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

K.L. Lunetta; F.R. Day; P. Sulem; K.S. Ruth; J.Y. Tung; D.A. Hinds; T. Esko; C.E. Elks; E. Altmaier; C. He; J.E. Huffman; E. Mihailov; E. Porcu; A. Robino; L.M. Rose; U.M. Schick; L. Stolk; A. Teumer; D.J. Thompson; M. Traglia; Carol Wang; L.M. Yerges-Armstrong; A.C. Antoniou; C. Barbieri; A.D. Coviello; F. Cucca; E.W. Demerath; A.M. Dunning; I. Gandin; M.L. Grove; D.F. Gudbjartsson; L.J. Hocking; A. Hofman; J. Huang; R.D. Jackson; D. Karasik; J. Kriebel; E.M. Lange; L.A. Lange; C. Langenberg; X. Li; J. Luan; R. Mägi; A.C. Morrison; S. Padmanabhan; A. Pirie; O. Polasek; D. Porteous; A.P. Reiner; F. Rivadeneira; I. Rudan; C.F. Sala; D. Schlessinger; R.A. Scott; D. Stöckl; J.A. Visser; U. Völker; D. Vozzi; J.G. Wilson; M. Zygmunt; E. Boerwinkle; J.E. Buring; L. Crisponi; D.F. Easton; C. Hayward; F.B. Hu; S. Liu; A. Metspalu; Craig Pennell; P.M. Ridker; K. Strauch; E.A. Streeten; D. Toniolo; A.G. Uitterlinden; S. Ulivi; H. Völzke; N.J. Wareham

doi:10.1038/ncomms8756

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

K.L. Lunetta, F.R. Day, P. Sulem, K.S. Ruth, J.Y. Tung, D.A. Hinds, T. Esko, C.E. Elks, E. Altmaier, C. He, J.E. Huffman, E. Mihailov, E. Porcu, A. Robino, L.M. Rose, U.M. Schick, L. Stolk, A. Teumer, D.J. Thompson, M. TragliaCarol Wang, L.M. Yerges-Armstrong, A.C. Antoniou, C. Barbieri, A.D. Coviello, F. Cucca, E.W. Demerath, A.M. Dunning, I. Gandin, M.L. Grove, D.F. Gudbjartsson, L.J. Hocking, A. Hofman, J. Huang, R.D. Jackson, D. Karasik, J. Kriebel, E.M. Lange, L.A. Lange, C. Langenberg, X. Li, J. Luan, R. Mägi, A.C. Morrison, S. Padmanabhan, A. Pirie, O. Polasek, D. Porteous, A.P. Reiner, F. Rivadeneira, I. Rudan, C.F. Sala, D. Schlessinger, R.A. Scott, D. Stöckl, J.A. Visser, U. Völker, D. Vozzi, J.G. Wilson, M. Zygmunt, E. Boerwinkle, J.E. Buring, L. Crisponi, D.F. Easton, C. Hayward, F.B. Hu, S. Liu, A. Metspalu, Craig Pennell, P.M. Ridker, K. Strauch, E.A. Streeten, D. Toniolo, A.G. Uitterlinden, S. Ulivi, H. Völzke, N.J. Wareham

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Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. 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-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
Pages (from-to)	1-8
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8756
Publication status	Published - 2015

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10.1038/ncomms8756

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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., ... Wareham, N. J. (2015). Rare coding variants and X-linked loci associated with age at menarche. Nature Communications, 6, 1-8. https://doi.org/10.1038/ncomms8756

