scholarly journals Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

2020 ◽  
Author(s):  
Segun Fatumo ◽  
Tinashe Chikowore ◽  
Robert Kalyesubula ◽  
Rebecca N Nsubuga ◽  
Gershim Asiki ◽  
...  
Keyword(s):  
Kidney Function ◽  
Fine Mapping ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Causal Variant ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractGenome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288 Ugandans and replicated the findings in 8224 African Americans. We identified two loci associated with eGFR at genome-wide significance (p<5×10−8). The most significantly associated variant (rs2433603, p=2.4×10−9) in GATM was distinct from previously reported signals. A second association signal mapping near HBB (rs141845179, p=3.0×10−8) was not significant after conditioning on a previously reported SNP (rs334) for eGFR. However, fine-mapping analyses highlighted rs141845179 to be the most likely causal variant at the HBB locus (posterior probability of 0.61). A trans-ethnic GRS of eGFR constructed from previously reported lead SNPs was not predictive into the Ugandan population, indicating that additional large-scale efforts in Africa are necessary to gain further insight into the genetic architecture of kidney disease.

scholarly journals Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

2021 ◽  
Author(s):  
Segun Fatumo ◽  
Tinashe Chikowore ◽  
Robert Kalyesubula ◽  
Rebecca N Nsubuga ◽  
Gershim Asiki ◽  
...  
Keyword(s):  
Kidney Function ◽  
Fine Mapping ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genetic Risk Score ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract 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 &lt; 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.

scholarly journals Genome-Wide Association Study Identifies Loci Associated with Sensitive Skin

Cosmetics ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. 49
Author(s):  
Miranda A. Farage ◽  
Yunxuan Jiang ◽  
Jay P. Tiesman ◽  
Pierre Fontanillas ◽  
Rosemarie Osborne
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
European Ancestry ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Online Questionnaire ◽  
Sensitive Skin ◽  
Genome Wide ◽  
Skin Conditions

Individuals suffering from sensitive skin often have other skin conditions and/or diseases, such as fair skin, freckles, rosacea, or atopic dermatitis. Genome-wide association studies (GWAS) have been performed for some of these conditions, but not for sensitive skin. In this study, a total of 23,426 unrelated participants of European ancestry from the 23andMe database were evaluated for self-declared sensitive skin, other skin conditions, and diseases using an online questionnaire format. Responders were separated into two groups: those who declared they had sensitive skin (n = 8971) and those who declared their skin was not sensitive (controls, n = 14,455). A GWAS of sensitive skin individuals identified three genome-wide significance loci (p-value < 5 × 10−8) and seven suggestive loci (p-value < 1 × 10−6). Of the three most significant loci, all have been associated with pigmentation and two have been associated with acne.

scholarly journals Genome-wide association studies on endometriosis and endometriosis-related infertility

2018 ◽  
Author(s):  
Geneviève Galarneau ◽  
Pierre Fontanillas ◽  
Caterina Clementi ◽  
Tina Hu-Seliger ◽  
David-Emlyn Parfitt ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Reproductive Age ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Model Organisms ◽  
Genome Wide Association Studies ◽  
Gwas Study ◽  
Genome Wide ◽  
Genome Wide Significance

AbstractEndometriosis affects ∼10% of women of reproductive age. It is characterized by the growth of endometrial-like tissue outside the uterus and is frequently associated with severe pain and infertility. We performed the largest endometriosis genome-wide association study (GWAS) to date, with 37,183 cases and 251,258 controls. All women were of European ancestry. We also performed the first GWAS of endometriosis-related infertility, including 2,969 cases and 3,770 controls. Our endometriosis GWAS study replicated, at genome-wide significance, seven loci identified in previous endometriosis GWASs (CELA3A-CDC42, SYNE1, KDR, FSHB-ARL14EP, GREB1, ID4, and CEP112) and identified seven new candidate loci with genome-wide significance (NGF, ATP1B1-F5, CD109, HEY2, OSR2-VPS13B, WT1, and TEX11-SLC7A3). No loci demonstrated genome-wide significance for endometriosis-related infertility, however, the three most strongly associated loci (MCTP1, EPS8L3-CSF1, and LPIN1) were in or near genes associated with female fertility or embryonic lethality in model organisms. These results reveal new candidate genes with potential involvement in the pathophysiology of endometriosis and endometriosis-related infertility.

