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

Generation Scotland, InterAct Consortium

doi:10.1038/ncomms8756

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

Generation Scotland, InterAct Consortium

Applied Medicine

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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 ~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 language	English
Article number	7756
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8756
Publication status	Published - 4 Aug 2015

Bibliographical note

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Keywords

biological sciences
genetics

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Rare coding variants and X-linked loci associated with age at menarche
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license,users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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Cite this

@article{8662e0c62b3242c889e012d10fcbdf09,

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 {\textquoteleft}missing heritability{\textquoteright} of this complex trait.",

keywords = "biological sciences, genetics",

author = "Lunetta, {Kathryn L.} and Day, {Felix R.} and Patrick Sulem and Ruth, {Katherine S.} and Tung, {Joyce Y.} and Hinds, {David A.} and Tonu Esko and Elks, {Cathy E.} and Elisabeth Altmaier and Chunyan He and Huffman, {Jennifer E} and Evelin Mihailov and Eleanora Porcu and Antoinetta Robino and Rose, {Lynda M.} and Ursula Schick and Lisette Stolk and Alexander Tuemer 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 Li Xin and Jian'an Luan and Reedik M{\"a}gi and Morrison, {Alana C.} and Sandosh Padmanabhan and Ailith Pirie and Ozren Polasek and David Porteous and Reiner, {David P.} and Fernando Rivadeneira and {Generation Scotland, InterAct Consortium}",

note = "This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. ",

year = "2015",

month = aug,

day = "4",

doi = "10.1038/ncomms8756",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

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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, Tonu

AU - Elks, Cathy E.

AU - Altmaier, Elisabeth

AU - He, Chunyan

AU - Huffman, Jennifer E

AU - Mihailov, Evelin

AU - Porcu, Eleanora

AU - Robino, Antoinetta

AU - Rose, Lynda M.

AU - Schick, Ursula

AU - Stolk, Lisette

AU - Tuemer, 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 - Xin, Li

AU - Luan, Jian'an

AU - Mägi, Reedik

AU - Morrison, Alana C.

AU - Padmanabhan, Sandosh

AU - Pirie, Ailith

AU - Polasek, Ozren

AU - Porteous, David

AU - Reiner, David P.

AU - Rivadeneira, Fernando

AU - Generation Scotland, InterAct Consortium

N1 - This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.

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.

KW - biological sciences

KW - genetics

U2 - 10.1038/ncomms8756

DO - 10.1038/ncomms8756

M3 - Article

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

Abstract

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Keywords

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