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 & 101 others 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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 languageEnglish
Article number7756
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 4 Aug 2015
Externally publishedYes

Fingerprint

Menarche
chromosomes
loci
mutations
genes
coding
Genes
X Chromosome
Chromosomes
homeostasis
genome
fatty acids
amides
Mutation
Hypogonadism
Penetrance
Genome-Wide Association Study
RNA Interference
low frequencies
proteins

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Lunetta, K. L., Day, F. R., Sulem, P., Ruth, K. S., Tung, J. Y., Hinds, D. A., ... McIntosh, A. M. (2015). Rare coding variants and X-linked loci associated with age at menarche. Nature Communications, 6, [7756]. https://doi.org/10.1038/ncomms8756

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

In: Nature Communications, Vol. 6, 7756, 04.08.2015.

Research output: Contribution to journalArticle

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
Lunetta KL, Day FR, Sulem P, Ruth KS, Tung JY, Hinds DA et al. Rare coding variants and X-linked loci associated with age at menarche. Nature Communications. 2015 Aug 4;6. 7756. https://doi.org/10.1038/ncomms8756
Lunetta, Kathryn L. ; Day, Felix R. ; Sulem, Patrick ; Ruth, Katherine S. ; Tung, Joyce Y. ; Hinds, David A. ; Esko, Toñu ; Elks, Cathy E. ; Altmaier, Elisabeth ; He, Chunyan ; Huffman, Jennifer E. ; Mihailov, Evelin ; Porcu, Eleonora ; Robino, Antonietta ; Rose, Lynda M. ; Schick, Ursula M. ; Stolk, Lisette ; Teumer, Alexander ; Thompson, Deborah J. ; Traglia, Michela ; Wang, Carol A. ; Yerges-Armstrong, Laura M. ; Antoniou, Antonis C. ; Barbieri, Caterina ; Coviello, Andrea D. ; Cucca, Francesco ; Demerath, Ellen W. ; Dunning, Alison M. ; Gandin, Ilaria ; Grove, Megan L. ; Gudbjartsson, Daniel F. ; Hocking, Lynne J. ; Hofman, Albert ; Huang, Jinyan ; Jackson, Rebecca D. ; Karasik, David ; Kriebel, Jennifer ; Lange, Ethan M. ; Lange, Leslie A. ; Langenberg, Claudia ; Li, Xin ; Luan, Jian'an ; Mägi, Reedik ; Morrison, Alanna C. ; Padmanabhan, Sandosh ; Pirie, Ailith ; Polasek, Ozren ; Porteous, David ; Reiner, Alex P. ; Rivadeneira, Fernando ; Rudan, Igor ; Sala, Cinzia F. ; Schlessinger, David ; Scott, Robert A. ; Stöckl, Doris ; Visser, Jenny A. ; Völker, Uwe ; Vozzi, Diego ; Wilson, James G. ; Zygmunt, Marek ; Boerwinkle, Eric ; Buring, Julie E. ; Crisponi, Laura ; Easton, Douglas F. ; Hayward, Caroline ; Hu, Frank B. ; Liu, Simin ; Metspalu, Andres ; Pennell, Craig E. ; Ridker, Paul M. ; Strauch, Konstantin ; Streeten, Elizabeth A. ; Toniolo, Daniela ; Uitterlinden, André G. ; Ulivi, Sheila ; Völzke, Henry ; Wareham, Nicholas J. ; Wellons, Melissa ; Franceschini, Nora ; Chasman, Daniel I. ; Thorsteinsdottir, Unnur ; Murray, Anna ; Stefansson, Kari ; Murabito, Joanne M. ; Ong, Ken K. ; Perry, John R.B. ; Forouhi, Nita G. ; Kerrison, Nicola D. ; Sharp, Stephen J. ; Sims, Matt ; Barroso, Inês ; Deloukas, Panos ; McCarthy, Mark I. ; Arriola, Larraitz ; Balkau, Beverley ; Barricarte, Aurelio ; Boeing, Heiner ; Franks, Paul W. ; Gonzalez, Carlos ; Grioni, Sara ; Kaaks, Rudolf ; Key, Timothy J. ; Navarro, Carmen ; Nilsson, Peter M. ; Overvad, Kim ; Palli, Domenico ; Panico, Salvatore ; Quirós, J. Ramón ; Rolandsson, Olov ; Sacerdote, Carlotta ; Sánchez, María José ; Slimani, Nadia ; Tjonneland, Anne ; Tumino, Rosario ; Van Der A, Daphne L. ; Van Der Schouw, Yvonne T. ; Riboli, Elio ; Smith, Blair H. ; Campbell, Archie ; Deary, Ian J. ; McIntosh, Andrew M. / Rare coding variants and X-linked loci associated with age at menarche. In: Nature Communications. 2015 ; Vol. 6.
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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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