Exploring the association between birthweight and breast cancer using summary statistics from a perspective of genetic correlation, mediation, and causality

Abstract

Background Previous studies demonstrated a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations also emerged, and the nature of such relationship remains unknown. Methods Using summary statistics of birthweight and breast cancer, we assessed the fetal/maternal-specific genetic correlation between them via LDSC and prioritized fetal/maternal-specific pleiotropic genes through MAIUP. Relying on summary statistics we conducted Mendelian randomization (MR) to evaluate the fetal/maternal-specific origin of causal relationship between birthweight, age of menarche, age at menopause and breast cancer. Results With summary statistics we identified a positive genetic correlation between fetal-specific birthweight and breast cancer (rg = 0.123 and P = 0.013) as well as a negative but insignificant correlation between maternal-specific birthweight and breast cancer (rg = − 0.068, P = 0.206); and detected 84 pleiotropic genes shared by fetal-specific birthweight and breast cancer, 49 shared by maternal-specific birthweight and breast cancer. We also revealed fetal-specific birthweight indirectly influenced breast cancer risk in adulthood via the path of age of menarche or age at menopause in terms of MR-based mediation analysis. Conclusion This study reveals that shared genetic foundation and causal mediation commonly drive the connection between the two traits, and that fetal/maternal-specific birthweight plays substantially distinct roles in such relationship. However, our work offers little supportive evidence for the fetal origins hypothesis of breast cancer originating in utero.

Evaluation of bi-directional causal association between obstructive sleep apnoea syndrome and diabetic microangiopathy: a Mendelian randomization study

“…First, it is used to reformat summary statistics and remove non-SNP variants (such as indels), chain-ambiguous SNPs, and duplicate SNPs. SNPs with imputation quality scores >0.9 and Minor Allele Frequency (MAF) > 0.01 were selected in our study to prevent bias due to variable imputation quality ( 24 ). Second, LD scores were estimated using the 1,000 Genomes Project as the linkage disequilibrium reference panel, following standard methods recommended by the developers.…”

“…Based on the literature review, we selected 15 variables that may serve as mediators that may lie on the pathway from sleep apnea syndrome to diabetic microangiopathy with available genetic tools from GWAS, including BMI, triglycerides, cholesterol, High-Density Lipoprotein (HDL), Low-Density Lipoprotein(LDL), apolipoprotein A, apolipoprotein B, blood glucose, C-reactive protein, heart rate, sleep duration, heme oxygenase 1 ( 53 , 54 , 57 ). Then, we screened the mediating factors of the relationship between OSAS and diabetic microangiopathy according to the following criteria: (1) There should be a causal relationship between OSAS and the mediator, and the effect of OSAS on the mediator should be unidirectional, because if the mediation analysis between Bidirectionality exists and the validity of the mediation analysis may be affected ( 24 ). (2) Regardless of whether OSAS is adjusted for, the causal relationship between mediators and diabetic microvasculopathy always exists; (3) Based on current scientific evidence, in practice, the relationship between OSAS and mediators, and the association between mediators and diabetic microvasculopathy, should be the other way around.…”

Review of mendelian randomization studies on age at natural menopause

“…Based on a principle of mediation analysis, Zhang et al. demonstrated that fetal-specific birthweight can indirectly affect BC risk in adulthood via the AAM and subsequently the ANM ( 229 ). This finding supported the findings of certain previous studies to an extent ( 230 , 231 ) and questioned the findings of others ( 232 , 233 ).…”

Maternal origin of children-onset asthma: evidence from observational study and instrumental variable analysis

“…The fetal-speci c SNP effect was calculated conditioning on mother's genotypes and the maternal-speci c SNP effect was calculated conditioning on offspring's genotypes, with 297,356 European individuals with their own birthweight and 210,248 European individuals with offspring birthweight. The selected instruments included 15 SNPs with directionally-opposing maternal and fetal effects, 26 SNPs with directionallyconcordant maternal and fetal effects, and 31 SNPs with maternal-only effects (Warrington, et al, 2019;Zhang, et al, 2022).…”

“…1). In terms of the interpretations given in this gure and the core of DOHaD, the maternal-speci c component can be employed to characterize the causal relation between birthweight and COA (Moen, et al, 2020;Zhang, et al, 2022). Maternal/fetal-speci c summary statistics of single nucleotide polymorphisms (SNPs) on birthweight were recently released (Warrington, et al, 2019), providing us an unprecedented opportunity to assess the intrauterine effect by elaborating the maternal contribution of birthweight to COA.…”