Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

Elks, C. E., Perry, J. R. B., Sulem, P., Chasman, D. I., Franceschini, N., He, C. Y., Lunetta, K. L., Visser, J. A., Byrne, E. M., Cousminer, D. L., Gudbjartsson, D. F., Esko, T., Feenstra, B., Hottenga, J. J., Koller, D. L., Kutalik, Z., Lin, P., Mangino, M., Marongiu, M., McArdle, P. F., Smith, A. V., Stolk, L., Van Wingerden, S. H., Zhao, J. H., Albrecht, E., Corre, T., Ingelsson, E., Hayward, C., Magnusson, P. K. E., Smith, E. N., Ulivi, S., Warrington, N. M., Zgaga, L., Alavere, H., Amin, N., Aspelund, T., Bandinelli, S., Barroso, I., Berenson, G. S., Bergmann, S., Blackburn, H., Boerwinkle, E., Buring, J. E., Busonero, F., Campbell, H., Chanock, S. J., Chen, W., Cornelis, M. C., Couper, D., Coviello, A. D., d'Adamo, P., de Faire, U., de Geus, E. J. C., Deloukas, P., Doring, A., Smith, G. D., Easton, D. F., Eiriksdottir, G., Emilsson, V., Eriksson, J., Ferrucci, L., Folsom, A. R., Foroud, T., Garcia, M., Gasparini, P., Geller, F., Gieger, C., Gudnason, V., Hall, P., Hankinson, S. E., Ferreli, L., Heath, A. C., Hernandez, D. G., Hofman, A., Hu, F. B., Illig, T., Jarvelin, M. R., Johnson, A. D., Karasik, D., Khaw, K. T., Kiel, D. P., Kilpelainen, T. O., Kolcic, I., Kraft, P., Launer, L. J., Laven, J. S. E., Li, S. X., Liu, J. J., Levy, D., Martin, N. G., McArdle, W. L., Melbye, M., Mooser, V., Murray, J. C., Murray, S. S., Nalls, M. A., Navarro, P., Nelis, M., Ness, A. R., Northstone, K., Oostra, B. A., Peacock, M., Palmer, L. J., Palotie, A., Pare, G., Parker, A. N., Pedersen, N. L., Peltonen, L., Pennell, C. E., Pharoah, P., Polasek, O., Plump, A. S., Pouta, A., Porcu, E., Rafnar, T., Rice, J. P., Ring, S. M., Rivadeneira, F., Rudan, I., Sala, C., Salomaa, V., Sanna, S., Schlessinger, D., Schork, N. J., Scuteri, A., Segre, A. V., Shuldiner, A. R., Soranzo, N., Sovio, U., Srinivasan, S. R., Strachan, D. P., Tammesoo, M. L., Tikkanen, E., Toniolo, D., Tsui, K., Tryggvadottir, L., Tyrer, J., Uda, M., van Dam, R. M., van Meurs, J. B. J., Vollenweider, P., Waeber, G., Wareham, N. J., Waterworth, D. M., Weedon, M. N., Wichmann, H. E., Willemsen, G., Wilson, J. F., Wright, A. F., Young, L., Zhai, G. J., Zhuang, W. V., Bierut, L. J., Boomsma, D. I., Boyd, H. A., Crisponi, L., Demerath, E. W., van Duijn, C. M., Econs, M. J., Harris, T. B., Hunter, D. J., Loos, R. J. F., Metspalu, A., Montgomery, G. W., Ridker, P. M., Spector, T. D., Streeten, E. A., Stefansson, K., Thorsteinsdottir, U., Uitterlinden, A. G., Widen, E., Murabito, J. M., Ong, K. K., Murray, A. and GIANT Consortium (2010) Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nature Genetics, 42 12: 1077-1085. doi:10.1038/ng.714

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Author Elks, C. E.
Perry, J. R. B.
Sulem, P.
Chasman, D. I.
Franceschini, N.
He, C. Y.
Lunetta, K. L.
Visser, J. A.
Byrne, E. M.
Cousminer, D. L.
Gudbjartsson, D. F.
Esko, T.
Feenstra, B.
Hottenga, J. J.
Koller, D. L.
Kutalik, Z.
Lin, P.
Mangino, M.
Marongiu, M.
McArdle, P. F.
Smith, A. V.
Stolk, L.
Van Wingerden, S. H.
Zhao, J. H.
