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

KL Lunetta; FR Day; P Sulem; KS Ruth; JY Tung; DA Hinds; T Esko; CE Elks; E Altmaier; CY He; JE Huffman; E Mihailov; E Porcu; A Robino; LM Rose; UM Schick; Lisette Stolk; A Teumer; DJ Thompson; M Traglia; CA Wang; LM Yerges-Armstrong; AC Antoniou; C Barbieri; AD Coviello; F Cucca; EW Demerath; AM Dunning; I Gandin; ML Grove; DF Gudbjartsson; LJ Hocking; Bert Hofman; JY Huang; RD Jackson; D Karasik; J Kriebel; Edmee Lange; LA Lange; C Langenberg; X Li; JA Luan; R Magi; AC Morrison; S Padmanabhan; A Pirie; O Polasek; D Porteous; AP Reiner; Fernando Rivadeneira; I Rudan; CF Sala; D Schlessinger; RA Scott; D Stockl; Jenny Visser; U Volker; D Vozzi; JG Wilson; M Zygmunt; E Boerwinkle; JE Buring; L Crisponi; DF Easton; C Hayward; FB Hu; SM (Simin) Liu; A Metspalu; CE Pennell; PM Ridker; K Strauch; EA Streeten; D Toniolo; André Uitterlinden; S Ulivi; H Volzke; NJ Wareham; M Wellons; N Franceschini; DI Chasman; U Thorsteinsdottir; A Murray; K Stefansson; JM Murabito; KK Ong; JRB Perry; NG Forouhi; ND Kerrison; SJ Sharp; M Sims; I Barroso; P Deloukas; MI McCarthy; L Arriola; B Balkau; A Barricarte; H Boeing; PW Franks; C Gonzalez; S Grioni; R Kaaks; TJ Key; C Navarro; PM Nilsson; K Overvad; D Palli; S Panico; JR Quiros; O Rolandsson; C Sacerdote; MJ (Maria-Jose) Sanchez; N Slimani; A Tjonneland; R Tumino; DL van der A; YT van der Schouw; E Riboli; BH Smith; A (Archie) Campbell; IJ Deary; AM McIntosh

doi:10.1038/ncomms8756

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

KL Lunetta, FR Day, P Sulem, KS Ruth, JY Tung, DA Hinds, T Esko, CE Elks, E Altmaier, CY He, JE Huffman, E Mihailov, E Porcu, A Robino, LM Rose, UM Schick, Lisette Stolk, A Teumer, DJ Thompson, M TragliaCA Wang, LM Yerges-Armstrong, AC Antoniou, C Barbieri, AD Coviello, F Cucca, EW Demerath, AM Dunning, I Gandin, ML Grove, DF Gudbjartsson, LJ Hocking, Bert Hofman, JY Huang, RD Jackson, D Karasik, J Kriebel, Edmee Lange, LA Lange, C Langenberg, X Li, JA Luan, R Magi, AC Morrison, S Padmanabhan, A Pirie, O Polasek, D Porteous, AP Reiner, Fernando Rivadeneira, I Rudan, CF Sala, D Schlessinger, RA Scott, D Stockl, Jenny Visser, U Volker, D Vozzi, JG Wilson, M Zygmunt, E Boerwinkle, JE Buring, L Crisponi, DF Easton, C Hayward, FB Hu, SM (Simin) Liu, A Metspalu, CE Pennell, PM Ridker, K Strauch, EA Streeten, D Toniolo, André Uitterlinden, S Ulivi, H Volzke, NJ Wareham, M Wellons, N Franceschini, DI Chasman, U Thorsteinsdottir, A Murray, K Stefansson, JM Murabito, KK Ong, JRB Perry, NG Forouhi, ND Kerrison, SJ Sharp, M Sims, I Barroso, P Deloukas, MI McCarthy, L Arriola, B Balkau, A Barricarte, H Boeing, PW Franks, C Gonzalez, S Grioni, R Kaaks, TJ Key, C Navarro, PM Nilsson, K Overvad, D Palli, S Panico, JR Quiros, O Rolandsson, C Sacerdote, MJ (Maria-Jose) Sanchez, N Slimani, A Tjonneland, R Tumino, DL van der A, YT van der Schouw, E Riboli, BH Smith, A (Archie) Campbell, IJ Deary, AM McIntosh

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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 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.

