Dataset Information

Pathway Analysis of Renal Cell Carcinoma Genome-Wide Association Studies Identifies Novel Associations.

ABSTRACT:

Background

Much of the heritable risk of renal cell carcinoma (RCC) associated with common genetic variation is unexplained. New analytic approaches have been developed to increase the discovery of risk variants in genome-wide association studies (GWAS), including multi-locus testing through pathway analysis.

Methods

We conducted a pathway analysis using GWAS summary data from six previous scans (10,784 cases and 20,406 controls) and evaluated 3,678 pathways and gene sets drawn from the Molecular Signatures Database. To replicate findings, we analyzed GWAS summary data from the UK Biobank (903 cases and 451,361 controls) and the Genetic Epidemiology Research on Adult Health and Aging cohort (317 cases and 50,511 controls).

Results

We identified 14 pathways/gene sets associated with RCC in both the discovery (P < 1.36 × 10^-5, the Bonferroni correction threshold) and replication (P < 0.05) sets, 10 of which include components of the PI3K/AKT pathway. In tests across 2,035 genes in these pathways, associations (Bonferroni corrected P < 2.46 × 10^-5 in discovery and replication sets combined) were observed for CASP9, TIPIN, and CDKN2C. The strongest SNP signal was for rs12124078 (P _Discovery = 2.6 × 10^-5; P _Replication = 1.5 × 10^-4; P _Combined = 6.9 × 10^-8), a CASP9 expression quantitative trait locus.

Conclusions

Our pathway analysis implicates genetic variation within the PI3K/AKT pathway as a source of RCC heritability and identifies several promising novel susceptibility genes, including CASP9, which warrant further investigation.

Impact

Our findings illustrate the value of pathway analysis as a complementary approach to analyzing GWAS data.

SUBMITTER: Purdue MP

PROVIDER: S-EPMC9438507 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Pathway Analysis of Renal Cell Carcinoma Genome-Wide Association Studies Identifies Novel Associations.

Purdue Mark P MP Song Lei L Scélo Ghislaine G Houlston Richard S RS Wu Xifeng X Sakoda Lori C LC Thai Khanh K Graff Rebecca E RE Rothman Nathaniel N Brennan Paul P Chanock Stephen J SJ Yu Kai K

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20200730 10

<h4>Background</h4>Much of the heritable risk of renal cell carcinoma (RCC) associated with common genetic variation is unexplained. New analytic approaches have been developed to increase the discovery of risk variants in genome-wide association studies (GWAS), including multi-locus testing through pathway analysis.<h4>Methods</h4>We conducted a pathway analysis using GWAS summary data from six previous scans (10,784 cases and 20,406 controls) and evaluated 3,678 pathways and gene sets drawn fr ...[more]

PMID: 32732251

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Project description:Skin trait variation impacts quality-of-life, especially for females from the viewpoint of beauty. To investigate genetic variation related to these traits, we conducted a GWAS of various skin phenotypes in 11,311 Japanese women and identified associations for age-spots, freckles, double eyelids, straight/curly hair, eyebrow thickness, hairiness, and sweating. In silico annotation with RoadMap Epigenomics epigenetic state maps and colocalization analysis of GWAS and GTEx Project eQTL signals provided information about tissue specificity, candidate causal variants, and functional target genes. Novel signals for skin-spot traits neighboured AKAP1/MSI2 (rs17833789; P = 2.2 × 10-9), BNC2 (rs10810635; P = 2.1 × 10-22), HSPA12A (rs12259842; P = 7.1 × 10-11), PPARGC1B (rs251468; P = 1.3 × 10-21), and RAB11FIP2 (rs10444039; P = 5.6 × 10-21). HSPA12A SNPs were the only protein-coding gene eQTLs identified across skin-spot loci. Double edged eyelid analysis identified that a signal around EMX2 (rs12570134; P = 8.2 × 10-15) was also associated with expression of EMX2 and the antisense-RNA gene EMX2OS in brain putamen basal ganglia tissue. A known hair morphology signal in EDAR was associated with both eyebrow thickness (rs3827760; P = 1.7 × 10-9) and straight/curly hair (rs260643; P = 1.6 × 10-103). Excessive hairiness signals' top SNPs were also eQTLs for TBX15 (rs984225; P = 1.6 × 10-8), BCL2 (rs7226979; P = 7.3 × 10-11), and GCC2 and LIMS1 (rs6542772; P = 2.2 × 10-9). For excessive sweating, top variants in two signals in chr2:28.82-29.05 Mb (rs56089836; P = 1.7 × 10-11) were eQTLs for either PPP1CB or PLB1, while a top chr16:48.26-48.45 Mb locus SNP was a known ABCC11 missense variant (rs6500380; P = 6.8 × 10-10). In total, we identified twelve loci containing sixteen association signals, of which fifteen were novel. These findings will help dermatologic researchers better understand the genetic underpinnings of skin-related phenotypic variation in human populations.

Dataset Information

Pathway Analysis of Renal Cell Carcinoma Genome-Wide Association Studies Identifies Novel Associations.

Background

Methods

Results

Conclusions

Impact

Publications

Pathway Analysis of Renal Cell Carcinoma Genome-Wide Association Studies Identifies Novel Associations.

Similar Datasets

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