@article{4c511727a787419eb7bf6c676b2d416e,

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

abstract = "{\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved. 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-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 = "K.L. Lunetta and F.R. Day and P. Sulem and K.S. Ruth and J.Y. Tung and D.A. Hinds and T. Esko and C.E. Elks and E. Altmaier and C. He and J.E. Huffman and E. Mihailov and E. Porcu and A. Robino and L.M. Rose and U.M. Schick and L. Stolk and A. Teumer and D.J. Thompson and M. Traglia and Carol Wang and L.M. Yerges-Armstrong and A.C. Antoniou and C. Barbieri and A.D. Coviello and F. Cucca and E.W. Demerath and A.M. Dunning and I. Gandin and M.L. Grove and D.F. Gudbjartsson and L.J. Hocking and A. Hofman and J. Huang and R.D. Jackson and D. Karasik and J. Kriebel and E.M. Lange and L.A. Lange and C. Langenberg and X. Li and J. Luan and R. M{\"a}gi and A.C. Morrison and S. Padmanabhan and A. Pirie and O. Polasek and D. Porteous and A.P. Reiner and F. Rivadeneira and I. Rudan and C.F. Sala and D. Schlessinger and R.A. Scott and D. St{\"o}ckl and J.A. Visser and U. V{\"o}lker and D. Vozzi and J.G. Wilson and M. Zygmunt and E. Boerwinkle and J.E. Buring and L. Crisponi and D.F. Easton and C. Hayward and F.B. Hu and S. Liu and A. Metspalu and Craig Pennell and P.M. Ridker and K. Strauch and E.A. Streeten and D. Toniolo and A.G. Uitterlinden and S. Ulivi and H. V{\"o}lzke and N.J. Wareham",

year = "2015",

doi = "10.1038/ncomms8756",

language = "English",

volume = "6",

pages = "1--8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group - Macmillan Publishers",

}

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, C, 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, C, Ridker, PM, Strauch, K, Streeten, EA, Toniolo, D, Uitterlinden, AG, Ulivi, S, Völzke, H & Wareham, NJ 2015, 'Rare coding variants and X-linked loci associated with age at menarche', Nature Communications, vol. 6, pp. 1-8. https://doi.org/10.1038/ncomms8756

TY - JOUR

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

AU - Lunetta, K.L.

AU - Day, F.R.

AU - Sulem, P.

AU - Ruth, K.S.

AU - Tung, J.Y.

AU - Hinds, D.A.

AU - Esko, T.

AU - Elks, C.E.

AU - Altmaier, E.

AU - He, C.

AU - Huffman, J.E.

AU - Mihailov, E.

AU - Porcu, E.

AU - Robino, A.

AU - Rose, L.M.

AU - Schick, U.M.

AU - Stolk, L.

AU - Teumer, A.

AU - Thompson, D.J.

AU - Traglia, M.

AU - Wang, Carol

AU - Yerges-Armstrong, L.M.

AU - Antoniou, A.C.

AU - Barbieri, C.

AU - Coviello, A.D.

AU - Cucca, F.

AU - Demerath, E.W.

AU - Dunning, A.M.

AU - Gandin, I.

AU - Grove, M.L.

AU - Gudbjartsson, D.F.

AU - Hocking, L.J.

AU - Hofman, A.

AU - Huang, J.

AU - Jackson, R.D.

AU - Karasik, D.

AU - Kriebel, J.

AU - Lange, E.M.

AU - Lange, L.A.

AU - Langenberg, C.

AU - Li, X.

AU - Luan, J.

AU - Mägi, R.

AU - Morrison, A.C.

AU - Padmanabhan, S.

AU - Pirie, A.

AU - Polasek, O.

AU - Porteous, D.

AU - Reiner, A.P.

AU - Rivadeneira, F.

AU - Rudan, I.

AU - Sala, C.F.

AU - Schlessinger, D.

AU - Scott, R.A.

AU - Stöckl, D.

AU - Visser, J.A.

AU - Völker, U.

AU - Vozzi, D.

AU - Wilson, J.G.

AU - Zygmunt, M.

AU - Boerwinkle, E.

AU - Buring, J.E.

AU - Crisponi, L.

AU - Easton, D.F.

AU - Hayward, C.

AU - Hu, F.B.

AU - Liu, S.

AU - Metspalu, A.

AU - Pennell, Craig

AU - Ridker, P.M.

AU - Strauch, K.

AU - Streeten, E.A.

AU - Toniolo, D.

AU - Uitterlinden, A.G.

AU - Ulivi, S.

AU - Völzke, H.

AU - Wareham, N.J.

PY - 2015

Y1 - 2015

N2 - © 2015 Macmillan Publishers Limited. All rights reserved. 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-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 - © 2015 Macmillan Publishers Limited. All rights reserved. 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-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.

U2 - 10.1038/ncomms8756

DO - 10.1038/ncomms8756

M3 - Article

C2 - 26239645

SN - 2041-1723

VL - 6

SP - 1

EP - 8

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

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