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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

Manhattan plot for Component 3 showing an association peak on chr 1p22.2.The red dotted line indicates the study-wide Meff significance threshold.
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pgen.1005593.g003: Manhattan plot for Component 3 showing an association peak on chr 1p22.2.The red dotted line indicates the study-wide Meff significance threshold.

Mentions: The other component trait to yield a statistically significant association peak was the most heritable component, Component 3. Fig 3 shows that the GWAS of Component 3 yielded three associated SNPs located at chr 1p22.2 (min P = 1.3x10-9 for rs1396315), as well as a supportive peak below the threshold of study-wide significance. GWAS of each of the 7 traits loaded into Component 3 individually did not show any significant peak at this locus (S1 Fig). Therefore, unlike Component 6 (explained by bilirubin alone) the Component 3 hit indicated a potential pleotropic effect locus that was further investigated.


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)

Manhattan plot for Component 3 showing an association peak on chr 1p22.2.The red dotted line indicates the study-wide Meff significance threshold.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005593.g003: Manhattan plot for Component 3 showing an association peak on chr 1p22.2.The red dotted line indicates the study-wide Meff significance threshold.
Mentions: The other component trait to yield a statistically significant association peak was the most heritable component, Component 3. Fig 3 shows that the GWAS of Component 3 yielded three associated SNPs located at chr 1p22.2 (min P = 1.3x10-9 for rs1396315), as well as a supportive peak below the threshold of study-wide significance. GWAS of each of the 7 traits loaded into Component 3 individually did not show any significant peak at this locus (S1 Fig). Therefore, unlike Component 6 (explained by bilirubin alone) the Component 3 hit indicated a potential pleotropic effect locus that was further investigated.

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