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

Lunetta, Kathryn L.; Day, Felix R.; Sulem, Patrick; Ruth, Katherine S.; Tung, Joyce Y.; Hinds, David A.; Esko, Tonu; Elks, Cathy E.; Altmaier, Elisabeth and He, Chunyan, et al. (2015) In Nature Communications 6.
Abstract
More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding 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 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing... (More)
More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding 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 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 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 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait. (Less)
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Nature Communications
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6
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Nature Publishing Group
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  • scopus:84938675474
ISSN
2041-1723
DOI
10.1038/ncomms8756
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English
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06e04520-0536-4bda-ac54-91521c73a325 (old id 7968995)
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2015-10-01 07:38:04
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@article{06e04520-0536-4bda-ac54-91521c73a325,
  abstract     = {More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding 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&lt;5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 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 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.},
  articleno    = {7756},
  author       = {Lunetta, Kathryn L. and Day, Felix R. and Sulem, Patrick and Ruth, Katherine S. and Tung, Joyce Y. and Hinds, David A. and Esko, Tonu and Elks, Cathy E. and Altmaier, Elisabeth and He, Chunyan and Huffman, Jennifer E. and Mihailov, Evelin and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M. and Schick, Ursula M. and Stolk, Lisette and Teumer, Alexander and Thompson, Deborah J. and Traglia, Michela and Wang, Carol A. and Yerges-Armstrong, Laura M. and Antoniou, Antonis C. and Barbieri, Caterina and Coviello, Andrea D. and Cucca, Francesco and Demerath, Ellen W. and Dunning, Alison M. and Gandin, Ilaria and Grove, Megan L. and Gudbjartsson, Daniel F. and Hocking, Lynne J. and Hofman, Albert and Huang, Jinyan and Jackson, Rebecca D. and Karasik, David and Kriebel, Jennifer and Lange, Ethan M. and Lange, Leslie A. and Langenberg, Claudia and Li, Xin and Luan, Jian'an and Maegi, Reedik and Morrison, Alanna C. and Padmanabhan, Sandosh and Pirie, Ailith and Polasek, Ozren and Porteous, David and Reiner, Alex P. and Rivadeneira, Fernando and Rudan, Igor and Sala, Cinzia F. and Schlessinger, David and Scott, Robert A. and Stoeckl, Doris and Visser, Jenny A. and Voelker, Uwe and Vozzi, Diego and Wilson, James G. and Zygmunt, Marek and Boerwinkle, Eric and Buring, Julie E. and Crisponi, Laura and Easton, Douglas F. and Hayward, Caroline and Hu, Frank B. and Liu, Simin and Metspalu, Andres and Pennell, Craig E. and Ridker, Paul M. and Strauch, Konstantin and Streeten, Elizabeth A. and Toniolo, Daniela and Uitterlinden, Andre G. and Ulivi, Sheila and Voelzke, Henry and Wareham, Nicholas J. and Wellons, Melissa and Franceschini, Nora and Chasman, Daniel I. and Thorsteinsdottir, Unnur and Murray, Anna and Stefansson, Kari 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 Sims, Matt and Barroso, Ines and Deloukas, Panos and McCarthy, Mark I. and Arriola, Larraitz and Balkau, Beverley and Barricarte, Aurelio and Boeing, Heiner and Franks, Paul and Gonzalez, Carlos and Grioni, Sara and Kaaks, Rudolf and Key, Timothy J. and Navarro, Carmen and Nilsson, Peter and Overvad, Kim and Palli, Domenico and Panico, Salvatore and Ramon Quiros, J. and Rolandsson, Olov and Sacerdote, Carlotta and Sanchez, Maria-Jose and Slimani, Nadia and Tjonneland, Anne and Tumino, Rosario and van der A, Daphne L. and van der Schouw, Yvonne T. and Riboli, Elio and Smith, Blair H. and Campbell, Archie and Deary, Ian J. and McIntosh, Andrew M.},
  issn         = {2041-1723},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Rare coding variants and X-linked loci associated with age at menarche},
  url          = {http://dx.doi.org/10.1038/ncomms8756},
  volume       = {6},
  year         = {2015},
}