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Characterizing the Relationship between Expression Quantitative Trait Loci (eQTLs), DNA Methylation Quantitative Trait Loci (mQTLs), and Breast Cancer Risk Variants

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Τίτλος: Characterizing the Relationship between Expression Quantitative Trait Loci (eQTLs), DNA Methylation Quantitative Trait Loci (mQTLs), and Breast Cancer Risk Variants
Συγγραφείς: Ho, PJ, Khng, A, Tan, BKT, Khor, CC, Tan, EY, Lim, GH, Yuan, JM, Tan, SM, Chang, X, Tan, VKM, Sim, X, Dorajoo, R, Koh, WP, Hartman, M, Li, J
Στοιχεία εκδότη: MDPI AG
Έτος έκδοσης: 2024
Συλλογή: The University of Melbourne: Digital Repository
Περιγραφή: PURPOSE: To assess the association of a polygenic risk score (PRS) for functional genetic variants with the risk of developing breast cancer. METHODS: Summary data-based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) were used to identify breast cancer risk variants associated with gene expression and DNA methylation levels. A new SMR-based PRS was computed from the identified variants (functional PRS) and compared to an established 313-variant breast cancer PRS (GWAS PRS). The two scores were evaluated in 3560 breast cancer cases and 3383 non-cancer controls and also in a prospective study (n = 10,213) comprising 418 cases. RESULTS: We identified 149 variants showing pleiotropic association with breast cancer risk (eQTLHEIDI > 0.05 = 9, mQTLHEIDI > 0.05 = 165). The discriminatory ability of the functional PRS (AUCcontinuous [95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUCcontinuous [95% CI]: 0.609 [0.596 to 0.622]). Even when utilizing 457 distinct variants from both the functional and GWAS PRS, the combined discriminatory performance remained below that of the GWAS PRS (AUCcontinuous, combined [95% CI]: 0.561 [0.548 to 0.575]). A binary high/low-risk classification based on the 80th centile PRS in controls revealed a 6% increase in cases using the GWAS PRS compared to the functional PRS. The functional PRS identified an additional 12% of high-risk cases but also led to a 13% increase in high-risk classification among controls. Similar findings were observed in the SCHS prospective cohort, where the GWAS PRS outperformed the functional PRS, and the highest-performing PRS, a combined model, did not significantly improve over the GWAS PRS. CONCLUSIONS: While this study identified potentially functional variants associated with breast cancer risk, their inclusion did not substantially enhance the predictive accuracy of the GWAS PRS.
Τύπος εγγράφου: article in journal/newspaper
Γλώσσα: English
ISSN: 2072-6694
Relation: pii: cancers16112072; https://hdl.handle.net/11343/353801
Διαθεσιμότητα: https://hdl.handle.net/11343/353801
Rights: https://creativecommons.org/licenses/by/4.0 ; CC BY
Αριθμός Καταχώρησης: edsbas.67D955C
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  Data: Characterizing the Relationship between Expression Quantitative Trait Loci (eQTLs), DNA Methylation Quantitative Trait Loci (mQTLs), and Breast Cancer Risk Variants
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  Data: 2024
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  Data: The University of Melbourne: Digital Repository
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  Data: PURPOSE: To assess the association of a polygenic risk score (PRS) for functional genetic variants with the risk of developing breast cancer. METHODS: Summary data-based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) were used to identify breast cancer risk variants associated with gene expression and DNA methylation levels. A new SMR-based PRS was computed from the identified variants (functional PRS) and compared to an established 313-variant breast cancer PRS (GWAS PRS). The two scores were evaluated in 3560 breast cancer cases and 3383 non-cancer controls and also in a prospective study (n = 10,213) comprising 418 cases. RESULTS: We identified 149 variants showing pleiotropic association with breast cancer risk (eQTLHEIDI > 0.05 = 9, mQTLHEIDI > 0.05 = 165). The discriminatory ability of the functional PRS (AUCcontinuous [95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUCcontinuous [95% CI]: 0.609 [0.596 to 0.622]). Even when utilizing 457 distinct variants from both the functional and GWAS PRS, the combined discriminatory performance remained below that of the GWAS PRS (AUCcontinuous, combined [95% CI]: 0.561 [0.548 to 0.575]). A binary high/low-risk classification based on the 80th centile PRS in controls revealed a 6% increase in cases using the GWAS PRS compared to the functional PRS. The functional PRS identified an additional 12% of high-risk cases but also led to a 13% increase in high-risk classification among controls. Similar findings were observed in the SCHS prospective cohort, where the GWAS PRS outperformed the functional PRS, and the highest-performing PRS, a combined model, did not significantly improve over the GWAS PRS. CONCLUSIONS: While this study identified potentially functional variants associated with breast cancer risk, their inclusion did not substantially enhance the predictive accuracy of the GWAS PRS.
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      – TitleFull: Characterizing the Relationship between Expression Quantitative Trait Loci (eQTLs), DNA Methylation Quantitative Trait Loci (mQTLs), and Breast Cancer Risk Variants
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