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; Tõnu 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; 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; EPIC-InterAct Consortium

doi:10.1038/ncomms8756

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, Tõnu 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 TragliaCarol 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, EPIC-InterAct Consortium

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

26 Citationer (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.

Originalsprog	Engelsk
Artikelnummer	7756
Tidsskrift	Nature Communications
Vol/bind	6
Antal sider	7
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms8756
Status	Udgivet - 2015

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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., ... EPIC-InterAct Consortium (2015). Rare coding variants and X-linked loci associated with age at menarche. Nature Communications, 6, Artikel 7756. https://doi.org/10.1038/ncomms8756

@article{a2493aa6aefd4f29a446fa3f0057b605,

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 ∼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.",

author = "Lunetta, {Kathryn L} and Day, {Felix R} and Patrick Sulem and Ruth, {Katherine S} and Tung, {Joyce Y} and Hinds, {David A} and T{\~o}nu Esko and Elks, {Cathy E} and Elisabeth Altmaier and Chunyan He and Huffman, {Jennifer E} and Evelin Mihailov and Eleonora Porcu and Antonietta Robino and Rose, {Lynda M} and Schick, {Ursula M} and Lisette Stolk and Alexander Teumer and Thompson, {Deborah J} and Michela Traglia and Wang, {Carol A} and Yerges-Armstrong, {Laura M} and Antoniou, {Antonis C} and Caterina Barbieri and Coviello, {Andrea D} and Francesco Cucca and Demerath, {Ellen W} and Dunning, {Alison M} and Ilaria Gandin and Grove, {Megan L} and Gudbjartsson, {Daniel F} and Hocking, {Lynne J} and Albert Hofman and Jinyan Huang and Jackson, {Rebecca D} and David Karasik and Jennifer Kriebel and Lange, {Ethan M} and Lange, {Leslie A} and Claudia Langenberg and Xin Li and Jian'an Luan and Reedik M{\"a}gi and Morrison, {Alanna C} and Sandosh Padmanabhan and Ailith Pirie and Ozren Polasek and David Porteous and Reiner, {Alex P} and {EPIC-InterAct Consortium} and Kim Overvad",

year = "2015",

doi = "10.1038/ncomms8756",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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 & EPIC-InterAct Consortium 2015, 'Rare coding variants and X-linked loci associated with age at menarche', Nature Communications, bind 6, 7756. https://doi.org/10.1038/ncomms8756

TY - JOUR

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

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, Tõnu

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 - EPIC-InterAct Consortium

A2 - Overvad, Kim

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 ∼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.

U2 - 10.1038/ncomms8756

DO - 10.1038/ncomms8756

M3 - Journal article

C2 - 26239645

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7756

ER -

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

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