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Identification of candidate genes for prostate cancer-risk SNPs utilizing a normal prostate tissue eQTL data set.

Thibodeau SN, French AJ, McDonnell SK, Cheville J, Middha S, Tillmans L, Riska S, Baheti S, Larson MC, Fogarty Z, Zhang Y, Larson N, Nair A, O'Brien D, Wang L, Schaid DJ - Nat Commun (2015)

Bottom Line: We focus on 146 PrCa-risk SNPs, including all SNPs in linkage disequilibrium with each risk SNP, resulting in 100 unique risk intervals.Of all SNP-gene combinations tested, 41.7% of SNPs demonstrate a significant eQTL signal after adjustment for sample histology and 14 expression principal component covariates.Of the 100 PrCa-risk intervals, 51 have a significant eQTL signal and these are associated with 88 genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.

ABSTRACT
Multiple studies have identified loci associated with the risk of developing prostate cancer but the associated genes are not well studied. Here we create a normal prostate tissue-specific eQTL data set and apply this data set to previously identified prostate cancer (PrCa)-risk SNPs in an effort to identify candidate target genes. The eQTL data set is constructed by the genotyping and RNA sequencing of 471 samples. We focus on 146 PrCa-risk SNPs, including all SNPs in linkage disequilibrium with each risk SNP, resulting in 100 unique risk intervals. We analyse cis-acting associations where the transcript is located within 2 Mb (±1 Mb) of the risk SNP interval. Of all SNP-gene combinations tested, 41.7% of SNPs demonstrate a significant eQTL signal after adjustment for sample histology and 14 expression principal component covariates. Of the 100 PrCa-risk intervals, 51 have a significant eQTL signal and these are associated with 88 genes. This study provides a rich resource to study biological mechanisms underlying genetic risk to PrCa.

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Related in: MedlinePlus

Schematic diagram outlining the eQTL analyses conducted for the primary and second stages.Schematic diagram outlining the analysis conducted for the primary analysis (focused on risk regions defined by PrCa-risk SNPs) and for the second stage (focused on target gene regions defined as all genes meeting a Bonferroni significance threshold in stage 1). Stage 2 results were classified into three groups (G1, G2 and G3) based on the magnitude of LD between the PrCa-risk SNP and the peak eQTL-associated SNP in each region; G1 defined as r2>0.5 between risk and peak SNPs, G2 having r2 between 0.2–0.5 and G3 having r2≤0.2. An example regional association plot is shown for each group. The x axis shows the chromosomal position of the SNPs (with analyzed gene in the region displayed below) and the y axis is the −log10(P value) obtained by regressing normalized expression levels for the gene listed in the panel title on the number of minor alleles of each SNP genotype adjusted for histologic characteristics and 14 expression principal components. The position of the PrCa-risk SNP is indicated by a dotted red vertical line with the eQTL result displayed as diamond. All Bonferroni significant results are coloured, with the colour defined by LD between the SNP and the PrCa-risk SNP listed in the panel title (LD r2>0.5 red, between 0.2–0.5 green and ≤0.2 blue). The right y axis shows the recombination rate (purple dotted lines mark recombination locations). The bottom half of each panel contains an LD heat map of the significant SNPs in the region (if >1,000 significant SNPs, only the top 1,000 SNPs in the region are shown).
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f1: Schematic diagram outlining the eQTL analyses conducted for the primary and second stages.Schematic diagram outlining the analysis conducted for the primary analysis (focused on risk regions defined by PrCa-risk SNPs) and for the second stage (focused on target gene regions defined as all genes meeting a Bonferroni significance threshold in stage 1). Stage 2 results were classified into three groups (G1, G2 and G3) based on the magnitude of LD between the PrCa-risk SNP and the peak eQTL-associated SNP in each region; G1 defined as r2>0.5 between risk and peak SNPs, G2 having r2 between 0.2–0.5 and G3 having r2≤0.2. An example regional association plot is shown for each group. The x axis shows the chromosomal position of the SNPs (with analyzed gene in the region displayed below) and the y axis is the −log10(P value) obtained by regressing normalized expression levels for the gene listed in the panel title on the number of minor alleles of each SNP genotype adjusted for histologic characteristics and 14 expression principal components. The position of the PrCa-risk SNP is indicated by a dotted red vertical line with the eQTL result displayed as diamond. All Bonferroni significant results are coloured, with the colour defined by LD between the SNP and the PrCa-risk SNP listed in the panel title (LD r2>0.5 red, between 0.2–0.5 green and ≤0.2 blue). The right y axis shows the recombination rate (purple dotted lines mark recombination locations). The bottom half of each panel contains an LD heat map of the significant SNPs in the region (if >1,000 significant SNPs, only the top 1,000 SNPs in the region are shown).

Mentions: Our primary analysis focused on identifying cis-eQTLs for 146 reported PrCa-risk SNPs (Supplementary Data 1), including all observed and high-quality imputed SNPs in LD with each risk SNP (r2>0.5), resulting in a total of 6,324 risk and LD-SNPs to be evaluated in 100 unique risk intervals (several of the risk SNPs were in close proximity to each other and were combined in a single risk interval) (Fig. 1). The risk SNPs and the number of SNPs evaluated for each of the risk intervals is provided in Supplementary Data 2.


