Rare coding variants and X-linked loci associated with age at menarche

Kathryn L. Lunetta; Felix R. Day; Patrick Sulem; Katherine S. Ruth; Joyce Y. Tung; David A. Hinds; Toñu Esko; Cathy E. Elks; Elisabeth Altmaier; Chunyan He; Jennifer E. Huffman; Evelin Mihailov; Eleonora Porcu; Antonietta Robino; Lynda M. Rose; Ursula M. Schick; Lisette Stolk; Alexander Teumer; Deborah J. Thompson; Michela Traglia; Carol A. Wang; Laura M. Yerges-Armstrong; Antonis C. Antoniou; Caterina Barbieri; Andrea D. Coviello; Francesco Cucca; Ellen W. Demerath; Alison M. Dunning; Ilaria Gandin; Megan L. Grove; Daniel F. Gudbjartsson; Lynne J. Hocking; Albert Hofman; Jinyan Huang; Rebecca D. Jackson; David Karasik; Jennifer Kriebel; Ethan M. Lange; Leslie A. Lange; Claudia Langenberg; Xin Li; Jian'an Luan; Reedik Mägi; Alanna C. Morrison; Sandosh Padmanabhan; Ailith Pirie; Ozren Polasek; David Porteous; Alex P. Reiner; Fernando Rivadeneira; Igor Rudan; Cinzia F. Sala; David Schlessinger; Robert A. Scott; Doris Stöckl; Jenny A. Visser; Uwe Völker; Diego Vozzi; James G. Wilson; Marek Zygmunt; Eric Boerwinkle; Julie E. Buring; Laura Crisponi; Douglas F. Easton; Caroline Hayward; Frank B. Hu; Simin Liu; Andres Metspalu; Craig E. Pennell; Paul M. Ridker; Konstantin Strauch; Elizabeth A. Streeten; Daniela Toniolo; André G. Uitterlinden; Sheila Ulivi; Henry Völzke; Nicholas J. Wareham; Melissa Wellons; Nora Franceschini; Daniel I. Chasman; Unnur Thorsteinsdottir; Anna Murray; Kari Stefansson; Joanne M. Murabito; Ken K. Ong; John R.B. Perry; Nita G. Forouhi; Nicola D. Kerrison; Stephen J. Sharp; Matt Sims; Inês Barroso; Panos Deloukas; Mark I. McCarthy; Larraitz Arriola; Beverley Balkau; Aurelio Barricarte; Heiner Boeing; Paul W. Franks; Carlos Gonzalez; Sara Grioni; Rudolf Kaaks; Timothy J. Key; Carmen Navarro; Peter M. Nilsson; Kim Overvad; Domenico Palli; Salvatore Panico; J. Ramón Quirós; Olov Rolandsson; Carlotta Sacerdote; María José Sánchez; Nadia Slimani; Anne Tjonneland; Rosario Tumino; Daphne L. Van Der A; Yvonne T. Van Der Schouw; Elio Riboli; Blair H. Smith; Archie Campbell; Ian J. Deary; Andrew M. McIntosh

