Differential Impact of Genetic Loci on Age at Thelarche and Menarche in Healthy Girls

Alexander S Busch; Casper P Hagen; Maria Assens; Katharina M Main; Kristian Almstrup; Anders Juul

doi:10.1210/jc.2017-01860

Differential Impact of Genetic Loci on Age at Thelarche and Menarche in Healthy Girls

Alexander S Busch, Casper P Hagen, Maria Assens, Katharina M Main, Kristian Almstrup, Anders Juul

Department of Clinical Medicine

8 Citations (Scopus)

Abstract

Context: Recent genetic studies have identified genetic variants associated with age at pubertal onset. Whereas genome-wide association studies reported associations of several hundred genetic variants with timing of self-reported age at menarche, a recent clinical study focused on genetic variation affecting follicle-stimulating hormone action and clinically determined age at thelarche. The observations appear to be incongruent, as effect sizes varied substantially among the studies. Alternatively, this may point to a differential impact of specific genetic loci on distinct pubertal events. Objective: To investigate whether top-candidate genetic variants exhibit a different impact on timing of thelarche vs menarche, respectively. Design: Cross-sectional and longitudinal study of healthy girls. Setting: Population-based study in the Copenhagen area. Patients or Other Participants: Girls (1478) were followed through puberty and genotyped for FSHB c.2211G>T (rs10835638), FSHR c.229G>A (rs1394205), FSHR c.2039A>G (rs6116), LIN28B (rs7759938), INHA (rs4141153), MKRN3 (rs12148769), TMEM38B (rs10453225), and ZNF483 (rs10980921). Main Outcome Measures: Clinical pubertal staging and anthropometric data. Results: We observed an association of LIN28B (rs7759938) with age at thelarche (P> 0.001, effect size: 0.27 year, 95% confidence interval: 0.12 to 0.42) and age at menarche (P = 0.005, 0.17 year, 0.05 to 0.29). FSHB c.2211G>T (rs10835638) and FSHR c.229G>A (rs1394205) minor allele count was associated with age at thelarche (P = 0.004, 0.19 year, 0.06 to 0.31) but not with age at menarche (P = 0.97; all adjusted for body mass index z scores). Conclusion: Our results indicate a differential impact of specific genetic loci on age at thelarche and menarche in healthy girls.

Original language	English
Journal	The Journal of clinical endocrinology and metabolism
Volume	103
Issue number	1
Pages (from-to)	228-234
ISSN	0021-972X
DOIs	https://doi.org/10.1210/jc.2017-01860
Publication status	Published - 2018

Keywords

Adolescent
Biomarkers/analysis
Child
Child, Preschool
Cross-Sectional Studies
Female
Follow-Up Studies
Genetic Loci
Genetic Variation
Genome-Wide Association Study
Genotype
Humans
Longitudinal Studies
Prognosis
Puberty/genetics

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@article{f10eb61636634ded890c5fc0ee9faaa4,

title = "Differential Impact of Genetic Loci on Age at Thelarche and Menarche in Healthy Girls",

abstract = "Context: Recent genetic studies have identified genetic variants associated with age at pubertal onset. Whereas genome-wide association studies reported associations of several hundred genetic variants with timing of self-reported age at menarche, a recent clinical study focused on genetic variation affecting follicle-stimulating hormone action and clinically determined age at thelarche. The observations appear to be incongruent, as effect sizes varied substantially among the studies. Alternatively, this may point to a differential impact of specific genetic loci on distinct pubertal events. Objective: To investigate whether top-candidate genetic variants exhibit a different impact on timing of thelarche vs menarche, respectively. Design: Cross-sectional and longitudinal study of healthy girls. Setting: Population-based study in the Copenhagen area. Patients or Other Participants: Girls (1478) were followed through puberty and genotyped for FSHB c.2211G>T (rs10835638), FSHR c.229G>A (rs1394205), FSHR c.2039A>G (rs6116), LIN28B (rs7759938), INHA (rs4141153), MKRN3 (rs12148769), TMEM38B (rs10453225), and ZNF483 (rs10980921). Main Outcome Measures: Clinical pubertal staging and anthropometric data. Results: We observed an association of LIN28B (rs7759938) with age at thelarche (P> 0.001, effect size: 0.27 year, 95% confidence interval: 0.12 to 0.42) and age at menarche (P = 0.005, 0.17 year, 0.05 to 0.29). FSHB c.2211G>T (rs10835638) and FSHR c.229G>A (rs1394205) minor allele count was associated with age at thelarche (P = 0.004, 0.19 year, 0.06 to 0.31) but not with age at menarche (P = 0.97; all adjusted for body mass index z scores). Conclusion: Our results indicate a differential impact of specific genetic loci on age at thelarche and menarche in healthy girls.",

keywords = "Adolescent, Biomarkers/analysis, Child, Child, Preschool, Cross-Sectional Studies, Female, Follow-Up Studies, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Longitudinal Studies, Prognosis, Puberty/genetics",

author = "Busch, {Alexander S} and Hagen, {Casper P} and Maria Assens and Main, {Katharina M} and Kristian Almstrup and Anders Juul",

note = "Copyright {\textcopyright} 2017 Endocrine Society",

year = "2018",

doi = "10.1210/jc.2017-01860",

language = "English",

volume = "103",

pages = "228--234",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Oxford University Press",

