Large-scale meta-analysis highlights the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length

Triin Laisk; Viktorija Kukuškina; Duncan Palmer; Samantha Laber; Chia-Yen Chen; Teresa Ferreira; Nilufer Rahmioglu; Krina Zondervan; Christian Becker; Jordan W Smoller; Margaret Lippincott; Andres Salumets; Ingrid Granne; Stephanie Seminara; Benjamin Neale; Reedik Mägi; Cecilia M Lindgren

doi:10.1093/hmg/ddy317

Large-scale meta-analysis highlights the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length

Hum Mol Genet. 2018 Dec 15;27(24):4323-4332. doi: 10.1093/hmg/ddy317.

Authors

Triin Laisk^{1

2

3}, Viktorija Kukuškina², Duncan Palmer^{4

5}, Samantha Laber^{6

7}, Chia-Yen Chen^{4

8

9}, Teresa Ferreira⁶, Nilufer Rahmioglu⁷, Krina Zondervan^{7

10}, Christian Becker¹⁰, Jordan W Smoller^{5

8}, Margaret Lippincott¹¹, Andres Salumets^{1

3

12

13}, Ingrid Granne¹⁴, Stephanie Seminara¹¹, Benjamin Neale^{4

8}, Reedik Mägi², Cecilia M Lindgren^{6

7

15}

Affiliations

¹ Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
² Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
³ Competence Centre on Health Technologies, Tartu, Estonia.
⁴ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁶ Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK.
⁷ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
⁸ Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁹ Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.
¹⁰ Oxford Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, UK.
¹¹ Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹² Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹³ Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
¹⁴ Nuffield Department of Women's and Reproductive Health, University of Oxford, UK.
¹⁵ Program in Medical and Population Genetics, Broad Institute, Boston, MA, USA.

Abstract

The normal menstrual cycle requires a delicate interplay between the hypothalamus, pituitary and ovary. Therefore, its length is an important indicator of female reproductive health. Menstrual cycle length has been shown to be partially controlled by genetic factors, especially in the follicle-stimulating hormone beta-subunit (FSHB) locus. A genome-wide association study meta-analysis of menstrual cycle length in 44 871 women of European ancestry confirmed the previously observed association with the FSHB locus and identified four additional novel signals in, or near, the GNRH1, PGR, NR5A2 and INS-IGF2 genes. These findings not only confirm the role of the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length but also highlight potential novel local regulatory mechanisms, such as those mediated by IGF2.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Female
Gene Expression Regulation / genetics
Genetic Predisposition to Disease*
Genome-Wide Association Study
Gonadotropin-Releasing Hormone / genetics
Humans
Hypothalamo-Hypophyseal System / metabolism
Hypothalamo-Hypophyseal System / pathology
Insulin-Like Growth Factor II / genetics*
Menstrual Cycle / genetics*
Menstrual Cycle / physiology
Ovary / growth & development
Ovary / metabolism
Polymorphism, Single Nucleotide / genetics
Promoter Regions, Genetic
Protein Precursors / genetics
Receptors, Cytoplasmic and Nuclear / genetics
Reproduction / genetics*

Substances

IGF2 protein, human
NR5A2 protein, human
Protein Precursors
Receptors, Cytoplasmic and Nuclear
progonadoliberin I
Gonadotropin-Releasing Hormone
Insulin-Like Growth Factor II

Abstract

Publication types

MeSH terms

Substances

Grants and funding