title: A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers.
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.
authors.affiliation: Genomics Research Centre, Institute of Biomedical Health and Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Miles C
authors.initials: MC
authors.lastname: Benton
authors.affiliation: Genomics Research Centre, Institute of Biomedical Health and Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Lea
authors.affiliation: Biomarkers Group, Kenepuru Science Centre, Institute of Environmental Science and Research, Wellington, New Zealand.
authors.forename: Donia
authors.initials: D
authors.lastname: Macartney-Coxson
authors.affiliation: Genomics Research Centre, Institute of Biomedical Health and Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hanna
authors.affiliation: Genomics Research Centre, Institute of Biomedical Health and Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Eccles
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
authors.affiliation: School of Biological Science, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Chambers
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Bellis
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Goring
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: Malaghan Institute of Medical Research, Wellington, New Zealand.
authors.forename: Jacquie L
authors.initials: JL
authors.lastname: Harper
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Gibson
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Genomics Research Centre, Institute of Biomedical Health and Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Lyn R
authors.initials: LR
authors.lastname: Griffiths
mesh_terms: D002318:Cardiovascular Diseases / Q000235:genetics* / Q000473:pathology; D005260:Female; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male; D008542:Melanesia; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis