficiency ◽  
Genome Wide Association ◽  
Whole Genome Sequence ◽  
Receptor Interaction ◽  
Genome Wide Association Studies ◽  
Autosomal Snps ◽  
Novel Object ◽  
Genome Wide

Abstract BackgroundCattle temperament is one of the most interesting traits owing to its correlation to productive efficiency, labor safety and animal welfare, but its genetic basis is not clearly understood.ResultsHere, we performed genome-wide association studies for a series of temperament traits, assessed in an open field and novel object test, using autosomal SNPs derived from the whole-genome sequence. We identified 37 and 29 genome-wide significant loci in an open field and novel object test, respectively. Gene set analysis implicated the neuroactive ligand-receptor interaction pathway. Analysis in tissue specific expressions showed enrichment in the brain. While some candidate genes were involved in psychiatric and neurodegenerative diseases in humans. The first principal component explained the largest variance in the data of open field and novel object test, and the most significant loci were assigned to SORCS3 and SESTD1, respectively.ConclusionsOur findings will facilitate cattle breeding for sound temperament by pyramiding favorable alleles to further improve the cattle production in the future.

scholarly journals VarGen: an R package for disease-associated variant discovery and annotation

2019 ◽  
Vol 36 (8) ◽  
pp. 2626-2627
Author(s):  
Corentin Molitor ◽  
Matt Brember ◽  
Fady Mohareb
Keyword(s):  
Association Studies ◽  
Genetic Disorders ◽  
R Package ◽  
Tissue Expression ◽  
Mendelian Inheritance ◽  
Supplementary Information ◽  
Genome Wide Association Studies ◽  
Variant Discovery ◽  
Genome Wide ◽  
High Quality Information

Abstract Summary Over the past decade, there has been an exponential increase in the amount of disease-related genomic data available in public databases. However, this high-quality information is spread across independent sources and researchers often need to access these separately. Hence, there is a growing need for tools that gather and compile this information in an easy and automated manner. Here, we present ‘VarGen’, an easy-to-use, customizable R package that fetches, annotates and rank variants related to diseases and genetic disorders, using a collection public databases (viz. Online Mendelian Inheritance in Man, the Functional Annotation of the Mammalian genome 5, the Genotype-Tissue Expression and the Genome Wide Association Studies catalog). This package is also capable of annotating these variants to identify the most impactful ones. We expect that this tool will benefit the research of variant-disease relationships. Availability and implementation VarGen is open-source and freely available via GitHub: https://github.com/MCorentin/VarGen. The software is implemented as an R package and is supported on Linux, MacOS and Windows. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Linkage disequilibrium maps for European and African populations constructed from whole genome sequence data

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Alejandra Vergara-Lope ◽  
M. Reza Jabalameli ◽  
Clare Horscroft ◽  
Sarah Ennis ◽  
Andrew Collins ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Genome Sequence ◽  
Sequence Data ◽  
Association Studies ◽  
Large Population ◽  
Whole Genome Sequence ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Genome Wide

Abstract Quantification of linkage disequilibrium (LD) patterns in the human genome is essential for genome-wide association studies, selection signature mapping and studies of recombination. Whole genome sequence (WGS) data provides optimal source data for this quantification as it is free from biases introduced by the design of array genotyping platforms. The Malécot-Morton model of LD allows the creation of a cumulative map for each choromosome, analogous to an LD form of a linkage map. Here we report LD maps generated from WGS data for a large population of European ancestry, as well as populations of Baganda, Ethiopian and Zulu ancestry. We achieve high average genetic marker densities of 2.3–4.6/kb. These maps show good agreement with prior, low resolution maps and are consistent between populations. Files are provided in BED format to allow researchers to readily utilise this resource.

Abstract 56: Genome-wide Association Studies of Incident Stroke: The Charge Consortium

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Stephanie Debette ◽  
Ganesh Chauhan ◽  
Audrey Chu ◽  
Myriam Fornage ◽  
Josh C Bis ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Acute Stage ◽  
Genome Wide Association ◽  
Population Substructure ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Large Artery ◽  
Aging Research ◽  
Genome Wide

