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A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers
Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608754/ https://www.ncbi.nlm.nih.gov/pubmed/26474483 http://dx.doi.org/10.1371/journal.pgen.1005593 |
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author | Benton, Miles C. Lea, Rodney A. Macartney-Coxson, Donia Hanna, Michelle Eccles, David A. Carless, Melanie A. Chambers, Geoffrey K. Bellis, Claire Goring, Harald H. Curran, Joanne E. Harper, Jacquie L. Gibson, Gregory Blangero, John Griffiths, Lyn R. |
author_facet | Benton, Miles C. Lea, Rodney A. Macartney-Coxson, Donia Hanna, Michelle Eccles, David A. Carless, Melanie A. Chambers, Geoffrey K. Bellis, Claire Goring, Harald H. Curran, Joanne E. Harper, Jacquie L. Gibson, Gregory Blangero, John Griffiths, Lyn R. |
author_sort | Benton, Miles C. |
collection | PubMed |
description | Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h(2)) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h(2) values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10(-8)). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk. |
format | Online Article Text |
id | pubmed-4608754 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46087542015-10-29 A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers Benton, Miles C. Lea, Rodney A. Macartney-Coxson, Donia Hanna, Michelle Eccles, David A. Carless, Melanie A. Chambers, Geoffrey K. Bellis, Claire Goring, Harald H. Curran, Joanne E. Harper, Jacquie L. Gibson, Gregory Blangero, John Griffiths, Lyn R. PLoS Genet Research Article Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h(2)) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h(2) values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10(-8)). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk. Public Library of Science 2015-10-16 /pmc/articles/PMC4608754/ /pubmed/26474483 http://dx.doi.org/10.1371/journal.pgen.1005593 Text en © 2015 Benton et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Benton, Miles C. Lea, Rodney A. Macartney-Coxson, Donia Hanna, Michelle Eccles, David A. Carless, Melanie A. Chambers, Geoffrey K. Bellis, Claire Goring, Harald H. Curran, Joanne E. Harper, Jacquie L. Gibson, Gregory Blangero, John Griffiths, Lyn R. A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers |
title | A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers |
title_full | A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers |
title_fullStr | A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers |
title_full_unstemmed | A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers |
title_short | A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers |
title_sort | phenomic scan of the norfolk island genetic isolate identifies a major pleiotropic effect locus associated with metabolic and renal disorder markers |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608754/ https://www.ncbi.nlm.nih.gov/pubmed/26474483 http://dx.doi.org/10.1371/journal.pgen.1005593 |
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