Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

John R B Perry; Felix Day; Cathy E Elks; Patrick Sulem; Deborah J Thompson; Teresa Ferreira; Chunyan He; Daniel I Chasman; Tõnu Esko; Gudmar Thorleifsson; Eva Albrecht; Wei Q Ang; Tanguy Corre; Diana L Cousminer; Bjarke Feenstra; Nora Franceschini; Andrea Ganna; Andrew D Johnson; Sanela Kjellqvist; Kathryn L Lunetta; George McMahon; Ilja M Nolte; Lavinia Paternoster; Eleonora Porcu; Albert V Smith; Lisette Stolk; Alexander Teumer; Natalia Tšernikova; Emmi Tikkanen; Sheila Ulivi; Erin K Wagner; Najaf Amin; Laura J Bierut; Enda M Byrne; Jouke-Jan Hottenga; Daniel L Koller; Massimo Mangino; Tune H Pers; Laura M Yerges-Armstrong; Jing Hua Zhao; Irene L Andrulis; Hoda Anton-Culver; Femke Atsma; Stefania Bandinelli; Matthias W Beckmann; Javier Benitez; Stig E Bojesen; Mads Melbye; Ellen A Nohr; Thorkild I A Sørensen; Australian Ovarian Cancer Study

doi:10.1038/nature13545

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

John R B Perry, Felix Day, Cathy E Elks, Patrick Sulem, Deborah J Thompson, Teresa Ferreira, Chunyan He, Daniel I Chasman, Tõnu Esko, Gudmar Thorleifsson, Eva Albrecht, Wei Q Ang, Tanguy Corre, Diana L Cousminer, Bjarke Feenstra, Nora Franceschini, Andrea Ganna, Andrew D Johnson, Sanela Kjellqvist, Kathryn L LunettaGeorge McMahon, Ilja M Nolte, Lavinia Paternoster, Eleonora Porcu, Albert V Smith, Lisette Stolk, Alexander Teumer, Natalia Tšernikova, Emmi Tikkanen, Sheila Ulivi, Erin K Wagner, Najaf Amin, Laura J Bierut, Enda M Byrne, Jouke-Jan Hottenga, Daniel L Koller, Massimo Mangino, Tune H Pers, Laura M Yerges-Armstrong, Jing Hua Zhao, Irene L Andrulis, Hoda Anton-Culver, Femke Atsma, Stefania Bandinelli, Matthias W Beckmann, Javier Benitez, Stig E Bojesen, Mads Melbye, Ellen A Nohr, Thorkild I A Sørensen, Australian Ovarian Cancer Study

299 Citations (Scopus)

Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10^-8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Original language	English
Journal	Nature
Volume	514
Issue number	7520
Pages (from-to)	92-7
Number of pages	6
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature13545
Publication status	Published - 2 Oct 2014

Keywords

Adolescent
Age Factors
Alleles
Body Mass Index
Breast Neoplasms
Cardiovascular Diseases
Child
Diabetes Mellitus, Type 2
Europe
Female
Genetic Loci
Genome-Wide Association Study
Genomic Imprinting
Humans
Hypothalamo-Hypophyseal System
Intercellular Signaling Peptides and Proteins
Male
Membrane Proteins
Menarche
Obesity
Ovary
Parents
Polymorphism, Single Nucleotide
Potassium Channels, Tandem Pore Domain
Proteins
Quantitative Trait Loci
Receptors, GABA-B
Receptors, Retinoic Acid
Ribonucleoproteins

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nature13545

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Perry, J. R. B., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., He, C., Chasman, D. I., Esko, T., Thorleifsson, G., Albrecht, E., Ang, W. Q., Corre, T., Cousminer, D. L., Feenstra, B., Franceschini, N., Ganna, A., Johnson, A. D., Kjellqvist, S., ... Australian Ovarian Cancer Study (2014). Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature, 514(7520), 92-7. https://doi.org/10.1038/nature13545

Perry, JRB, Day, F, Elks, CE, Sulem, P, Thompson, DJ, Ferreira, T, He, C, Chasman, DI, Esko, T, Thorleifsson, G, Albrecht, E, Ang, WQ, Corre, T, Cousminer, DL, Feenstra, B, Franceschini, N, Ganna, A, Johnson, AD, Kjellqvist, S, Lunetta, KL, McMahon, G, Nolte, IM, Paternoster, L, Porcu, E, Smith, AV, Stolk, L, Teumer, A, Tšernikova, N, Tikkanen, E, Ulivi, S, Wagner, EK, Amin, N, Bierut, LJ, Byrne, EM, Hottenga, J-J, Koller, DL, Mangino, M, Pers, TH, Yerges-Armstrong, LM, Hua Zhao, J, Andrulis, IL, Anton-Culver, H, Atsma, F, Bandinelli, S, Beckmann, MW, Benitez, J, Bojesen, SE , Melbye, M, Nohr, EA, Sørensen, TIA & Australian Ovarian Cancer Study 2014, 'Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche', Nature, vol. 514, no. 7520, pp. 92-7. https://doi.org/10.1038/nature13545