scholarly journals Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections

2016 ◽  
Author(s):  
Chao Tian ◽  
Bethann S. Hromatka ◽  
Amy K Kiefer ◽  
Nicholas Eriksson ◽  
Joyce Y Tung ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Association Studies ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Multiple Infections ◽  
Genome Wide Association Studies ◽  
Missense Mutations ◽  
Genome Wide ◽  
Tract Infections ◽  
Common Infections

ABSTRACTWe performed 23 genome-wide association studies for common infections, including chickenpox, shingles, cold sores, mononucleosis, mumps, hepatitis B, plantar warts, positive tuberculosis test results, strep throat, scarlet fever, pneumonia, bacterial meningitis, yeast infections, urinary tract infections, tonsillectomy, childhood ear infections, myringotomy, measles, hepatitis A, rheumatic fever, common colds, rubella and chronic sinus infection, in more than 200,000 individuals of European ancestry. For the first time, genome-wide significant associations (P< 5 × 10−8) were identified for many common infections. The associations were mapped to genes with key roles in acquired and innate immunity(HLA, IFNA21, FUT2, ST3GAL4, ABO, IFNL4, LCE3E, DSG1, LTBR, MTMR3, TNFRSF13B, TNFSF13B, NFKB1, CD40) and in regulation of embryonic developmental process(TBX1, FGF, FOXA1 and FOXN1).Several missense mutations were also identified (inLCE5A, DSG1, FUT2, TBX1, CDHR3, PLG, TNFRSF13B, FOXA1, SH2B3, ST5andFOXN1). Missense mutations inFUT2andTBX1were implicated in multiple infections. We applied fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggested important roles of specific amino acid polymorphisms in the antigen-binding clefts. Our findings provide an important step toward dissecting the host genetic architecture of response to common infections.

scholarly journals Brief Overview of a Decade of Genome-Wide Association Studies on Primary Hypertension

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Afifah Binti Azam ◽  
Elena Aisha Binti Azizan
Keyword(s):  
Dna Sequence ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Heart Diseases ◽  
Association Studies ◽  
Primary Hypertension ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Single Base Pair

Primary hypertension is widely believed to be a complex polygenic disorder with the manifestation influenced by the interactions of genomic and environmental factors making identification of susceptibility genes a major challenge. With major advancement in high-throughput genotyping technology, genome-wide association study (GWAS) has become a powerful tool for researchers studying genetically complex diseases. GWASs work through revealing links between DNA sequence variation and a disease or trait with biomedical importance. The human genome is a very long DNA sequence which consists of billions of nucleotides arranged in a unique way. A single base-pair change in the DNA sequence is known as a single nucleotide polymorphism (SNP). With the help of modern genotyping techniques such as chip-based genotyping arrays, thousands of SNPs can be genotyped easily. Large-scale GWASs, in which more than half a million of common SNPs are genotyped and analyzed for disease association in hundreds of thousands of cases and controls, have been broadly successful in identifying SNPs associated with heart diseases, diabetes, autoimmune diseases, and psychiatric disorders. It is however still debatable whether GWAS is the best approach for hypertension. The following is a brief overview on the outcomes of a decade of GWASs on primary hypertension.

scholarly journals Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal

2017 ◽  
Vol 55 (1) ◽  
pp. 64-71 ◽  
Author(s):  
Dayana A Delgado ◽  
Chenan Zhang ◽  
Lin S Chen ◽  
Jianjun Gao ◽  
Shantanu Roy ◽  
...  
Keyword(s):  
Telomere Length ◽  
South Asian ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Age Related ◽  
Genome Wide ◽  
Potential Biomarker

BackgroundLeucocyte telomere length (TL) is a potential biomarker of ageing and risk for age-related disease. Leucocyte TL is heritable and shows substantial differences by race/ethnicity. Recent genome-wide association studies (GWAS) report ~10 loci harbouring SNPs associated with leucocyte TL, but these studies focus primarily on populations of European ancestry.ObjectiveThis study aims to enhance our understanding of genetic determinants of TL across populations.MethodsWe performed a GWAS of TL using data on 5075 Bangladeshi adults. We measured TL using one of two technologies (qPCR or a Luminex-based method) and used standardised variables as TL phenotypes.ResultsOur results replicate previously reported associations in the TERC and TERT regions (P=2.2×10−8 and P=6.4×10−6, respectively). We observed a novel association signal in the RTEL1 gene (intronic SNP rs2297439; P=2.82×10−7) that is independent of previously reported TL-associated SNPs in this region. The minor allele for rs2297439 is common in South Asian populations (≥0.25) but at lower frequencies in other populations (eg, 0.07 in Northern Europeans). Among the eight other previously reported association signals, all were directionally consistent with our study, but only rs8105767 (ZNF208) was nominally significant (P=0.003). SNP-based heritability estimates were as high as 44% when analysing close relatives but much lower when analysing distant relatives only.ConclusionsIn this first GWAS of TL in a South Asian population, we replicate some, but not all, of the loci reported in prior GWAS of individuals of European ancestry, and we identify a novel second association signal at the RTEL1 locus.

scholarly journals Fine Mapping of Intracranial Aneurysm Susceptibility Based on a Genome-wide Association Study

2021 ◽  
Author(s):  
Eun Pyo Hong ◽  
Dong Hyuk Youn ◽  
Bong Jun Kim ◽  
Jun Hyong Ahn ◽  
Jeong Jin Park ◽  
...  
Keyword(s):  
Intracranial Aneurysm ◽  
Fine Mapping ◽  
Bayes Factor ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Network Analyses ◽  
Genome Wide ◽  
A Genome

Abstract In addition to conventional genome-wide association studies (GWAS), a fine-mapping is increasingly used to identify the genetic function of variants associated with disease susceptibilities. Here, we used a fine-mapping approach to evaluate the casual variants based on a previous GWAS involving patients with intracranial aneurysm (IA). Fine-mapping analysis was conducted based on the chromosomal data provided by GWAS consisting 250 patients diagnosed with IA and 296 controls using posterior inclusion probability (PIP) and log10 transformed Bayes factor (log10BF). The narrow sense of heritability (h2) explained by each casual variant was estimated. Subsequent gene expression and functional network analyses were used to calculate the transcripts per million (TPM) values. Twenty causal candidate single nucleotide polymorphisms (SNPs) surpassed a genome-wide significance threshold for creditable evidence (log10BF > 6.1). Four SNPs including rs75822236 (R535H, GBA; log10BF = 15.06), rs112859779 (G141S, TCF24; log10BF = 12.12), rs79134766 (A208T, OLFML2A; log10BF = 14.92), and rs371331393 (Q1932X, ARHGAP32; log10BF = 20.88) showed a completed PIP value in each chromosomal region, suggesting a high probability of variant causality associated with IA. Expression in GBA was highly enriched in the whole blood (TPM = 33.13), while TCF24 were rarely expressed in all tissues and cells. No direct interaction was observed between the four casual genes; however, PSAP appeared to be particularly important via indirect correlation between other genes. Our results suggested that four mutations of GBA, TCF24, OLFML2A, and ARHGAP32 were linked to IA susceptibility and pathogenesis. Our approach may promise more informative mutations in the following GWAS.

scholarly journals Genome-Wide Association Scan of Serum Urea in European Populations Identifies Two Novel Loci

