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

K.S. Ruth, P.J. Campbell, S. Chew, E.M. Lim, N. Hadlow, Bronwyn Stuckey, S.J. Brown, B. Feenstra, J. Joseph, G.L. Surdulescu, H.F. Zheng, J.B. Richards, A. Murray, T.D. Spector, Scott Wilson, J.R.B. Perry

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Abstract

© 2016 Macmillan Publishers Limited All rights reserved. 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<5x10-8), 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.
Original languageEnglish
Pages (from-to)284-290
Number of pages7
JournalEuropean Journal of Human Genetics
Volume24
Issue number2
DOIs
Publication statusPublished - 2016

Fingerprint

Genome-Wide Association Study
Gonadal Steroid Hormones
Progesterone
Dehydroepiandrosterone Sulfate
Follicle Stimulating Hormone
Genome
Hormones
Luteinizing Hormone
Phenotype
Androgens
Estradiol
Genotype
Sex Hormone-Binding Globulin
Twin Studies
Chromosomes, Human, Pair 7
Menstrual Cycle
Gene Frequency
Prolactin
Single Nucleotide Polymorphism
Testosterone

Cite this

Ruth, K.S. ; Campbell, P.J. ; Chew, S. ; Lim, E.M. ; Hadlow, N. ; Stuckey, Bronwyn ; Brown, S.J. ; Feenstra, B. ; Joseph, J. ; Surdulescu, G.L. ; Zheng, H.F. ; Richards, J.B. ; Murray, A. ; Spector, T.D. ; Wilson, Scott ; Perry, J.R.B. / Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. In: European Journal of Human Genetics. 2016 ; Vol. 24, No. 2. pp. 284-290.
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title = "Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes",
abstract = "{\circledC} 2016 Macmillan Publishers Limited All rights reserved. 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<5x10-8), 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.",
author = "K.S. Ruth and P.J. Campbell and S. Chew and E.M. Lim and N. Hadlow and Bronwyn Stuckey and S.J. Brown and B. Feenstra and J. Joseph and G.L. Surdulescu and H.F. Zheng and J.B. Richards and A. Murray and T.D. Spector and Scott Wilson and J.R.B. Perry",
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Ruth, KS, Campbell, PJ, Chew, S, Lim, EM, Hadlow, N, Stuckey, B, Brown, SJ, Feenstra, B, Joseph, J, Surdulescu, GL, Zheng, HF, Richards, JB, Murray, A, Spector, TD, Wilson, S & Perry, JRB 2016, 'Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes' European Journal of Human Genetics, vol. 24, no. 2, pp. 284-290. https://doi.org/10.1038/ejhg.2015.102

Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. / Ruth, K.S.; Campbell, P.J.; Chew, S.; Lim, E.M.; Hadlow, N.; Stuckey, Bronwyn; Brown, S.J.; Feenstra, B.; Joseph, J.; Surdulescu, G.L.; Zheng, H.F.; Richards, J.B.; Murray, A.; Spector, T.D.; Wilson, Scott; Perry, J.R.B.

In: European Journal of Human Genetics, Vol. 24, No. 2, 2016, p. 284-290.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes

AU - Ruth, K.S.

AU - Campbell, P.J.

AU - Chew, S.

AU - Lim, E.M.

AU - Hadlow, N.

AU - Stuckey, Bronwyn

AU - Brown, S.J.

AU - Feenstra, B.

AU - Joseph, J.

AU - Surdulescu, G.L.

AU - Zheng, H.F.

AU - Richards, J.B.

AU - Murray, A.

AU - Spector, T.D.

AU - Wilson, Scott

AU - Perry, J.R.B.

PY - 2016

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N2 - © 2016 Macmillan Publishers Limited All rights reserved. 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<5x10-8), 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.

AB - © 2016 Macmillan Publishers Limited All rights reserved. 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<5x10-8), 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.

U2 - 10.1038/ejhg.2015.102

DO - 10.1038/ejhg.2015.102

M3 - Article

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EP - 290

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

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ER -