Albrecht, E.
Corre, T.
Ingelsson, E.
Hayward, C.
Magnusson, P. K. E.
Smith, E. N.
Ulivi, S.
Warrington, N. M.
Zgaga, L.
Alavere, H.
Amin, N.
Aspelund, T.
Bandinelli, S.
Barroso, I.
Berenson, G. S.
Bergmann, S.
Blackburn, H.
Boerwinkle, E.
Buring, J. E.
Busonero, F.
Campbell, H.
Chanock, S. J.
Chen, W.
Cornelis, M. C.
Couper, D.
Coviello, A. D.
d'Adamo, P.
de Faire, U.
de Geus, E. J. C.
Deloukas, P.
Doring, A.
Smith, G. D.
Easton, D. F.
Eiriksdottir, G.
Emilsson, V.
Eriksson, J.
Ferrucci, L.
Folsom, A. R.
Foroud, T.
Garcia, M.
Gasparini, P.
Geller, F.
Gieger, C.
Gudnason, V.
Hall, P.
Hankinson, S. E.
Ferreli, L.
Heath, A. C.
Hernandez, D. G.
Hofman, A.
Hu, F. B.
Illig, T.
Jarvelin, M. R.
Johnson, A. D.
Karasik, D.
Khaw, K. T.
Kiel, D. P.
Kilpelainen, T. O.
Kolcic, I.
Kraft, P.
Launer, L. J.
Laven, J. S. E.
Li, S. X.
Liu, J. J.
Levy, D.
Martin, N. G.
McArdle, W. L.
Melbye, M.
Mooser, V.
Murray, J. C.
Murray, S. S.
Nalls, M. A.
Navarro, P.
Nelis, M.
Ness, A. R.
Northstone, K.
Oostra, B. A.
Peacock, M.
Palmer, L. J.
Palotie, A.
Pare, G.
Parker, A. N.
Pedersen, N. L.
Peltonen, L.
Pennell, C. E.
Pharoah, P.
Polasek, O.
Plump, A. S.
Pouta, A.
Porcu, E.
Rafnar, T.
Rice, J. P.
Ring, S. M.
Rivadeneira, F.
Rudan, I.
Sala, C.
Salomaa, V.
Sanna, S.
Schlessinger, D.
Schork, N. J.
Scuteri, A.
Segre, A. V.
Shuldiner, A. R.
Soranzo, N.
Sovio, U.
Srinivasan, S. R.
Strachan, D. P.
Tammesoo, M. L.
Tikkanen, E.
Toniolo, D.
Tsui, K.
Tryggvadottir, L.
Tyrer, J.
Uda, M.
van Dam, R. M.
van Meurs, J. B. J.
Vollenweider, P.
Waeber, G.
Wareham, N. J.
Waterworth, D. M.
Weedon, M. N.
Wichmann, H. E.
Willemsen, G.
Wilson, J. F.
Wright, A. F.
Young, L.
Zhai, G. J.
Zhuang, W. V.
Bierut, L. J.
Boomsma, D. I.
Boyd, H. A.
Crisponi, L.
Demerath, E. W.
van Duijn, C. M.
Econs, M. J.
Harris, T. B.
Hunter, D. J.
Loos, R. J. F.
Metspalu, A.
Montgomery, G. W.
Ridker, P. M.
Spector, T. D.
Streeten, E. A.
Stefansson, K.
Thorsteinsdottir, U.
Uitterlinden, A. G.
Widen, E.
Murabito, J. M.
Ong, K. K.
Murray, A.
GIANT Consortium
Title Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1061-4036
Publication date 2010-12-01
Year available 2010
Sub-type Article (original research)
DOI 10.1038/ng.714
Open Access Status DOI
Volume 42
Issue 12
Start page 1077
End page 1085
Total pages 9
Place of publication New York, NY, U.S.A.
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
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.
Formatted abstract
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10 -60) and 9q31.2 (P = 2.2 × 10 -33), we identified 30 new menarche loci (all P < 5 × 10 -8) and found suggestive evidence for a further 10 loci (P < 1.9 × 10 -6). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing. © 2010 Nature America, Inc. All rights reserved.
Keyword Puberty
Sequence variants
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID R01 NS017950
R01 AG041517
UL1 TR001108
P50 CA116201
U01 AG049505
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 255 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 12 Dec 2010, 10:02:35 EST