Genome-wide Association Study of Estradiol Levels and the Causal Effect of Estradiol on Bone Mineral Density

Abstract

Context: Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism, but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels.

Objective: Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD).

Design: We performed GWAS for estradiol in males (n = 147 690) and females (n = 163 985) from UK Biobank. Estradiol was analyzed as a binary phenotype above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization.

Results: We identified 14 independent loci associated (P < 5 × 10-8) with estradiol levels in males, of which 1 (CYP3A7) was genome-wide and 7 nominally (P < 0.05) significant in females. In addition, 1 female-specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS (eg, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7, which encode enzymes likely to be involved in estradiol elimination). The allele that tags the O blood group at the ABO locus was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P = 1.58 × 10-11) and females (P = 7.48 × 10-6).

Conclusion: Our findings further support the importance of the body's own estrogen to maintain skeletal health in males and in females.

Keywords: GWAS; bone mineral density; estrogen; mendelian randomization.

Figure 1.

Flowchart of UK Biobank participants included in the four GWAS. Abbreviations: DT, detection limit (for estradiol measurement); QC, quality control.

Figure 2.

Hudson plot for the estradiol GWAS in males (upper) and females (lower). The red horizontal line indicated the genome-wide significance threshold (5 × 10⁻⁸).

Figure 3.

ORs and 95% CIs for the lead SNPs in the male and female strata, as well as the 2 female subgroups: pre- and postmenopause. The lead SNP for each locus that reached genome-wide significance in males or females in the primary analyses are included. Non-overlapping confidence intervals typically indicate a significant difference in ORs well below P = 0.05.

Figure 4.

Mendelian Randomization analyses to estimate the causal effect of estradiol on BMD. (A) One-sample MR in UKB males, (B) 1-sample MR in UKB females, (C) 2-sample MR with GEFOS males, and (D) 2-sample MR in GEFOS females. Abbreviation: LS, Lumbar Spine.