Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes

Eur J Hum Genet. 2016 Feb;24(2):284-90. doi: 10.1038/ejhg.2015.102. Epub 2015 May 27.


Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dehydroepiandrosterone Sulfate* / metabolism
  • Estradiol / genetics
  • Female
  • Follicle Stimulating Hormone / genetics*
  • Follicle Stimulating Hormone / metabolism
  • Genome, Human
  • Genome-Wide Association Study
  • Genotype
  • Gonadal Steroid Hormones / genetics*
  • Gonadal Steroid Hormones / metabolism
  • Humans
  • Luteinizing Hormone / genetics*
  • Luteinizing Hormone / metabolism
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Progesterone / genetics*
  • Prolactin / genetics
  • Prolactin / metabolism
  • Sex Hormone-Binding Globulin / genetics
  • Sex Hormone-Binding Globulin / metabolism
  • Testosterone / genetics


  • Gonadal Steroid Hormones
  • Sex Hormone-Binding Globulin
  • Testosterone
  • Progesterone
  • Estradiol
  • Dehydroepiandrosterone Sulfate
  • Prolactin
  • Luteinizing Hormone
  • Follicle Stimulating Hormone