Background: Despite a high heritability, only few stroke risk genes are known. Genetic association studies performed in a hospital-based setting may fail to detect genes modulating both stroke susceptibility and severity, given early deaths at the acute stage. This selection bias is avoided when studying incident stroke in a population-based setting. Methods: We conducted a meta-analysis of genome-wide association studies of incident stroke in 11 community-based longitudinal studies from the Cohorts of Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Genome-wide Cox regressions were performed adjusting for age, gender and population substructure, using 1000GpIv3 imputed genotypes. Results were combined using inverse variance weighted meta-analysis. Results: The study sample comprised 65,204 participants (71.5% women) of European ancestry, aged 66.2±8.0 years at DNA draw, followed up for 10.8±3.8 years. In 11 studies, 3,389 participants developed incident stroke, and in 8 studies, 2,223 developed incident ischemic stroke (IS): 531 cardioembolic [CE] and 1,576 atherothrombotic [AT]. The most significant association with incident stroke was for a novel variant on chr9p23 (MAF=0.35), HR=1.15 [95%CI:1.09[[Unable to Display Character: &#8210;]]1.21], p=8.5х10-8: p=2.54x10-5 for IS; 1.19x10-4, AT-IS; and 0.019, CE-IS. Associations were in the same direction for all participating studies, and 5 additional SNPs in this locus reached p<10-6. The most significant association with incident IS was for rs11833579 [NINJ2], HR=1.21[1.13[[Unable to Display Character: &#8210;]]1.30], p=2.1х10-7, but p-random-effects=9.54x10-3 (p-heterogeneity=0.02, I2=57.9%). We replicated published associations for CE-IS (rs6843082-G [PITX2], HR=1.30[1.13-1.49], p=1.95x10-4) and for large artery stroke with AT-IS (rs2107595-A [HDAC9], HR=1.13[1.03[[Unable to Display Character: &#8210;]]1.24], p=0.012) Conclusion: In the largest GWAS of incident stroke, we detected one novel association with all stroke, requiring confirmation in independent samples. Expansion of the discovery sample and replication of findings are planned in the coming months. Detecting genetic variants associated with incident stroke may provide important clues for understanding pathways involved in stroke susceptibility and tolerance to acute vascular brain injury.

scholarly journals Imputation to whole-genome sequence using multiple pig populations and its use in genome-wide association studies

2019 ◽  
Vol 51 (1) ◽  
Author(s):  
Sanne van den Berg ◽  
Jérémie Vandenplas ◽  
Fred A. van Eeuwijk ◽  
Aniek C. Bouwman ◽  
Marcos S. Lopes ◽  
...  
Keyword(s):  
Genome Sequence ◽  
Association Studies ◽  
Genome Wide Association ◽  
Whole Genome Sequence ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Genome Wide

scholarly journals Hair of the Dog: Identification of a Cis-Regulatory Module Predicted to Influence Canine Coat Composition

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 323 ◽  
Author(s):  
Whitaker ◽  
Ostrander
Keyword(s):  
Association Studies ◽  
Snp Array ◽  
Single Layer ◽  
Domestic Dog ◽  
Whole Genome Sequence ◽  
Genome Wide Association Studies ◽  
Ancestral State ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Regulatory Module

Each domestic dog breed is characterized by a strict set of physical and behavioral characteristics by which breed members are judged and rewarded in conformation shows. One defining feature of particular interest is the coat, which is comprised of either a double- or single-layer of hair. The top coat contains coarse guard hairs and a softer undercoat, similar to that observed in wolves and assumed to be the ancestral state. The undercoat is absent in single-coated breeds which is assumed to be the derived state. We leveraged single nucleotide polymorphism (SNP) array and whole genome sequence (WGS) data to perform genome-wide association studies (GWAS), identifying a locus on chromosome (CFA) 28 which is strongly associated with coat number. Using WGS data, we identified a locus of 18.4 kilobases containing 62 significant variants within the intron of a long noncoding ribonucleic acid (lncRNA) upstream of ADRB1. Multiple lines of evidence highlight the locus as a potential cis-regulatory module. Specifically, two variants are found at high frequency in single-coated dogs and are rare in wolves, and both are predicted to affect transcription factor (TF) binding. This report is among the first to exploit WGS data for both GWAS and variant mapping to identify a breed-defining trait.

scholarly journals Genome-wide association analysis of idiopathic epilepsy in the Belgian shepherd

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
J. M. Belanger ◽  
T. R. Famula ◽  
L. C. Gershony ◽  
M. K. Palij ◽  
A. M. Oberbauer
Keyword(s):  
Association Studies ◽  
High Sensitivity ◽  
Genome Wide Association ◽  
Domestic Dog ◽  
Idiopathic Epilepsy ◽  
Incomplete Penetrance ◽  
Genome Wide Association Studies ◽  
Potential Candidate ◽  
Genome Wide ◽  
Causal Variants

Abstract Background Idiopathic epilepsy (IE) is a common neurological disorder in the domestic dog, and is defined as repeated seizure activity having no identifiable underlying cause. Some breeds, such as the Belgian shepherd dog, have a greater prevalence of the disorder. Previous studies in this and other breeds have identified ADAM23 as a gene that confers risk of IE, although additional loci are known to exist. The present study sought to identify additional loci that influence IE in the Belgian shepherd dog. Results Genome-wide association studies (GWAS) revealed a significant association between IE and CFA 14 (p < 1.03 E− 08) and a suggestive association on CFA 37 (p < 2.91 E− 06) in a region in linkage disequilibrium with ADAM23. Logistic regression identified a 2-loci model that demonstrated interaction between the two chromosomal regions that when combined predicted IE risk with high sensitivity. Conclusions Two interacting loci, one each on CFAs 14 and 37, predictive of IE in the Belgian shepherd were identified. The loci are adjacent to potential candidate genes associated with neurological function. Further exploration of the region is warranted to identify causal variants underlying the association. Additionally, although the two loci were very good at predicting IE, they failed to capture all the risk, indicating additional loci or incomplete penetrance are also likely contributing to IE expression in the Belgian shepherd dog.

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