Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

Abstract

Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.

Methods: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients.

Results: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8).

Conclusions: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.

Figure 1.

Meta-analysis of associations between height and risk of breast cancer in prospective cohort studies. All tests for meta-analyses were two-sided. CI = confidence interval; ER = estrogen receptor; PR = progesterone receptor; RR = relative risk.

Figure 2.

Association of the weighted height genetic score with breast cancer risk in the Breast Cancer Association Consortium. CI = confidence interval; OR = odds ratio.

Figure 3.

Sensitivity analyses for associations between genetically predicted height and breast cancer risk in the Breast Cancer Association Consortium. *The details of the formula to construct height genetic score are presented in Supplementary Table 3 (available online). †Phenotypic variation of height explained by height genetic scores in the study population. BC = breast cancer; HGS = height genetic score; LD = linkage disequilibrium; SNP = single-nucleotide polymorphism.

Figure 4.

Regional association plots of the three new loci associated with breast cancer risk in the Breast Cancer Association Consortium. The three plots represent: (A) 1q21.2, (B) 2p23.3, and (C) 12p11.22. For each plot, the -log₁₀ (P values) (y-axis) of single-nucleotide polymorphisms (SNPs) are shown according to their chromosomal positions (x-axis) in National Center for Biological Information (NCBI) Build 37. Blue lines represent the estimated recombination rates from the HapMap Project (NCBI Build 37). Arrows indicate genomic locations of genes within the LD block centered on the index SNPs in the NCBI Build 37 human assembly. The color of SNPs represents their LD (r ², the 1000 Genomes Project Europeans), with the index SNP shown as a purple diamond at each locus.