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.2023 Apr 7;26(5):106590.
doi: 10.1016/j.isci.2023.106590. eCollection 2023 May 19.

Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

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Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

Xuemin Wang et al. iScience..

Abstract

To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression ofCYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.

Keywords: Bioinformatics; Cancer; Genomics; Systems biology.

© 2023 The Author(s).

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Conflict of interest statement

The authors declare no competing interests.

Figures

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Graphical abstract
Figure 1
Figure 1
Multi-trait GWAS results and effects of endometrial cancer risk variants on traits included in the GWAS (A) Manhattan plot of the -log10 p values of the Bayes Factor (x-axis; PBF) for endometrial cancer risk (all histologies) of GWAS variants (chromosmal location shown on x-axis). Novel loci are annotated in red text and known risk loci in black. The red line indicates genome-wide significance at p < 5 × 10−8. (B) Heatmap of prior effects of endometrial cancer risk variants on risk factors included in the bGWAS analysis. Effect alleles of variants are shown. NA: variant not available for trait assessment, asterisk (∗) indicates variant is significantly associated with risk factor (p < 5 × 10−8).
Figure 2
Figure 2
Endometrial cancer risk locus at 7q22.1 identified by multi-trait BF GWAS (A–C) Regional association plot for 7q22.1. Genetic variants at each locus are plotted by their genomic position (hg19; x-axis) and GWAS P-value -log10(P) for association with endometrial cancer risk from meta-analysis of all endometrial cancer GWAS datasets on the left y-axis. Recombination rate (cM/Mb) is on the right y axis and plotted as blue lines. The color of the circles indicates the level of linkage disequilibrium between each variant and the lead variant (purple diamond) from the 1000 Genomes 2014 EUR reference panel (see legend, inset). Expression quantitative trait loci variants (eQTLs) are labeled with associated genes highlighted in the same color. Violin plots of expression by genotype for eQTLs are provided for (B) rs45446698 andCYP3A7 (adrenal gland) and (C) rs1139380031 andZKSCAN5 (skin not sun exposed – suprapubic). See also Tables S6–S8.
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