| Title: | Genome-wide Association Study of Estradiol Levels and the Causal Effect of Estradiol on Bone Mineral Density |
| Journal: | The Journal of Clinical Endocrinology & Metabolism |
| Published: | 13 Jul 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34255042/ |
| DOI: | https://doi.org/10.1210/clinem/dgab507 |
| URL: | https://academic.oup.com/jcem/article-pdf/106/11/e4471/41378653/dgab507.pdf |
| Citations: | 50 (39 in last 2 years) as of 8 Aug 2024 |
Publication 5037
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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.</p>
OBJECTIVE: Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD).</p>
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.</p>
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).</p>
CONCLUSION: Our findings further support the importance of the body's own estrogen to maintain skeletal health in males and in females.</p>
20 Keywords
- 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
- ABO Blood-Group System
- Bone Density
- Cohort Studies
- Cross-Sectional Studies
- Cytochrome P-450 CYP3A
- Estradiol
- Estrogens
- Female
- Genome-Wide Association Study
- Genotype
- Glucuronosyltransferase
- Humans
- Male
- Membrane Proteins
- Mendelian Randomization Analysis
- Middle Aged
- N-Acetylglucosaminyltransferases
- Polymorphism, Single Nucleotide
- United Kingdom
6 Authors
- Daniel Schmitz
- Weronica E Ek
- Elin Berggren
- Julia Höglund
- Torgny Karlsson
- Åsa Johansson
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