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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.

Benton MC, Lea RA, Macartney-Coxson D, Hanna M, Eccles DA, Carless MA, Chambers GK, Bellis C, Goring HH, Curran JE, Harper JL, Gibson G, Blangero J, Griffiths LR - PLoS Genet. (2015)

Bottom Line: Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05).Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05).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.

View Article: PubMed Central - PubMed

Affiliation: Genomics Research Centre, Institute of Biomedical Health and Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

Significantly enriched pathways identified from KEGG enrichment analysis.
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pgen.1005593.g005: Significantly enriched pathways identified from KEGG enrichment analysis.

Mentions: Due to the lack of functional genes in close proximity to the identified region on chromosome 1p22.2 we explored the potential of trans (distal) associations with the rs1396315 and available gene expression data. We interrogated 1712 genetically heritable expression transcripts previously identified in the Norfolk Island population and measured in the same individuals [22]. Analysis revealed 55 significantly associated (P<0.05) transcripts, with the majority of transcripts showing positive association with this SNP (S3 Fig). When annotated, 35/55 transcripts were assigned to well documented genes of known function, with the remaining 20 residing in regions of the genome that are less well annotated. Gene set enrichment analysis of these 35 genes identified 5 functional pathways exhibiting significant enrichment (Fig 5). The most significantly enriched pathway was found to be that of purine metabolism (P = 0.0015), with 3 genes showing enrichment; PDE6D, GART, and NME2. This finding is interesting as previous work in Norfolk Island reported on a set of eQTL associated genes implicated with CVD-risk traits which also resided with the purine metabolism pathway [22].


A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers.

Benton MC, Lea RA, Macartney-Coxson D, Hanna M, Eccles DA, Carless MA, Chambers GK, Bellis C, Goring HH, Curran JE, Harper JL, Gibson G, Blangero J, Griffiths LR - PLoS Genet. (2015)

Significantly enriched pathways identified from KEGG enrichment analysis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608754&req=5

pgen.1005593.g005: Significantly enriched pathways identified from KEGG enrichment analysis.
Mentions: Due to the lack of functional genes in close proximity to the identified region on chromosome 1p22.2 we explored the potential of trans (distal) associations with the rs1396315 and available gene expression data. We interrogated 1712 genetically heritable expression transcripts previously identified in the Norfolk Island population and measured in the same individuals [22]. Analysis revealed 55 significantly associated (P<0.05) transcripts, with the majority of transcripts showing positive association with this SNP (S3 Fig). When annotated, 35/55 transcripts were assigned to well documented genes of known function, with the remaining 20 residing in regions of the genome that are less well annotated. Gene set enrichment analysis of these 35 genes identified 5 functional pathways exhibiting significant enrichment (Fig 5). The most significantly enriched pathway was found to be that of purine metabolism (P = 0.0015), with 3 genes showing enrichment; PDE6D, GART, and NME2. This finding is interesting as previous work in Norfolk Island reported on a set of eQTL associated genes implicated with CVD-risk traits which also resided with the purine metabolism pathway [22].

Bottom Line: Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05).Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05).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.

View Article: PubMed Central - PubMed

Affiliation: Genomics Research Centre, Institute of Biomedical Health and Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

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.

No MeSH data available.


Related in: MedlinePlus