Identification of candidate genes for prostate cancer-risk SNPs utilizing a normal prostate tissue eQTL data set.

Thibodeau SN, French AJ, McDonnell SK, Cheville J, Middha S, Tillmans L, Riska S, Baheti S, Larson MC, Fogarty Z, Zhang Y, Larson N, Nair A, O'Brien D, Wang L, Schaid DJ - Nat Commun (2015)

Schematic diagram outlining the eQTL analyses conducted for the primary and second stages.Schematic diagram outlining the analysis conducted for the primary analysis (focused on risk regions defined by PrCa-risk SNPs) and for the second stage (focused on target gene regions defined as all genes meeting a Bonferroni significance threshold in stage 1). Stage 2 results were classified into three groups (G1, G2 and G3) based on the magnitude of LD between the PrCa-risk SNP and the peak eQTL-associated SNP in each region; G1 defined as r2>0.5 between risk and peak SNPs, G2 having r2 between 0.2–0.5 and G3 having r2≤0.2. An example regional association plot is shown for each group. The x axis shows the chromosomal position of the SNPs (with analyzed gene in the region displayed below) and the y axis is the −log10(P value) obtained by regressing normalized expression levels for the gene listed in the panel title on the number of minor alleles of each SNP genotype adjusted for histologic characteristics and 14 expression principal components. The position of the PrCa-risk SNP is indicated by a dotted red vertical line with the eQTL result displayed as diamond. All Bonferroni significant results are coloured, with the colour defined by LD between the SNP and the PrCa-risk SNP listed in the panel title (LD r2>0.5 red, between 0.2–0.5 green and ≤0.2 blue). The right y axis shows the recombination rate (purple dotted lines mark recombination locations). The bottom half of each panel contains an LD heat map of the significant SNPs in the region (if >1,000 significant SNPs, only the top 1,000 SNPs in the region are shown).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663677&req=5

f1: Schematic diagram outlining the eQTL analyses conducted for the primary and second stages.Schematic diagram outlining the analysis conducted for the primary analysis (focused on risk regions defined by PrCa-risk SNPs) and for the second stage (focused on target gene regions defined as all genes meeting a Bonferroni significance threshold in stage 1). Stage 2 results were classified into three groups (G1, G2 and G3) based on the magnitude of LD between the PrCa-risk SNP and the peak eQTL-associated SNP in each region; G1 defined as r2>0.5 between risk and peak SNPs, G2 having r2 between 0.2–0.5 and G3 having r2≤0.2. An example regional association plot is shown for each group. The x axis shows the chromosomal position of the SNPs (with analyzed gene in the region displayed below) and the y axis is the −log10(P value) obtained by regressing normalized expression levels for the gene listed in the panel title on the number of minor alleles of each SNP genotype adjusted for histologic characteristics and 14 expression principal components. The position of the PrCa-risk SNP is indicated by a dotted red vertical line with the eQTL result displayed as diamond. All Bonferroni significant results are coloured, with the colour defined by LD between the SNP and the PrCa-risk SNP listed in the panel title (LD r2>0.5 red, between 0.2–0.5 green and ≤0.2 blue). The right y axis shows the recombination rate (purple dotted lines mark recombination locations). The bottom half of each panel contains an LD heat map of the significant SNPs in the region (if >1,000 significant SNPs, only the top 1,000 SNPs in the region are shown).
Mentions: Our primary analysis focused on identifying cis-eQTLs for 146 reported PrCa-risk SNPs (Supplementary Data 1), including all observed and high-quality imputed SNPs in LD with each risk SNP (r2>0.5), resulting in a total of 6,324 risk and LD-SNPs to be evaluated in 100 unique risk intervals (several of the risk SNPs were in close proximity to each other and were combined in a single risk interval) (Fig. 1). The risk SNPs and the number of SNPs evaluated for each of the risk intervals is provided in Supplementary Data 2.

Bottom Line: We focus on 146 PrCa-risk SNPs, including all SNPs in linkage disequilibrium with each risk SNP, resulting in 100 unique risk intervals.Of all SNP-gene combinations tested, 41.7% of SNPs demonstrate a significant eQTL signal after adjustment for sample histology and 14 expression principal component covariates.Of the 100 PrCa-risk intervals, 51 have a significant eQTL signal and these are associated with 88 genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.

ABSTRACT
Multiple studies have identified loci associated with the risk of developing prostate cancer but the associated genes are not well studied. Here we create a normal prostate tissue-specific eQTL data set and apply this data set to previously identified prostate cancer (PrCa)-risk SNPs in an effort to identify candidate target genes. The eQTL data set is constructed by the genotyping and RNA sequencing of 471 samples. We focus on 146 PrCa-risk SNPs, including all SNPs in linkage disequilibrium with each risk SNP, resulting in 100 unique risk intervals. We analyse cis-acting associations where the transcript is located within 2 Mb (±1 Mb) of the risk SNP interval. Of all SNP-gene combinations tested, 41.7% of SNPs demonstrate a significant eQTL signal after adjustment for sample histology and 14 expression principal component covariates. Of the 100 PrCa-risk intervals, 51 have a significant eQTL signal and these are associated with 88 genes. This study provides a rich resource to study biological mechanisms underlying genetic risk to PrCa.

Show MeSH
Related in: MedlinePlus