Genetics of Estrogen-Related Traits; From Candidate Genes to GWAS

In the first part of this thesis, the association of polymorphisms in three candidate genes (estrogen receptor alpha (ESR1), retinoblastoma interacting zinc finger domain (RIZ1) and catechol-O-methyltransferase (COMT)) with estradiol levels, age at natural menopause, BMD and fracture risk in the Rotterdam Study is shown. For the ESR1 gene, fine-mapping of the PvuII and XbaI LD-block is presented, together with a haplotype analysis, showing that one additional SNP in the promoter region of the gene could distinguish a third haplotype in the previously defined PvuII–XbaI haplotype 1 and explain the associations we found before. In another study it was shown that the Pro704 insertion-deletion polymorphism in RIZ1 was not associated with BMD or fracture risk in men and women. The third study showed that the Met158Val polymorphism in the estradiol degrading enzyme COMT was associated with fracture risk, independent of BMD. In the last part genome-wide association studies (GWAS) for sex hormone binding globuline, age at menarche and age at natural menopause are presented. A GWAS on sex-hormone-binding-globuline (SHBG) levels showed highly significant associations of several SNPs in the SHBG-gene region with plasma SHBG-levels. A study on age at menarche in 17,510 women of seven studies from the CHARGE consortium identified two loci with P<5x10-8. A genome-wide association study for age at natural menopause in 2,979 European women identified three loci located on chromosome 13, 19 and 20 associated with age at natural menopause. The three loci have not been indicated to play a role in natural menopause before, and therefore the functional mechanism underlying these associations remains unknown.

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