2019 ◽  
Vol 49 (3) ◽  
pp. 193-202
Author(s):  
Chris H.L. Thio ◽  
Anna Reznichenko ◽  
Peter J. van der Most ◽  
Zoha Kamali ◽  
Ahmad Vaez ◽  
...  
Keyword(s):  
Kidney Function ◽  
Association Studies ◽  
Serum Magnesium ◽  
East Asian ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Serum Urea ◽  
Genome Wide ◽  
European Populations

Background: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. Methods: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. Results: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. Conclusions: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.

scholarly journals A Fast Multi-Locus Ridge Regression Algorithm for High-Dimensional Genome-Wide Association Studies

2021 ◽  
Vol 12 ◽  
Author(s):  
Jin Zhang ◽  
Min Chen ◽  
Yangjun Wen ◽  
Yin Zhang ◽  
Yunan Lu ◽  
...  
Keyword(s):  
Ridge Regression ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Real Data ◽  
Genome Wide Association ◽  
High Dimensional ◽  
Minor Effect ◽  
Genome Wide Association Studies ◽  
Genome Wide

The mixed linear model (MLM) has been widely used in genome-wide association study (GWAS) to dissect quantitative traits in human, animal, and plant genetics. Most methodologies consider all single nucleotide polymorphism (SNP) effects as random effects under the MLM framework, which fail to detect the joint minor effect of multiple genetic markers on a trait. Therefore, polygenes with minor effects remain largely unexplored in today’s big data era. In this study, we developed a new algorithm under the MLM framework, which is called the fast multi-locus ridge regression (FastRR) algorithm. The FastRR algorithm first whitens the covariance matrix of the polygenic matrix K and environmental noise, then selects potentially related SNPs among large scale markers, which have a high correlation with the target trait, and finally analyzes the subset variables using a multi-locus deshrinking ridge regression for true quantitative trait nucleotide (QTN) detection. Results from the analyses of both simulated and real data show that the FastRR algorithm is more powerful for both large and small QTN detection, more accurate in QTN effect estimation, and has more stable results under various polygenic backgrounds. Moreover, compared with existing methods, the FastRR algorithm has the advantage of high computing speed. In conclusion, the FastRR algorithm provides an alternative algorithm for multi-locus GWAS in high dimensional genomic datasets.

scholarly journals Comparing genome-wide association study results from different measurements of an underlying phenotype

2018 ◽  
Author(s):  
Joseph L. Gage ◽  
de Leon Natalia ◽  
Clayton Murray
Keyword(s):  
Large Scale ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Roc Curves ◽  
Genome Wide Association ◽  
Alternative Methods ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Study Results ◽  
The Difference

AbstractIncreasing popularity of high-throughput phenotyping technologies, such as image-based phenotyping, offer novel ways for quantifying plant growth and morphology. These new methods can be more or less accurate and precise than traditional, manual measurements. Many large-scale phenotyping efforts are conducted to enable genome-wide association studies (GWAS), but it is unclear exactly how alternative methods of phenotyping will affect GWAS results. In this study we simulate phenotypes that are controlled by the same set of causal loci but have differing heritability, similar to two different measurements of the same morphological character. We then perform GWAS with the simulated traits and create receiver operating characteristic (ROC) curves from the results. The areas under the ROC curves (AUCs) provide a metric that allows direct comparisons of GWAS results from different simulated traits. We use this framework to evaluate the effects of heritability and the number of causative loci on the AUCs of simulated traits; we also test the differences between AUCs of traits with differing heritability. We find that both increasing the number of causative loci and decreasing the heritability reduce a trait’s AUC. We also find that when two traits are controlled by a greater number of causative loci, they are more likely to have significantly different AUCs as the difference between their heritabilities increases. These results provide a framework for deciding between competing phenotyping strategies when the ultimate goal is to generate and use phenotype-genotype associations from GWAS.

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