
School of Medicine Publications and Presentations
Document Type
Article
Publication Date
10-16-2015
Abstract
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 (h2) 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 h2 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.
Recommended Citation
Benton, M. C., Lea, R. A., Macartney-Coxson, D., Hanna, M., Eccles, D. A., Carless, M. A., ... & Griffiths, L. R. (2015). A Phenomic scan of the Norfolk Island genetic isolate identifies a major pleiotropic effect locus associated with metabolic and renal disorder markers. PLoS genetics, 11(10), e1005593. https://doi.org/10.1371/journal.pgen.1005593
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Publication Title
PLoS Genetics
DOI
10.1371/journal.pgen.1005593
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
Comments
© 2015 Benton et al. 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 credited