The association between weight at birth and breast cancer risk revisited using Mendelian randomisation
AuthorKar, SP; Andrulis, IL; Brenner, H; Burgess, S; Chang-Claude, J; Considine, D; Doerk, T; Evans, DGR; Gago-Dominguez, M; Giles, GG; ...
Source TitleEuropean Journal of Epidemiology
University of Melbourne Author/sMilne, Roger
AffiliationMelbourne School of Population and Global Health
Document TypeJournal Article
CitationsKar, S. P., Andrulis, I. L., Brenner, H., Burgess, S., Chang-Claude, J., Considine, D., Doerk, T., Evans, D. G. R., Gago-Dominguez, M., Giles, G. G., Hartman, M., Huo, D., Kaaks, R., Li, J., Lophatananon, A., Margolin, S., Milne, R. L., Muir, K. R., Olsson, H. ,... Pharoah, P. D. P. (2019). The association between weight at birth and breast cancer risk revisited using Mendelian randomisation. EUROPEAN JOURNAL OF EPIDEMIOLOGY, 34 (6), pp.591-600. https://doi.org/10.1007/s10654-019-00485-7.
Access StatusOpen Access
Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73-1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.
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