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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

LocusTrack plot showing detailed annotation information of the associated chr1p22.2 region.The significance level of association is given on the left y axis (-log10(p-value)), while genomic recombination is displayed on the right y axis. Pairwise LD between the tagging SNP and each other SNP is indicated by colour. In the bottom panel several relevant tracks of UCSC data are provided, including: evofold RNA loop prediction; ENCODE transcription factor binding sites from ChIP-SEQ, and tissue specific RRBS methylation information from liver and kidney (both relevant tissue types for the identified phenotype).
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pgen.1005593.g004: LocusTrack plot showing detailed annotation information of the associated chr1p22.2 region.The significance level of association is given on the left y axis (-log10(p-value)), while genomic recombination is displayed on the right y axis. Pairwise LD between the tagging SNP and each other SNP is indicated by colour. In the bottom panel several relevant tracks of UCSC data are provided, including: evofold RNA loop prediction; ENCODE transcription factor binding sites from ChIP-SEQ, and tissue specific RRBS methylation information from liver and kidney (both relevant tissue types for the identified phenotype).

Mentions: To determine if there were any other additional independently associated variants in this region we performed an association analysis conditioning on rs1396315. This revealed no further associations indicating that only a single locus and resultant haplotype for Component 3 is present in this region. Linkage disequilibrium (LD) analysis of the SNPs spanning the Component 3 peak on chr 1p22.2 illustrated that rs1396315 tagged the associated haplotype and could be used as the reference SNP for further analysis (Fig 4). The allele frequency of the rarer allele (C) in the Norfolk pedigree was 0.24, which is consistent with the frequency in European populations [19]. Genotype association analysis of rs1396315 against the Component 3 score showed that the rare allele (C) was associated with elevated Component 3 score in an additive fashion. Locus-specific heritability estimates showed that this haplotype explained ~11% of the variation in the Component 3 score, indicating this is a major effect locus in the Norfolk Island population. Association analysis of rs1396315 against the individual phenotypes comprising Component 3 indicated that the strongest association was with blood urea nitrogen (P = 0.00006), followed by creatinine (P = 0.003) and uric acid (P = 0.005). The other traits loaded into Component 3 were not associated with rs1396315 when analysed independently (P>0.1). This indicates that the association of this SNP with Component 3 is primarily due to blood urea nitrogen, creatinine and uric acid—potential metabolic and renal functional markers.


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)

LocusTrack plot showing detailed annotation information of the associated chr1p22.2 region.The significance level of association is given on the left y axis (-log10(p-value)), while genomic recombination is displayed on the right y axis. Pairwise LD between the tagging SNP and each other SNP is indicated by colour. In the bottom panel several relevant tracks of UCSC data are provided, including: evofold RNA loop prediction; ENCODE transcription factor binding sites from ChIP-SEQ, and tissue specific RRBS methylation information from liver and kidney (both relevant tissue types for the identified phenotype).
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005593.g004: LocusTrack plot showing detailed annotation information of the associated chr1p22.2 region.The significance level of association is given on the left y axis (-log10(p-value)), while genomic recombination is displayed on the right y axis. Pairwise LD between the tagging SNP and each other SNP is indicated by colour. In the bottom panel several relevant tracks of UCSC data are provided, including: evofold RNA loop prediction; ENCODE transcription factor binding sites from ChIP-SEQ, and tissue specific RRBS methylation information from liver and kidney (both relevant tissue types for the identified phenotype).
Mentions: To determine if there were any other additional independently associated variants in this region we performed an association analysis conditioning on rs1396315. This revealed no further associations indicating that only a single locus and resultant haplotype for Component 3 is present in this region. Linkage disequilibrium (LD) analysis of the SNPs spanning the Component 3 peak on chr 1p22.2 illustrated that rs1396315 tagged the associated haplotype and could be used as the reference SNP for further analysis (Fig 4). The allele frequency of the rarer allele (C) in the Norfolk pedigree was 0.24, which is consistent with the frequency in European populations [19]. Genotype association analysis of rs1396315 against the Component 3 score showed that the rare allele (C) was associated with elevated Component 3 score in an additive fashion. Locus-specific heritability estimates showed that this haplotype explained ~11% of the variation in the Component 3 score, indicating this is a major effect locus in the Norfolk Island population. Association analysis of rs1396315 against the individual phenotypes comprising Component 3 indicated that the strongest association was with blood urea nitrogen (P = 0.00006), followed by creatinine (P = 0.003) and uric acid (P = 0.005). The other traits loaded into Component 3 were not associated with rs1396315 when analysed independently (P>0.1). This indicates that the association of this SNP with Component 3 is primarily due to blood urea nitrogen, creatinine and uric acid—potential metabolic and renal functional markers.

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