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The association between weight at birth and breast cancer risk revisited using Mendelian randomisation

Kar, Siddhartha P.; Andrulis, Irene L.; Brenner, Hermann; Burgess, Stephen; Chang-Claude, Jenny; Considine, Daniel; Dörk, Thilo; Evans, Dafydd Gareth R.; Gago-Domínguez, Manuela and Giles, Graham G., et al. (2019) In European Journal of Epidemiology 34(6). p.591-600
Abstract

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... (More)

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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@article{8d406351-5fed-47a3-b49f-559536a74574,
  abstract     = {<p>                             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 &lt; 5 × 10                             <sup>−8</sup>                              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.                         </p>},
  author       = {Kar, Siddhartha P. and Andrulis, Irene L. and Brenner, Hermann and Burgess, Stephen and Chang-Claude, Jenny and Considine, Daniel and Dörk, Thilo and Evans, Dafydd Gareth R. and Gago-Domínguez, Manuela and Giles, Graham G. and Hartman, Mikael and Huo, Dezheng and Kaaks, Rudolf and Li, Jingmei and Lophatananon, Artitaya and Margolin, Sara and Milne, Roger L. and Muir, Kenneth R. and Olsson, Håkan and Punie, Kevin and Radice, Paolo and Simard, Jacques and Tamimi, Rulla M. and Van Nieuwenhuysen, Els and Wendt, Camilla and Zheng, Wei and Pharoah, Paul D.P.},
  issn         = {0393-2990},
  keyword      = {Birth weight,Breast cancer,Mendelian randomisation},
  language     = {eng},
  month        = {02},
  number       = {6},
  pages        = {591--600},
  publisher    = {Springer},
  series       = {European Journal of Epidemiology},
  title        = {The association between weight at birth and breast cancer risk revisited using Mendelian randomisation},
  url          = {http://dx.doi.org/10.1007/s10654-019-00485-7},
  volume       = {34},
  year         = {2019},
}