Genetic causal relationship between age at menarche and benign oesophageal neoplasia identified by a Mendelian randomization study

Abstract

Objective: The occurrence and development of oesophageal neoplasia (ON) is closely related to hormone changes. The aim of this study was to investigate the causal relationships between age at menarche (AAMA) or age at menopause (AAMO) and benign oesophageal neoplasia (BON) or malignant oesophageal neoplasia (MON) from a genetic perspective.

Methods: Genome-wide association study (GWAS) summary data of exposures (AAMA and AAMO) and outcomes (BON and MON) were obtained from the IEU OpenGWAS database. We performed a two-sample Mendelian randomization (MR) study between them. The inverse variance weighted (IVW) was used as the main analysis method, while the MR Egger, weighted median, simple mode, and weighted mode were supplementary methods. The maximum likelihood, penalized weighted median, and IVW (fixed effects) were validation methods. We used Cochran's Q statistic and Rucker's Q statistic to detect heterogeneity. The intercept test of the MR Egger and global test of MR pleiotropy residual sum and outlier (MR-PRESSO) were used to detect horizontal pleiotropy, and the distortion test of the MR-PRESSO analysis was used to detect outliers. The leave-one-out analysis was used to detect whether the MR analysis was affected by single nucleotide polymorphisms (SNPs). In addition, the MR robust adjusted profile score (MR-RAPS) method was used to assess the robustness of MR analysis.

Results: The random-effects IVW results showed that AAMA had a negative genetic causal relationship with BON (odds ratio [OR] = 0.285 [95% confidence interval [CI]: 0.130-0.623], P = 0.002). The weighted median, maximum likelihood, penalized weighted median, and IVW (fixed effects) were consistent with random-effects IVW (P < 0.05). The MR Egger, simple mode and weighted mode results showed that AAMA had no genetic causal relationship with BON (P > 0.05). However, there were no causal genetic relationships between AAMA and MON (OR = 1.132 [95%CI: 0.621-2.063], P = 0.685), AAMO and BON (OR = 0.989 [95%CI: 0.755-1.296], P = 0.935), or AAMO and MON (OR = 1.129 [95%CI: 0.938-1.359], P = 0.200). The MR Egger, weighted median, simple mode, weighted mode, maximum likelihood, penalized weighted median, and IVW (fixed effects) were consistent with a random-effects IVW (P > 0.05). MR analysis results showed no heterogeneity, the horizontal pleiotropy and outliers (P > 0.05). They were not driven by a single SNP, and were normally distributed (P > 0.05).

Conclusion: Only AAMA has a negative genetic causal relationship with BON, and no genetic causal relationships exist between AAMA and MON, AAMO and BON, or AAMO and MON. However, it cannot be ruled out that they are related at other levels besides genetics.

Keywords: age at menopause; confounding factor; genetic; hormone; instrumental variables.

Figure 1

MR analysis of exposures (age at menarche and age at menopause) and outcomes (benign oesophageal neoplasia and malignant oesophageal neoplasia). Five methods: random-effects IVW, MR Egger, weighted median, simple mode, and weighted mode. Our MR analysis follows the results of random-effects IVW. The blue vertical line represents OR = 1. The green square is the OR value of the MR analysis result. The black line segment is the OR 95% confidence interval.

Figure 2

MR analysis scatter plot. Different colored lines in the figure represent the results of the different MR analysis methods. Oblique upward indicates positive causality, oblique downward indicates negative causality. (A) age at menarche and benign oesophageal neoplasia; (B) age at menopause and benign oesophageal neoplasia; (C) age at menarche and malignant oesophageal neoplasia; (D) age at menopause and malignant oesophageal neoplasia.

Figure 3

Leave-one-out analysis of the results from MR analysis. Each black line in the figure refers to the result of MR analysis with the remaining SNPs after deleting one SNP on the left. (A) age at menarche and benign oesophageal neoplasia; (B) age at menopause and benign oesophageal neoplasia; (C) age at menarche and malignant oesophageal neoplasia; (D) age at menopause and malignant oesophageal neoplasia.

Figure 4

Normal distribution plots of the MR analysis. Circles in the figure represent SNPs for MR Analysis. (A) age at menarche and benign oesophageal neoplasia; (B) age at menopause and benign oesophageal neoplasia; (C) age at menarche and malignant oesophageal neoplasia; (D) age at menopause and malignant oesophageal neoplasia.

Figure 5

MR analysis between exposures (age at menarche and age at menopause) and outcomes (benign oesophageal neoplasia and malignant oesophageal neoplasia). Three methods used: maximum likelihood, penalized weighted median, and IVW (fixed effects). The blue vertical line represents OR = 1. The green square is the OR value of MR analysis result. The black line segment is the OR 95% confidence interval.