@article{c706445b96e04a90bd02928274730760,

title = "Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche",

abstract = "Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10-8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.",

keywords = "Adolescent, Age Factors, Alleles, Body Mass Index, Breast Neoplasms, Cardiovascular Diseases, Child, Diabetes Mellitus, Type 2, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genomic Imprinting, Humans, Hypothalamo-Hypophyseal System, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Obesity, Ovary, Parents, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Proteins, Quantitative Trait Loci, Receptors, GABA-B, Receptors, Retinoic Acid, Ribonucleoproteins",

author = "Perry, {John R B} and Felix Day and Elks, {Cathy E} and Patrick Sulem and Thompson, {Deborah J} and Teresa Ferreira and Chunyan He and Chasman, {Daniel I} and T{\~o}nu Esko and Gudmar Thorleifsson and Eva Albrecht and Ang, {Wei Q} and Tanguy Corre and Cousminer, {Diana L} and Bjarke Feenstra and Nora Franceschini and Andrea Ganna and Johnson, {Andrew D} and Sanela Kjellqvist and Lunetta, {Kathryn L} and George McMahon and Nolte, {Ilja M} and Lavinia Paternoster and Eleonora Porcu and Smith, {Albert V} and Lisette Stolk and Alexander Teumer and Natalia T{\v s}ernikova and Emmi Tikkanen and Sheila Ulivi and Wagner, {Erin K} and Najaf Amin and Bierut, {Laura J} and Byrne, {Enda M} and Jouke-Jan Hottenga and Koller, {Daniel L} and Massimo Mangino and Pers, {Tune H} and Yerges-Armstrong, {Laura M} and {Hua Zhao}, Jing and Andrulis, {Irene L} and Hoda Anton-Culver and Femke Atsma and Stefania Bandinelli and Beckmann, {Matthias W} and Javier Benitez and Bojesen, {Stig E} and Mads Melbye and Nohr, {Ellen A} and S{\o}rensen, {Thorkild I A} and {Australian Ovarian Cancer Study}",

year = "2014",

month = oct,

day = "2",

doi = "10.1038/nature13545",

language = "English",

volume = "514",

pages = "92--7",

journal = "Nature",

issn = "0028-0836",

publisher = "nature publishing group",

number = "7520",

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TY - JOUR

T1 - Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

AU - Perry, John R B

AU - Day, Felix

AU - Elks, Cathy E

AU - Sulem, Patrick

AU - Thompson, Deborah J

AU - Ferreira, Teresa

AU - He, Chunyan

AU - Chasman, Daniel I

AU - Esko, Tõnu

AU - Thorleifsson, Gudmar

AU - Albrecht, Eva

AU - Ang, Wei Q

AU - Corre, Tanguy

AU - Cousminer, Diana L

AU - Feenstra, Bjarke

AU - Franceschini, Nora

AU - Ganna, Andrea

AU - Johnson, Andrew D

AU - Kjellqvist, Sanela

AU - Lunetta, Kathryn L

AU - McMahon, George

AU - Nolte, Ilja M

AU - Paternoster, Lavinia

AU - Porcu, Eleonora

AU - Smith, Albert V

AU - Stolk, Lisette

AU - Teumer, Alexander

AU - Tšernikova, Natalia

AU - Tikkanen, Emmi

AU - Ulivi, Sheila

AU - Wagner, Erin K

AU - Amin, Najaf

AU - Bierut, Laura J

AU - Byrne, Enda M

AU - Hottenga, Jouke-Jan

AU - Koller, Daniel L

AU - Mangino, Massimo

AU - Pers, Tune H

AU - Yerges-Armstrong, Laura M

AU - Hua Zhao, Jing

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Atsma, Femke

AU - Bandinelli, Stefania

AU - Beckmann, Matthias W

AU - Benitez, Javier

AU - Bojesen, Stig E

AU - Melbye, Mads

AU - Nohr, Ellen A

AU - Sørensen, Thorkild I A

AU - Australian Ovarian Cancer Study

PY - 2014/10/2

Y1 - 2014/10/2

N2 - Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10-8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

AB - Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10-8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

KW - Adolescent

KW - Age Factors

KW - Alleles

KW - Body Mass Index

KW - Breast Neoplasms

KW - Cardiovascular Diseases

KW - Child

KW - Diabetes Mellitus, Type 2

KW - Europe

KW - Female

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Genomic Imprinting

KW - Humans

KW - Hypothalamo-Hypophyseal System

KW - Intercellular Signaling Peptides and Proteins

KW - Male

KW - Membrane Proteins

KW - Menarche

KW - Obesity

KW - Ovary

KW - Parents

KW - Polymorphism, Single Nucleotide

KW - Potassium Channels, Tandem Pore Domain

KW - Proteins

KW - Quantitative Trait Loci

KW - Receptors, GABA-B

KW - Receptors, Retinoic Acid

KW - Ribonucleoproteins

U2 - 10.1038/nature13545

DO - 10.1038/nature13545

M3 - Journal article

C2 - 25231870

SN - 0028-0836

VL - 514

SP - 92

EP - 97

JO - Nature

JF - Nature

IS - 7520

ER -

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Abstract

Keywords

UN SDGs

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