doi:10.1038/ncomms8756

Rare coding variants and X-linked loci associated with age at menarche

Kathryn L. Lunetta, Felix R. Day, Patrick Sulem, Katherine S. Ruth, Joyce Y. Tung, David A. Hinds, Toñu Esko, Cathy E. Elks, Elisabeth Altmaier, Chunyan He, Jennifer E. Huffman, Evelin Mihailov, Eleonora Porcu, Antonietta Robino, Lynda M. Rose, Ursula M. Schick, Lisette Stolk, Alexander Teumer, Deborah J. Thompson, Michela TragliaCarol A. Wang, Laura M. Yerges-Armstrong, Antonis C. Antoniou, Caterina Barbieri, Andrea D. Coviello, Francesco Cucca, Ellen W. Demerath, Alison M. Dunning, Ilaria Gandin, Megan L. Grove, Daniel F. Gudbjartsson, Lynne J. Hocking, Albert Hofman, Jinyan Huang, Rebecca D. Jackson, David Karasik, Jennifer Kriebel, Ethan M. Lange, Leslie A. Lange, Claudia Langenberg, Xin Li, Jian'an Luan, Reedik Mägi, Alanna C. Morrison, Sandosh Padmanabhan, Ailith Pirie, Ozren Polasek, David Porteous, Alex P. Reiner, Fernando Rivadeneira, Igor Rudan, Cinzia F. Sala, David Schlessinger, Robert A. Scott, Doris Stöckl, Jenny A. Visser, Uwe Völker, Diego Vozzi, James G. Wilson, Marek Zygmunt, Eric Boerwinkle, Julie E. Buring, Laura Crisponi, Douglas F. Easton, Caroline Hayward, Frank B. Hu, Simin Liu, Andres Metspalu, Craig E. Pennell, Paul M. Ridker, Konstantin Strauch, Elizabeth A. Streeten, Daniela Toniolo, André G. Uitterlinden, Sheila Ulivi, Henry Völzke, Nicholas J. Wareham, Melissa Wellons, Nora Franceschini, Daniel I. Chasman, Unnur Thorsteinsdottir, Anna Murray, Kari Stefansson, Joanne M. Murabito, Ken K. Ong, John R.B. Perry, Nita G. Forouhi, Nicola D. Kerrison, Stephen J. Sharp, Matt Sims, Inês Barroso, Panos Deloukas, Mark I. McCarthy, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Heiner Boeing, Paul W. Franks, Carlos Gonzalez, Sara Grioni, Rudolf Kaaks, Timothy J. Key, Carmen Navarro, Peter M. Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J. Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, María José Sánchez, Nadia Slimani, Anne Tjonneland, Rosario Tumino, Daphne L. Van Der A, Yvonne T. Van Der Schouw, Elio Riboli, Blair H. Smith, Archie Campbell, Ian J. Deary, Andrew M. McIntosh

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10^-8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10^-13) and FAAH2 (rs5914101, P=4.9 × 10^-10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10^-11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

Original language	English
Article number	7756
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8756
State	Published - Aug 4 2015

Bibliographical note

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.

Funding

Funders	Funder number
Medical Research Council-São Paulo Research Foundation	MC_UU_12015/1, MC_UP_A100_1003, MR/K026992/1, MC_PC_U127561128, MC_UU_12015/5, MC_UU_12015/2, MC_U106179471
Medical Research Council-São Paulo Research Foundation
National Institute on Aging	ZIAAG000647, R21AG032598, R01AG029451, ZIAAG000675
National Institute on Aging
National Childhood Cancer Registry – National Cancer Institute	P30CA015704, UM1CA182913
National Childhood Cancer Registry – National Cancer Institute
Australian National Health and Medical Research Council	454382
Australian National Health and Medical Research Council
European Commission	305280
European Commission
National Center for Advancing Translational Sciences (NCATS)	UL1TR001108, UL1TR002529
National Center for Advancing Translational Sciences (NCATS)
Horizon 2020 Framework Programme	692065
Horizon 2020 Framework Programme

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms8756

Cite this

Lunetta, K. L., Day, F. R., Sulem, P., Ruth, K. S., Tung, J. Y., Hinds, D. A., Esko, T., Elks, C. E., Altmaier, E., He, C., Huffman, J. E., Mihailov, E., Porcu, E., Robino, A., Rose, L. M., Schick, U. M., Stolk, L., Teumer, A., Thompson, D. J., ... McIntosh, A. M. (2015). Rare coding variants and X-linked loci associated with age at menarche. Nature Communications, 6, Article 7756. https://doi.org/10.1038/ncomms8756

@article{1a0acfb9709947bc9ea25f9da78fee7c,

title = "Rare coding variants and X-linked loci associated with age at menarche",

abstract = "More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3\% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6\%; effect sizes 0.08-1.25 years per allele; P<5 × 10-8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10-13) and FAAH2 (rs5914101, P=4.9 × 10-10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10-11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5\% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.",

author = "Lunetta, \{Kathryn L.\} and Day, \{Felix R.\} and Patrick Sulem and Ruth, \{Katherine S.\} and Tung, \{Joyce Y.\} and Hinds, \{David A.\} and To{\~n}u Esko and Elks, \{Cathy E.\} and Elisabeth Altmaier and Chunyan He and Huffman, \{Jennifer E.\} and Evelin Mihailov and Eleonora Porcu and Antonietta Robino and Rose, \{Lynda M.\} and Schick, \{Ursula M.\} and Lisette Stolk and Alexander Teumer and Thompson, \{Deborah J.\} and Michela Traglia and Wang, \{Carol A.\} and Yerges-Armstrong, \{Laura M.\} and Antoniou, \{Antonis C.\} and Caterina Barbieri and Coviello, \{Andrea D.\} and Francesco Cucca and Demerath, \{Ellen W.\} and Dunning, \{Alison M.\} and Ilaria Gandin and Grove, \{Megan L.\} and Gudbjartsson, \{Daniel F.\} and Hocking, \{Lynne J.\} and Albert Hofman and Jinyan Huang and Jackson, \{Rebecca D.\} and David Karasik and Jennifer Kriebel and Lange, \{Ethan M.\} and Lange, \{Leslie A.\} and Claudia Langenberg and Xin Li and Jian'an Luan and Reedik M{\"a}gi and Morrison, \{Alanna C.\} and Sandosh Padmanabhan and Ailith Pirie and Ozren Polasek and David Porteous and Reiner, \{Alex P.\} and Fernando Rivadeneira and Igor Rudan and Sala, \{Cinzia F.\} and David Schlessinger and Scott, \{Robert A.\} and Doris St{\"o}ckl and Visser, \{Jenny A.\} and Uwe V{\"o}lker and Diego Vozzi and Wilson, \{James G.\} and Marek Zygmunt and Eric Boerwinkle and Buring, \{Julie E.\} and Laura Crisponi and Easton, \{Douglas F.\} and Caroline Hayward and Hu, \{Frank B.\} and Simin Liu and Andres Metspalu and Pennell, \{Craig E.\} and Ridker, \{Paul M.\} and Konstantin Strauch and Streeten, \{Elizabeth A.\} and Daniela Toniolo and Uitterlinden, \{Andr{\'e} G.\} and Sheila Ulivi and Henry V{\"o}lzke and Wareham, \{Nicholas J.\} and Melissa Wellons and Nora Franceschini and Chasman, \{Daniel I.\} and Unnur Thorsteinsdottir and Anna Murray and Kari Stefansson and Murabito, \{Joanne M.\} and Ong, \{Ken K.\} and Perry, \{John R.B.\} and Forouhi, \{Nita G.\} and Kerrison, \{Nicola D.\} and Sharp, \{Stephen J.\} and Matt Sims and In{\^e}s Barroso and Panos Deloukas and McCarthy, \{Mark I.\} and Larraitz Arriola and Beverley Balkau and Aurelio Barricarte and Heiner Boeing and Franks, \{Paul W.\} and Carlos Gonzalez and Sara Grioni and Rudolf Kaaks and Key, \{Timothy J.\} and Carmen Navarro and Nilsson, \{Peter M.\} and Kim Overvad and Domenico Palli and Salvatore Panico and Quir{\'o}s, \{J. Ram{\'o}n\} and Olov Rolandsson and Carlotta Sacerdote and S{\'a}nchez, \{Mar{\'i}a Jos{\'e}\} and Nadia Slimani and Anne Tjonneland and Rosario Tumino and \{Van Der A\}, \{Daphne L.\} and \{Van Der Schouw\}, \{Yvonne T.\} and Elio Riboli and Smith, \{Blair H.\} and Archie Campbell and Deary, \{Ian J.\} and McIntosh, \{Andrew M.\}",

