33 research outputs found
Complimentary Methods for Multivariate Genome-Wide Association Study Identify New Susceptibility Genes for Blood Cell Traits.
Genome-wide association studies (GWAS) have found hundreds of novel loci associated with full blood count (FBC) phenotypes. However, most of these studies were performed in a single phenotype framework without putting into consideration the clinical relatedness among traits. In this work, in addition to the standard univariate GWAS, we also use two different multivariate methods to perform the first multiple traits GWAS of FBC traits in ∼7000 individuals from the Ugandan General Population Cohort (GPC). We started by performing the standard univariate GWAS approach. We then performed our first multivariate method, in this approach, we tested for marker associations with 15 FBC traits simultaneously in a multivariate mixed model implemented in GEMMA while accounting for the relatedness of individuals and pedigree structures, as well as population substructure. In this analysis, we provide a framework for the combination of multiple phenotypes in multivariate GWAS analysis and show evidence of multi-collinearity whenever the correlation between traits exceeds the correlation coefficient threshold of r 2 >=0.75. This approach identifies two known and one novel loci. In the second multivariate method, we applied principal component analysis (PCA) to the same 15 correlated FBC traits. We then tested for marker associations with each PC in univariate linear mixed models implemented in GEMMA. We show that the FBC composite phenotype as assessed by each PC expresses information that is not completely encapsulated by the individual FBC traits, as this approach identifies three known and five novel loci that were not identified using both the standard univariate and multivariate GWAS methods. Across both multivariate methods, we identified six novel loci. As a proof of concept, both multivariate methods also identified known loci, HBB and ITFG3. The two multivariate methods show that multivariate genotype-phenotype methods increase power and identify novel genotype-phenotype associations not found with the standard univariate GWAS in the same dataset
Transcription-translation error: In-silico investigation of the structural and functional impact of deleterious single nucleotide polymorphisms in GULP1 gene
Nonsynonymous single nucleotide polymorphisms (nsSNPs) are one of the most common forms of mutations known to disrupt the product of translation thereby altering the protein structure-function relationship. GULP1 (PTB domain-containing engulfment adaptor protein 1) is an evolutionarily conserved adaptor protein that has been associated with glycated hemoglobin (HbA1c) in Genome-Wide Association Studies (GWAS). In order to understand the role of GULP1 in the etiology of diabetes, it is important to study some functional nsSNPs present within the GULP1 protein. We, therefore, used a SNPinformatics approach to retrieve, classify, and determine the stability effect of some nsSNPs. Y27C, G142D, A144T, and Y149C were jointly predicted by the pathogenic-classifying tools to be disease-causing, however, only G142D, A144T, and Y149C had their structural architecture perturbed as predicted by I-MUTANT and MuPro. Interestingly, G142D and Y149C occur at positions 142 and 149 of GULP1 which coincidentally are found within the binding site of GULP1. Protein-Protein interaction analysis also revealed that GULP1 interacted with 10 proteins such as Cell division cycle 5-like protein (CDC5L), ADP-ribosylation factor 6 (ARF6), Arf-GAP with coiled-coil (ACAP1), and Multiple epidermal growth factor-like domains protein 10 (MEGF10), etc. Taken together, rs1357922096, rs1264999716, and rs128246649 could be used as genetic biomarkers for the diagnosis of diabetes. However, being a computational study, these nsSNPs require experimental validation to explore their metabolic involvement in the pathogenesis of diseases
Computational and drug target analysis of functional single nucleotide polymorphisms associated with Haemoglobin Subunit Beta (HBB) gene
There is overwhelming evidence implicating Haemoglobin Subunit Beta (HBB) protein in the onset of beta
thalassaemia. In this study for the first time, we used a combined SNP informatics and computer algorithms such
as Neural network, Bayesian network, and Support Vector Machine to identify deleterious non-synonymous
Single Nucleotide Polymorphisms (nsSNPs) present in the HBB gene. Our findings highlight three major mutation
points (R31G, W38S, and Q128P) within the HBB gene sequence that have significant statistical and
computational associations with the onset of beta thalassaemia. The dynamic simulation study revealed that
