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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 of Chromosome 2 showing Component 6 associations.A) shows the genome-wide associations statistics with a distinct peak on chromosome 2 for bilirubin, B) refines the location of the peak to chr2q37.1, a region containing the UDP-glucuronosyltransferase gene family well known to metabolise bilirubin (UCSC track demonstrates the numerous isoforms). The blue dotted line indicates genome-wide significance level.
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pgen.1005593.g002: Manhattan plot of Chromosome 2 showing Component 6 associations.A) shows the genome-wide associations statistics with a distinct peak on chromosome 2 for bilirubin, B) refines the location of the peak to chr2q37.1, a region containing the UDP-glucuronosyltransferase gene family well known to metabolise bilirubin (UCSC track demonstrates the numerous isoforms). The blue dotted line indicates genome-wide significance level.

Mentions: Following the PCA, we performed GWAS analysis for the 9 nominally significantly (p<0.05) heritable components shown in Table 1. We decided to test all heritable components regardless of multiple testing to explore the potential biological relevance of association hits. Of the 9 components only 2 showed association peaks with clusters of SNPs that exceeded the genome-wide statistical significance threshold (P = 1.8x10-7). Fig 2A shows that Component 6—loaded with iron and bilirubin measures—yielded the strongest association peak on chr 2q37.1 (P = 1x10-11). Analysis of the individual component traits revealed that this peak was entirely associated with total and direct bilirubin, and maps to the well-known bilirubin metabolising gene—UGT1A1 [16–18], Fig 2B.


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 of Chromosome 2 showing Component 6 associations.A) shows the genome-wide associations statistics with a distinct peak on chromosome 2 for bilirubin, B) refines the location of the peak to chr2q37.1, a region containing the UDP-glucuronosyltransferase gene family well known to metabolise bilirubin (UCSC track demonstrates the numerous isoforms). The blue dotted line indicates genome-wide significance level.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005593.g002: Manhattan plot of Chromosome 2 showing Component 6 associations.A) shows the genome-wide associations statistics with a distinct peak on chromosome 2 for bilirubin, B) refines the location of the peak to chr2q37.1, a region containing the UDP-glucuronosyltransferase gene family well known to metabolise bilirubin (UCSC track demonstrates the numerous isoforms). The blue dotted line indicates genome-wide significance level.
Mentions: Following the PCA, we performed GWAS analysis for the 9 nominally significantly (p<0.05) heritable components shown in Table 1. We decided to test all heritable components regardless of multiple testing to explore the potential biological relevance of association hits. Of the 9 components only 2 showed association peaks with clusters of SNPs that exceeded the genome-wide statistical significance threshold (P = 1.8x10-7). Fig 2A shows that Component 6—loaded with iron and bilirubin measures—yielded the strongest association peak on chr 2q37.1 (P = 1x10-11). Analysis of the individual component traits revealed that this peak was entirely associated with total and direct bilirubin, and maps to the well-known bilirubin metabolising gene—UGT1A1 [16–18], Fig 2B.

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