Original language	Undefined/Unknown
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8756
Publication status	Published - 2015

Research programs

EMC MM-01-39-04
EMC MM-01-39-09-A
EMC NIHES-01-64-02

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Cite this

Lunetta, KL., Day, FR., Sulem, P., Ruth, KS., Tung, JY., Hinds, DA., Esko, T., Elks, CE., Altmaier, E., He, CY., Huffman, JE., Mihailov, E., Porcu, E., Robino, A., Rose, LM., Schick, UM., Stolk, L., Teumer, A., Thompson, DJ., ... McIntosh, AM. (2015). Rare coding variants and X-linked loci associated with age at menarche. Nature Communications, 6. https://doi.org/10.1038/ncomms8756

@article{2c736ee2be6e40dba690404eed5c26e0,

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 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.",

author = "KL Lunetta and FR Day and P Sulem and KS Ruth and JY Tung and DA Hinds and T Esko and CE Elks and E Altmaier and CY He and JE Huffman and E Mihailov and E Porcu and A Robino and LM Rose and UM Schick and Lisette Stolk and A Teumer and DJ Thompson and M Traglia and CA Wang and LM Yerges-Armstrong and AC Antoniou and C Barbieri and AD Coviello and F Cucca and EW Demerath and AM Dunning and I Gandin and ML Grove and DF Gudbjartsson and LJ Hocking and Bert Hofman and JY Huang and RD Jackson and D Karasik and J Kriebel and Edmee Lange and LA Lange and C Langenberg and X Li and JA Luan and R Magi and AC Morrison and S Padmanabhan and A Pirie and O Polasek and D Porteous and AP Reiner and Fernando Rivadeneira and I Rudan and CF Sala and D Schlessinger and RA Scott and D Stockl and Jenny Visser and U Volker and D Vozzi and JG Wilson and M Zygmunt and E Boerwinkle and JE Buring and L Crisponi and DF Easton and C Hayward and FB Hu and Liu, {SM (Simin)} and A Metspalu and CE Pennell and PM Ridker and K Strauch and EA Streeten and D Toniolo and Andr{\'e} Uitterlinden and S Ulivi and H Volzke and NJ Wareham and M Wellons and N Franceschini and DI Chasman and U Thorsteinsdottir and A Murray and K Stefansson and JM Murabito and KK Ong and JRB Perry and NG Forouhi and ND Kerrison and SJ Sharp and M Sims and I Barroso and P Deloukas and MI McCarthy and L Arriola and B Balkau and A Barricarte and H Boeing and PW Franks and C Gonzalez and S Grioni and R Kaaks and TJ Key and C Navarro and PM Nilsson and K Overvad and D Palli and S Panico and JR Quiros and O Rolandsson and C Sacerdote and Sanchez, {MJ (Maria-Jose)} and N Slimani and A Tjonneland and R Tumino and {van der A}, DL and {van der Schouw}, YT and E Riboli and BH Smith and Campbell, {A (Archie)} and IJ Deary and AM McIntosh",

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language = "Undefined/Unknown",

volume = "6",

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Lunetta, KL, Day, FR, Sulem, P, Ruth, KS, Tung, JY, Hinds, DA, Esko, T, Elks, CE, Altmaier, E, He, CY, 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, B, Huang, JY, Jackson, RD, Karasik, D, Kriebel, J, Lange, E, Lange, LA, Langenberg, C, Li, X, Luan, JA, Magi, R, Morrison, AC, Padmanabhan, S, Pirie, A, Polasek, O, Porteous, D, Reiner, AP, Rivadeneira, F, Rudan, I, Sala, CF, Schlessinger, D, Scott, RA, Stockl, D, Visser, J, Volker, U, Vozzi, D, Wilson, JG, Zygmunt, M, Boerwinkle, E, Buring, JE, Crisponi, L, Easton, DF, Hayward, C, Hu, FB, Liu, SM, Metspalu, A, Pennell, CE, Ridker, PM, Strauch, K, Streeten, EA, Toniolo, D, Uitterlinden, A, Ulivi, S, Volzke, 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, Quiros, JR, Rolandsson, O, Sacerdote, C, Sanchez, 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. https://doi.org/10.1038/ncomms8756