year = "2015",

month = aug,

day = "4",

doi = "10.1038/ncomms8756",

language = "English",

volume = "6",

}

Lunetta, KL, Day, FR, Sulem, P, Ruth, KS, Tung, JY, Hinds, DA, Esko, T, Elks, CE, Altmaier, E, He, C, Huffman, JE, Mihailov, E, Porcu, E, Robino, A, Rose, LM, Schick, UM, Stolk, L, Teumer, A, Thompson, DJ, Traglia, M, Wang, CA, Yerges-Armstrong, LM, Antoniou, AC, Barbieri, C, Coviello, AD, Cucca, F, Demerath, EW, Dunning, AM, Gandin, I, Grove, ML, Gudbjartsson, DF, Hocking, LJ, Hofman, A, Huang, J, Jackson, RD, Karasik, D, Kriebel, J, Lange, EM, Lange, LA, Langenberg, C, Li, X, Luan, J, Mägi, R, Morrison, AC, Padmanabhan, S, Pirie, A, Polasek, O, Porteous, D, Reiner, AP, Rivadeneira, F, Rudan, I, Sala, CF, Schlessinger, D, Scott, RA, Stöckl, D, Visser, JA, Völker, U, Vozzi, D, Wilson, JG, Zygmunt, M, Boerwinkle, E, Buring, JE, Crisponi, L, Easton, DF, Hayward, C, Hu, FB, Liu, S, Metspalu, A, Pennell, CE, Ridker, PM, Strauch, K, Streeten, EA, Toniolo, D, Uitterlinden, AG, Ulivi, S, Völzke, H, Wareham, NJ, Wellons, M, Franceschini, N, Chasman, DI, Thorsteinsdottir, U, Murray, A, Stefansson, K, Murabito, JM, Ong, KK, Perry, JRB, Forouhi, NG, Kerrison, ND, Sharp, SJ, Sims, M, Barroso, I, Deloukas, P, McCarthy, MI, Arriola, L, Balkau, B, Barricarte, A, Boeing, H, Franks, PW, Gonzalez, C, Grioni, S, Kaaks, R, Key, TJ, Navarro, C, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quirós, JR, Rolandsson, O, Sacerdote, C, Sánchez, MJ, Slimani, N, Tjonneland, A, Tumino, R, Van Der A, DL, Van Der Schouw, YT, Riboli, E, Smith, BH, Campbell, A, Deary, IJ & McIntosh, AM 2015, 'Rare coding variants and X-linked loci associated with age at menarche', Nature Communications, vol. 6, 7756. https://doi.org/10.1038/ncomms8756

TY - JOUR

T1 - Rare coding variants and X-linked loci associated with age at menarche

AU - Lunetta, Kathryn L.

AU - Day, Felix R.

AU - Sulem, Patrick

AU - Ruth, Katherine S.

AU - Tung, Joyce Y.

AU - Hinds, David A.

AU - Esko, Toñu

AU - Elks, Cathy E.

AU - Altmaier, Elisabeth

AU - He, Chunyan

AU - Huffman, Jennifer E.

AU - Mihailov, Evelin

AU - Porcu, Eleonora

AU - Robino, Antonietta

AU - Rose, Lynda M.

AU - Schick, Ursula M.

AU - Stolk, Lisette

AU - Teumer, Alexander

AU - Thompson, Deborah J.

AU - Traglia, Michela

AU - Wang, Carol A.

AU - Yerges-Armstrong, Laura M.

AU - Antoniou, Antonis C.

AU - Barbieri, Caterina

AU - Coviello, Andrea D.

AU - Cucca, Francesco

AU - Demerath, Ellen W.

