[OA] Genetic Determinants of Circulating Estrogen Levels, and Evidence of a Causal Effect of Estradiol on Bone Density in Men
Context: 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.
Objective: To investigate the genetic regulation of serum E2 and E1 in men.
Design, setting and participants: GWAS in 11,097 men of European origin from nine epidemiological cohorts.
Main Outcome Measures: Genetic determinants of serum E2 and E1 levels.
Results: 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.
Conclusions: 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.
Eriksson AL, Perry JRB, Coviello AD, et al. Genetic Determinants of Circulating Estrogen Levels, and Evidence of a Causal Effect of Estradiol on Bone Density in Men. The Journal of clinical endocrinology and metabolism 2018. Genetic Determinants of Circulating Estrogen Levels, and Evidence of a Causal Effect of Estradiol on Bone Density in Men | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic
Context: 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.
Objective: To investigate the genetic regulation of serum E2 and E1 in men.
Design, setting and participants: GWAS in 11,097 men of European origin from nine epidemiological cohorts.
Main Outcome Measures: Genetic determinants of serum E2 and E1 levels.
Results: 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.
Conclusions: 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.
Eriksson AL, Perry JRB, Coviello AD, et al. Genetic Determinants of Circulating Estrogen Levels, and Evidence of a Causal Effect of Estradiol on Bone Density in Men. The Journal of clinical endocrinology and metabolism 2018. Genetic Determinants of Circulating Estrogen Levels, and Evidence of a Causal Effect of Estradiol on Bone Density in Men | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic