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}

TY - JOUR

T1 - Differential Impact of Genetic Loci on Age at Thelarche and Menarche in Healthy Girls

AU - Busch, Alexander S

AU - Hagen, Casper P

AU - Assens, Maria

AU - Main, Katharina M

AU - Almstrup, Kristian

AU - Juul, Anders

PY - 2018

Y1 - 2018

N2 - Context: Recent genetic studies have identified genetic variants associated with age at pubertal onset. Whereas genome-wide association studies reported associations of several hundred genetic variants with timing of self-reported age at menarche, a recent clinical study focused on genetic variation affecting follicle-stimulating hormone action and clinically determined age at thelarche. The observations appear to be incongruent, as effect sizes varied substantially among the studies. Alternatively, this may point to a differential impact of specific genetic loci on distinct pubertal events. Objective: To investigate whether top-candidate genetic variants exhibit a different impact on timing of thelarche vs menarche, respectively. Design: Cross-sectional and longitudinal study of healthy girls. Setting: Population-based study in the Copenhagen area. Patients or Other Participants: Girls (1478) were followed through puberty and genotyped for FSHB c.2211G>T (rs10835638), FSHR c.229G>A (rs1394205), FSHR c.2039A>G (rs6116), LIN28B (rs7759938), INHA (rs4141153), MKRN3 (rs12148769), TMEM38B (rs10453225), and ZNF483 (rs10980921). Main Outcome Measures: Clinical pubertal staging and anthropometric data. Results: We observed an association of LIN28B (rs7759938) with age at thelarche (P> 0.001, effect size: 0.27 year, 95% confidence interval: 0.12 to 0.42) and age at menarche (P = 0.005, 0.17 year, 0.05 to 0.29). FSHB c.2211G>T (rs10835638) and FSHR c.229G>A (rs1394205) minor allele count was associated with age at thelarche (P = 0.004, 0.19 year, 0.06 to 0.31) but not with age at menarche (P = 0.97; all adjusted for body mass index z scores). Conclusion: Our results indicate a differential impact of specific genetic loci on age at thelarche and menarche in healthy girls.

AB - Context: Recent genetic studies have identified genetic variants associated with age at pubertal onset. Whereas genome-wide association studies reported associations of several hundred genetic variants with timing of self-reported age at menarche, a recent clinical study focused on genetic variation affecting follicle-stimulating hormone action and clinically determined age at thelarche. The observations appear to be incongruent, as effect sizes varied substantially among the studies. Alternatively, this may point to a differential impact of specific genetic loci on distinct pubertal events. Objective: To investigate whether top-candidate genetic variants exhibit a different impact on timing of thelarche vs menarche, respectively. Design: Cross-sectional and longitudinal study of healthy girls. Setting: Population-based study in the Copenhagen area. Patients or Other Participants: Girls (1478) were followed through puberty and genotyped for FSHB c.2211G>T (rs10835638), FSHR c.229G>A (rs1394205), FSHR c.2039A>G (rs6116), LIN28B (rs7759938), INHA (rs4141153), MKRN3 (rs12148769), TMEM38B (rs10453225), and ZNF483 (rs10980921). Main Outcome Measures: Clinical pubertal staging and anthropometric data. Results: We observed an association of LIN28B (rs7759938) with age at thelarche (P> 0.001, effect size: 0.27 year, 95% confidence interval: 0.12 to 0.42) and age at menarche (P = 0.005, 0.17 year, 0.05 to 0.29). FSHB c.2211G>T (rs10835638) and FSHR c.229G>A (rs1394205) minor allele count was associated with age at thelarche (P = 0.004, 0.19 year, 0.06 to 0.31) but not with age at menarche (P = 0.97; all adjusted for body mass index z scores). Conclusion: Our results indicate a differential impact of specific genetic loci on age at thelarche and menarche in healthy girls.

KW - Adolescent

KW - Biomarkers/analysis

KW - Child

KW - Child, Preschool

KW - Cross-Sectional Studies

KW - Female

KW - Follow-Up Studies

KW - Genetic Loci

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Longitudinal Studies

KW - Prognosis

KW - Puberty/genetics

U2 - 10.1210/jc.2017-01860

DO - 10.1210/jc.2017-01860

M3 - Journal article

C2 - 29077908

SN - 0021-972X

VL - 103

SP - 228

EP - 234

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 1

ER -

Differential Impact of Genetic Loci on Age at Thelarche and Menarche in Healthy Girls

Abstract

Keywords

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