AU - Dunning, Alison M.

AU - Gandin, Ilaria

AU - Grove, Megan L.

AU - Gudbjartsson, Daniel F.

AU - Hocking, Lynne J.

AU - Hofman, Albert

AU - Huang, Jinyan

AU - Jackson, Rebecca D.

AU - Karasik, David

AU - Kriebel, Jennifer

AU - Lange, Ethan M.

AU - Lange, Leslie A.

AU - Langenberg, Claudia

AU - Li, Xin

AU - Luan, Jian'an

AU - Mägi, Reedik

AU - Morrison, Alanna C.

AU - Padmanabhan, Sandosh

AU - Pirie, Ailith

AU - Polasek, Ozren

AU - Porteous, David

AU - Reiner, Alex P.

AU - Rivadeneira, Fernando

AU - Rudan, Igor

AU - Sala, Cinzia F.

AU - Schlessinger, David

AU - Scott, Robert A.

AU - Stöckl, Doris

AU - Visser, Jenny A.

AU - Völker, Uwe

AU - Vozzi, Diego

AU - Wilson, James G.

AU - Zygmunt, Marek

AU - Boerwinkle, Eric

AU - Buring, Julie E.

AU - Crisponi, Laura

AU - Easton, Douglas F.

AU - Hayward, Caroline

AU - Hu, Frank B.

AU - Liu, Simin

AU - Metspalu, Andres

AU - Pennell, Craig E.

AU - Ridker, Paul M.

AU - Strauch, Konstantin

AU - Streeten, Elizabeth A.

AU - Toniolo, Daniela

AU - Uitterlinden, André G.

AU - Ulivi, Sheila

AU - Völzke, Henry

AU - Wareham, Nicholas J.

AU - Wellons, Melissa

AU - Franceschini, Nora

AU - Chasman, Daniel I.

AU - Thorsteinsdottir, Unnur

AU - Murray, Anna

AU - Stefansson, Kari

AU - Murabito, Joanne M.

AU - Ong, Ken K.

AU - Perry, John R.B.

AU - Forouhi, Nita G.

AU - Kerrison, Nicola D.

AU - Sharp, Stephen J.

AU - Sims, Matt

AU - Barroso, Inês

AU - Deloukas, Panos

AU - McCarthy, Mark I.

AU - Arriola, Larraitz

AU - Balkau, Beverley

AU - Barricarte, Aurelio

AU - Boeing, Heiner

AU - Franks, Paul W.

AU - Gonzalez, Carlos

AU - Grioni, Sara

AU - Kaaks, Rudolf

AU - Key, Timothy J.

AU - Navarro, Carmen

AU - Nilsson, Peter M.

AU - Overvad, Kim

AU - Palli, Domenico

AU - Panico, Salvatore

AU - Quirós, J. Ramón

AU - Rolandsson, Olov

AU - Sacerdote, Carlotta

AU - Sánchez, María José

AU - Slimani, Nadia

AU - Tjonneland, Anne

AU - Tumino, Rosario

AU - Van Der A, Daphne L.

AU - Van Der Schouw, Yvonne T.

AU - Riboli, Elio

AU - Smith, Blair H.

AU - Campbell, Archie

AU - Deary, Ian J.

AU - McIntosh, Andrew M.

PY - 2015/8/4

Y1 - 2015/8/4

N2 - More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10-8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10-13) and FAAH2 (rs5914101, P=4.9 × 10-10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10-11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

AB - More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼ 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10-8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10-13) and FAAH2 (rs5914101, P=4.9 × 10-10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10-11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

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UR - http://www.scopus.com/inward/citedby.url?scp=84938675474&partnerID=8YFLogxK

U2 - 10.1038/ncomms8756

DO - 10.1038/ncomms8756

M3 - Article

C2 - 26239645

AN - SCOPUS:84938675474

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7756

ER -

Rare coding variants and X-linked loci associated with age at menarche

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