Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. No genome-wide association study (GWAS) of estrogen levels has been performed in men of European origin.
To investigate the genetic regulation of serum E2 and E1 in men.
GWAS in 11,097 men of European origin from nine epidemiological cohorts.
Genetic determinants of serum E2 and E1 levels.
Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAM9B, rs5934505 (p-value 3.4 x 10-8) and Xq27.3, rs5951794 (p-value 3.1 x 10-10). E1 signals were found in CYP19A1 (rs2899472, p-value 5.5 x 10-23), in TRIM4 (rs17277546, p = 5.8 x 10-14) and in CYP11B1/B2 (rs10093796, p-value 1.2 x 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian Randomization analysis suggested a causal effect of serum E2 on BMD in men. 1 pg/ml genetically increased E2 was associated with a 0.048 SD increase in lumbar spine BMD (p-value 2.8 x 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.
Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels, and strengthen the causal importance of E2 for bone health in men. We also report 2 new independent loci on the X-chromosome for E2, one new locus each in TRIM4 and CYP11B1/B2, for E1.
This research output has an Altmetric Attention Score of 65. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 February 2025.
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