Limits...
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

Venn diagram showing the inter-correlation and heritabilities of components extracted from the PCA of 37 quantitative traits.Relationships between components were inferred either by variable overlap, or loadings on a component greater than 0.35. Heritability of each component is colour coded (as per key) with the non-significant traits being coloured white.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4608754&req=5

pgen.1005593.g001: Venn diagram showing the inter-correlation and heritabilities of components extracted from the PCA of 37 quantitative traits.Relationships between components were inferred either by variable overlap, or loadings on a component greater than 0.35. Heritability of each component is colour coded (as per key) with the non-significant traits being coloured white.

Mentions: An ‘unsupervised’ PCA of 37 CVD related traits was conducted (trait summaries listed in S1 Table). The PCA extracted 13 composite phenotypes which together explained >75% of the total variance (Table 1). Trait loading scores for each of these components is available in S2 Table. Heritability values for all 13 components, as well as a total combined component were calculated. Nine components showed nominal significance with heritability estimates ranging from 0.22–0.55 (P<0.05). After correction for multiple testing was applied only Component 3 and Component 9 remained significant (P<0.0038). Component 3 was the most heritable (h2 = 0.55) and was loaded with 7 measures related to CVD—% body fat, waist-to-hip ratio, systolic and diastolic blood pressure, creatinine, blood urea nitrogen, and uric acid. The measures most strongly correlated with Component 3 were blood urea nitrogen (0.76), creatinine (0.74) and uric acid (0.61) which are all kidney function markers suggesting that the Component 3 phenotype may represent renal dysfunction. The relationship between all extracted components is displayed in Fig 1. Overlap between components is suggestive of co-morbidity among traits as well as the possibility of genetic commonalities. The clinical relevance of the Component 3 score was explored by comparison with the formal Framingham CVD score [15] and showed a positive correlation (r = 0.4, P = 1.2x10-8).


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)

Venn diagram showing the inter-correlation and heritabilities of components extracted from the PCA of 37 quantitative traits.Relationships between components were inferred either by variable overlap, or loadings on a component greater than 0.35. Heritability of each component is colour coded (as per key) with the non-significant traits being coloured white.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005593.g001: Venn diagram showing the inter-correlation and heritabilities of components extracted from the PCA of 37 quantitative traits.Relationships between components were inferred either by variable overlap, or loadings on a component greater than 0.35. Heritability of each component is colour coded (as per key) with the non-significant traits being coloured white.
Mentions: An ‘unsupervised’ PCA of 37 CVD related traits was conducted (trait summaries listed in S1 Table). The PCA extracted 13 composite phenotypes which together explained >75% of the total variance (Table 1). Trait loading scores for each of these components is available in S2 Table. Heritability values for all 13 components, as well as a total combined component were calculated. Nine components showed nominal significance with heritability estimates ranging from 0.22–0.55 (P<0.05). After correction for multiple testing was applied only Component 3 and Component 9 remained significant (P<0.0038). Component 3 was the most heritable (h2 = 0.55) and was loaded with 7 measures related to CVD—% body fat, waist-to-hip ratio, systolic and diastolic blood pressure, creatinine, blood urea nitrogen, and uric acid. The measures most strongly correlated with Component 3 were blood urea nitrogen (0.76), creatinine (0.74) and uric acid (0.61) which are all kidney function markers suggesting that the Component 3 phenotype may represent renal dysfunction. The relationship between all extracted components is displayed in Fig 1. Overlap between components is suggestive of co-morbidity among traits as well as the possibility of genetic commonalities. The clinical relevance of the Component 3 score was explored by comparison with the formal Framingham CVD score [15] and showed a positive correlation (r = 0.4, P = 1.2x10-8).

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