Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

AbstractIn genome-wide association studies (GWAS), it is of interest to identify genetic variants associated with phenotypes. For a given phenotype, the associated genetic variants are usually a sparse subset of all possible variants. Traditional Lasso-type estimation methods can therefore be used to detect important genes. But the relationship between genotypes at one variant and a phenotype may be influenced by other variables, such as sex and life style. Hence it is important to be able to incorporate gene-covariate interactions into the sparse regression model. In addition, because there is biological knowledge on the manner in which genes work together in structured groups, it is desirable to incorporate this information as well. In this paper, we present a novel sparse regression methodology for gene-covariate models in association studies that not only allows such interactions but also considers biological group structure. Simulation results show that our method substantially outperforms another method, in which interaction is considered, but group structure is ignored. Application to data on total plasma immunoglobulin E (IgE) concentrations in the Framingham Heart Study (FHS), using sex and smoking status as covariates, yields several potentially interesting gene-covariate interactions.

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Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height

Human Molecular Genetics ◽

10.1093/hmg/dds347 ◽

2012 ◽

Vol 21 (23) ◽

pp. 5193-5201 ◽

Cited By ~ 45

Author(s):

Julian C. Lui ◽

Ola Nilsson ◽

Yingleong Chan ◽

Cameron D. Palmer ◽

Anenisia C. Andrade ◽

...

Keyword(s):

Growth Plate ◽

Association Studies ◽

Human Growth ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Expression Microarray ◽

Novel Genes ◽

Genome Wide

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Incorporating biological knowledge in the search for gene × gene interaction in genome-wide association studies

BMC Proceedings ◽

10.1186/1753-6561-3-s7-s81 ◽

2009 ◽

Vol 3 (S7) ◽

Cited By ~ 3

Author(s):

Alisa K Manning ◽

Julius Suh Ngwa ◽

Audrey E Hendricks ◽

Ching-Ti Liu ◽

Andrew D Johnson ◽

...

Keyword(s):

Association Studies ◽

Gene Interaction ◽

Genome Wide Association ◽

Biological Knowledge ◽

Genome Wide Association Studies ◽

Genome Wide

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Genome-Wide Association Studies of CKD and Related Traits

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.00020120 ◽

2020 ◽

Vol 15 (11) ◽

pp. 1643-1656

Author(s):

Adrienne Tin ◽

Anna Köttgen

Keyword(s):

Kidney Function ◽

Complex Traits ◽

Kidney Diseases ◽

Association Studies ◽

Genome Wide Association ◽

Model Organisms ◽

Genome Wide Association Studies ◽

Genetic Loci ◽

Genome Wide ◽

Causal Genes

The past few years have seen major advances in genome-wide association studies (GWAS) of CKD and kidney function–related traits in several areas: increases in sample size from >100,000 to >1 million, enabling the discovery of >250 associated genetic loci that are highly reproducible; the inclusion of participants not only of European but also of non-European ancestries; and the use of advanced computational methods to integrate additional genomic and other unbiased, high-dimensional data to characterize the underlying genetic architecture and prioritize potentially causal genes and variants. Together with other large-scale biobank and genetic association studies of complex traits, these GWAS of kidney function–related traits have also provided novel insight into the relationship of kidney function to other diseases with respect to their genetic associations, genetic correlation, and directional relationships. A number of studies also included functional experiments using model organisms or cell lines to validate prioritized potentially causal genes and/or variants. In this review article, we will summarize these recent GWAS of CKD and kidney function–related traits, explain approaches for downstream characterization of associated genetic loci and the value of such computational follow-up analyses, and discuss related challenges along with potential solutions to ultimately enable improved treatment and prevention of kidney diseases through genetics.

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Post Genome-Wide Association Studies of Novel Genes Associated with Type 2 Diabetes Show Gene-Gene Interaction and High Predictive Value

PLoS ONE ◽

10.1371/journal.pone.0002031 ◽

2008 ◽

Vol 3 (5) ◽

pp. e2031 ◽

Cited By ~ 107

Author(s):

Stéphane Cauchi ◽

David Meyre ◽

Emmanuelle Durand ◽

Christine Proença ◽

Michel Marre ◽

...

Keyword(s):

Type 2 Diabetes ◽

Predictive Value ◽

Association Studies ◽

Gene Interaction ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Novel Genes ◽

Genome Wide

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Multi-phenotype genome-wide association studies of the Norfolk Island isolate implicate pleiotropic loci involved in chronic kidney disease

Scientific Reports ◽

10.1038/s41598-021-98935-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ngan K. Tran ◽

Rodney A. Lea ◽

Samuel Holland ◽

Quan Nguyen ◽

Arti M. Raghubar ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Function ◽

Principal Components ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Functional Variants ◽

Genome Wide ◽

Norfolk Island

AbstractChronic kidney disease (CKD) is a persistent impairment of kidney function. Genome-wide association studies (GWAS) have revealed multiple genetic loci associated with CKD susceptibility but the complete genetic basis is not yet clear. Since CKD shares risk factors with cardiovascular diseases and diabetes, there may be pleiotropic loci at play but may go undetected when using single phenotype GWAS. Here, we used multi-phenotype GWAS in the Norfolk Island isolate (n = 380) to identify new loci associated with CKD. We performed a principal components analysis on different combinations of 29 quantitative traits to extract principal components (PCs) representative of multiple correlated phenotypes. GWAS of a PC derived from glomerular filtration rate, serum creatinine, and serum urea identified a suggestive peak (pmin = 1.67 × 10–7) that mapped to KCNIP4. Inclusion of other secondary CKD measurements with these three kidney function traits identified the KCNIP4 locus with GWAS significance (pmin = 1.59 × 10–9). Finally, we identified a group of two SNPs with increased minor allele frequencies as potential functional variants. With the use of genetic isolate and the PCA-based multi-phenotype GWAS approach, we have revealed a potential pleotropic effect locus for CKD. Further studies are required to assess functional relevance of this locus.

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

10.1101/2020.06.09.142463 ◽

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.

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

Human Molecular Genetics ◽

10.1093/hmg/ddab088 ◽

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 < 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.

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

American Journal of Nephrology ◽

10.1159/000496930 ◽

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.

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