Sex specific associations in genome wide association analysis of renal cell carcinoma


Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10−8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90–1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10−8 compared with ORfemale = 0.93 [95% CI = 0.82–1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

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Data availability

Genome-wide summary statistics are made available through the NHGRI-EBI GWAS Catalog Data from the first IARC GWAS scan included in the study are available from Paul Brennan upon reasonable request. The data from second IARC scan are accessible on dbGaP: (phs001271.v1.p1). The first and second NCI scans are accessible on dbGaP (phs000351.v1.p1 and phs001736.v1.p1 respectively). Data from the MDA scan is available from Xifeng Wu upon reasonable request.


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We thank all of the participants who took part in this research and the funders and support staff who made this study possible. Funding for the genome-wide genotyping was provided by the US National Institutes of Health (NIH), National Cancer Institute (U01CA155309) for those studies coordinated by IARC, and by the intramural research program of the National Cancer Institute, US NIH, for those studies coordinated by the NCI. MD Anderson GWAS was supported by NIH (grant R01 CA170298) and the Center for Translational and Public Health Genomics, Duncan Family Institute for Cancer Prevention and Risk Assessment, The University of Texas MD Anderson Cancer Center. Funding for the IARC gene expression and eQTL study was provided by the US National Institutes of Health (NIH), National Cancer Institute (U01CA155309). RSL received IARC Postdoctoral fellowship from the IARC, partially supported by EC FP7 Marie Curie Actions – People – Co- Funding of regional, national and international programmes (COFUND). DCM is supported by a Cancer Research UK Population Research Fellowship. MMCI- supported by MH CZ - DRO (MMCI, 00209805).

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Correspondence to Ghislaine Scelo.

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