TY - JOUR

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

AU - Lunetta, KL

AU - Day, FR

AU - Sulem, P

AU - Ruth, KS

AU - Tung, JY

AU - Hinds, DA

AU - Esko, T

AU - Elks, CE

AU - Altmaier, E

AU - He, CY

AU - Huffman, JE

AU - Mihailov, E

AU - Porcu, E

AU - Robino, A

AU - Rose, LM

AU - Schick, UM

AU - Stolk, Lisette

AU - Teumer, A

AU - Thompson, DJ

AU - Traglia, M

AU - Wang, CA

AU - Yerges-Armstrong, LM

AU - Antoniou, AC

AU - Barbieri, C

AU - Coviello, AD

AU - Cucca, F

AU - Demerath, EW

AU - Dunning, AM

AU - Gandin, I

AU - Grove, ML

AU - Gudbjartsson, DF

AU - Hocking, LJ

AU - Hofman, Bert

AU - Huang, JY

AU - Jackson, RD

AU - Karasik, D

AU - Kriebel, J

AU - Lange, Edmee

AU - Lange, LA

AU - Langenberg, C

AU - Li, X

AU - Luan, JA

AU - Magi, R

AU - Morrison, AC

AU - Padmanabhan, S

AU - Pirie, A

AU - Polasek, O

AU - Porteous, D

AU - Reiner, AP

AU - Rivadeneira, Fernando

AU - Rudan, I

AU - Sala, CF

AU - Schlessinger, D

AU - Scott, RA

AU - Stockl, D

AU - Visser, Jenny

AU - Volker, U

AU - Vozzi, D

AU - Wilson, JG

AU - Zygmunt, M

AU - Boerwinkle, E

AU - Buring, JE

AU - Crisponi, L

AU - Easton, DF

AU - Hayward, C

AU - Hu, FB

AU - Liu, SM (Simin)

AU - Metspalu, A

AU - Pennell, CE

AU - Ridker, PM

AU - Strauch, K

AU - Streeten, EA

AU - Toniolo, D

AU - Uitterlinden, André

AU - Ulivi, S

AU - Volzke, H

AU - Wareham, NJ

AU - Wellons, M

AU - Franceschini, N

AU - Chasman, DI

AU - Thorsteinsdottir, U

AU - Murray, A

AU - Stefansson, K

AU - Murabito, JM

AU - Ong, KK

AU - Perry, JRB

AU - Forouhi, NG

AU - Kerrison, ND

AU - Sharp, SJ

AU - Sims, M

AU - Barroso, I

AU - Deloukas, P

AU - McCarthy, MI

AU - Arriola, L

AU - Balkau, B

AU - Barricarte, A

AU - Boeing, H

AU - Franks, PW

AU - Gonzalez, C

AU - Grioni, S

AU - Kaaks, R

AU - Key, TJ

AU - Navarro, C

AU - Nilsson, PM

AU - Overvad, K

AU - Palli, D

AU - Panico, S

AU - Quiros, JR

AU - Rolandsson, O

AU - Sacerdote, C

AU - Sanchez, MJ (Maria-Jose)

AU - Slimani, N

AU - Tjonneland, A

AU - Tumino, R

AU - van der A, DL

AU - van der Schouw, YT

AU - Riboli, E

AU - Smith, BH

AU - Campbell, A (Archie)

AU - Deary, IJ

AU - McIntosh, AM

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms8756

DO - 10.1038/ncomms8756

M3 - Article

C2 - 26239645

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

ER -