R31G, W38S, and Q128P elicited high structural perturbation and instability, however, the wild type protein
was considerably stable. Ten compounds with therapeutic potential against HBB were also predicted by
structure-based virtual screening. Interestingly, the instability caused by the mutations was reversed upon
binding to a ligand. This study has been able to predict potential deleterious mutants that can be further explored
in the understanding of the pathological basis of beta thalassaemia and the design of tailored inhibitors
The Nigerian Bioinformatics and Genomics Network (NBGN): a collaborative platform to advance bioinformatics and genomics in Nigeria
Africa plays a central importance role in the human origins, and disease susceptibility,
agriculture and biodiversity conservation. Nigeria as the most populous and most diverse
country in Africa, owing to its 250 ethnic groups and over 500 different native languages is
imperative to any global genomic initiative. The newly inaugurated Nigerian Bioinformatics
and Genomics Network (NBGN) becomes necessary to facilitate research collaborative activ�ities and foster opportunities for skills’ development amongst Nigerian bioinformatics and
genomics investigators. NBGN aims to advance and sustain the fields of genomics and bio�informatics in Nigeria by serving as a vehicle to foster collaboration, provision of new oppor�tunities for interactions between various interdisciplinary subfields of genomics,
computational biology and bioinformatics as this will provide opportunities for early career
researchers. To provide the foundation for sustainable collaborations, the network organises
conferences, workshops, trainings and create opportunities for collaborative research studies
and internships, recognise excellence, openly share information and create opportunities for
more Nigerians to develop the necessary skills to exceed in genomics and bioinformatics.
NBGN currently has attracted more than 650 members around the world. Research collabora�tions between Nigeria, Africa and the West will grow and all stakeholders, including funding
partners, African scientists, researchers across the globe, physicians and patients will be the
eventual winners. The exponential membership growth and diversity of research interests
of NBGN just within weeks of its establishment and the unanticipated attendance of its activ�ities suggest the significant importance of the network to bioinformatics and genomics
research in Nigeria
Meta-Analysis and Multivariate GWAS Analyses in 77,850 Individuals of African Ancestry Identify Novel Variants Associated with Blood Pressure Traits
High blood pressure (HBP) has been implicated as a major risk factor for cardiovascular diseases in several populations, including individuals of African ancestry. Despite the elevated burden of HBP-induced cardiovascular diseases in Africa and other populations of African descent, limited genetic studies have been carried out to explore the genetic mechanism driving this phenomenon. We performed genome-wide association univariate and multivariate analyses of both systolic (SBP) and diastolic blood pressure (DBP) traits in 77, 850 individuals of African ancestry. We used summary statistics data from six independent cohorts, including the African Partnership for Chronic Disease Research (APCDR), the UK Biobank, and the Million Veteran Program (MVP). FUMA was used to annotate, prioritize, visualize, and interpret our findings to gain a better understanding of the molecular mechanism(s) underlying the genetics of BP traits. Finally, we undertook a Bayesian fine-mapping analysis to identify potential causal variants. Our meta-analysis identified 10 independent variants associated with SBP and 9 with DBP traits. Whilst our multivariate GWAS method identified 21 independent signals, 18 of these SNPs have been previously identified. SBP was linked to gene sets involved in biological processes such as synapse assembly and cell-cell adhesion via plasma membrane adhesion. Of the 19 independent SNPs identified in the BP meta-analysis, only 11 variants had posterior probability (PP) of > 50%, including one novel variant: rs562545 (MOBP, PP = 77%). To facilitate further research and fine-mapping of high-risk loci/variants in highly susceptible groups for cardiovascular disease and other related traits, large-scale genomic datasets are needed. Our findings highlight the importance of including ancestrally diverse populations in large GWASs and the need for diversity in genetic research
Multi-trait discovery and fine-mapping of lipid loci in 125,000 individuals of African ancestry
Genetic loci implicated in meta-analysis of body shape in Africans.
BACKGROUND AND AIMS: Obesity is one of the leading causes of non-communicable diseases (NCD). Thus, NCD risk varies in obese individuals based on the location of their fat depots; while subcutaneous adiposity is protective, visceral adiposity increases NCD risk. Although, previously anthropometric traits have been used to quantify body shape in low-income settings, there is no consensus on how it should be assessed. Hence, there is a growing interest to evaluate body shape derived from the principal component analysis (PCA) of anthropometric traits; however, this is yet to be explored in individuals of African ancestry whose body shape is different from those of Europeans. We set out to capture body shape in its multidimensional structure and examine the association between genetic variants and body shape in individuals of African ancestry. METHOD AND RESULTS: We performed a genome-wide association study (GWAS) for body shape derived from PCA analysis of anthropometric traits in the Ugandan General Population Cohort (GPC, n = 6407) and the South African Zulu Cohort (SZC, n = 2595), followed by a GWAS meta-analysis to assess the genetic variants associated with body shape. We identified variants in FGF12, GRM8, TLX1NB and TRAP1 to be associated with body shape. These genes were different from the genes been associated with BMI, height, weight, WC and waist-hip ration in continental Africans. Notably, we also observed that a standard deviation change in body shape was associated with an increase in blood pressure and blood lipids. CONCLUSION: Variants associated with body shape, as a composite variable might be different for those of individual anthropometric traits. Larger studies are required to further explore these phenomena
Strengthening Bioinformatics and Genomics Analysis Skills in Africa for Attainment of the Sustainable Development Goals Report of the 2nd Conference of the Nigerian Bioinformatics and Genomics Network
The second conference of the Nigerian Bioinformatics and Genomics Network (NBGN21) was held from
October 11 to October 13, 2021. The event was organized by the Nigerian Bioinformatics and Genomics Network. A
1-day genomic analysis workshop on genome-wide association study and polygenic risk score analysis was organized
as part of the conference. It was organized primarily as a research capacity building initiative to empower Nigerian
researchers to take a leading role in this cutting-edge field of genomic data science. The theme of the conference was
“Leveraging Bioinformatics and Genomics for the attainments of the Sustainable Development Goals.” The conference
used a hybrid approach—virtual and in-person. It served as a platform to bring together 235 registered participants
mainly from Nigeria and virtually, from all over the world. NBGN21 had four keynote speakers and four leading Nigerian
scientists received awards for their contributions to genomics and bioinformatics development in Nigeria. A total of 100
travel fellowships were awarded to delegates within Nigeria. A major topic of discussion was the application of bioinformatics and genomics in the achievement of the Sustainable Development Goals (SDG3—Good Health and Well-Being,
SDG4—Quality Education, and SDG 15—Life on Land [Biodiversity]). In closing, most of the NBGN21 conference participants were interviewed and interestingly they agreed that bioinformatics and genomic analysis of African genomes are
vital in identifying population-specific genetic variants that confer susceptibility to different diseases that are endemic in
Africa. The knowledge of this can empower African healthcare systems and governments for timely intervention, thereby
enhancing good health and well-bein
Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans
Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women's Health Initiative. Loci attaining genome-wide significant evidence for association (P < 5 × 10-8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10-8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10-8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD
Computational Biology and Bioinformatics in Nigeria
Over the past few decades, major advances in the field of molecular biology, coupled with advances in genomic technologies, have led to an explosive growth in the biological data generated by the scientific community. The critical need to process and analyze such a deluge of data and turn it into useful knowledge has caused bioinformatics to gain prominence and importance. Bioinformatics is an interdisciplinary research area that applies techniques, methodologies, and tools in computer and information science to solve biological problems. In Nigeria, bioinformatics has recently played a vital role in the advancement of biological sciences. As a developing country, the importance of bioinformatics is rapidly gaining acceptance, and bioinformatics groups comprised of biologists, computer scientists, and computer engineers are being constituted at Nigerian universities and research institutes. In this article, we present an overview of bioinformatics education and research in Nigeria. We also discuss professional societies and academic and research institutions that play central roles in advancing the discipline in Nigeria. Finally, we propose strategies that can bolster bioinformatics education and support from policy makers in Nigeria, with potential positive implications for other developing countries. © 2014 Fatumo et al.SAF was supported by H3ABioNet NABDA Node, Abuja, Nigeria with NIH Common Fund Award/NHGRI Grant Number U41HG006941 and Genetic Epidemiology Group at Wellcome Trust Sanger Institute.Published versio