No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis

Christina Loley; Maris Alver; Themistocles L. Assimes; Andrew Bjonnes; Anuj Goel; Stefan Gustafsson; Jussi Hernesniemi; Jemma C. Hopewell; Stavroula Kanoni; Marcus E. Kleber; King Wai Lau; Yingchang Lu; Leo Pekka Lyytikaïnen; Christopher P. Nelson; Majid Nikpay; Liming Qu; Elias Salfati; Markus Scholz; Taru Tukiainen; Christina Willenborg; Hong Hee Won; Lingyao Zeng; Weihua Zhang; Sonia S. Anand; Frank Beutner; Erwin P. Bottinger; Robert Clarke; George Dedoussis; Ron Do; Toñu Esko; Markku Eskola; Martin Farrall; Dominique Gauguier; Vilmantas Giedraitis; Christopher B. Granger; Alistair S. Hall; Anders Hamsten; Stanley L. Hazen; Jie Huang; Mika Kähönen; Theodosios Kyriakou; Reijo Laaksonen; Lars Lind; Cecilia Lindgren; Patrik K.E. Magnusson; Eirini Marouli; Evelin Mihailov; Andrew P. Morris; Kjell Nikus; Nancy Pedersen; Loukianos Rallidis; Veikko Salomaa; Svati H. Shah; Alexandre F.R. Stewart; John R. Thompson; Pierre A. Zalloua; John C. Chambers; Rory Collins; Erik Ingelsson; Carlos Iribarren; Pekka J. Karhunen; Jaspal S. Kooner; Terho Lehtimäki; Ruth J.F. Loos; Winfried März; Ruth McPherson; Andres Metspalu; Muredach P. Reilly; Samuli Ripatti; Dharambir K. Sanghera; Joachim Thiery; Hugh Watkins; Panos Deloukas; Sekar Kathiresan; Nilesh J. Samani; Heribert Schunkert; Jeanette Erdmann; Inke R. König

doi:10.1038/srep35278

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis

Christina Loley
, Maris Alver
, Themistocles L. Assimes
, Andrew Bjonnes
, Anuj Goel
, Stefan Gustafsson
, Jussi Hernesniemi
, Jemma C. Hopewell
, Stavroula Kanoni
, Marcus E. Kleber
, King Wai Lau
, Yingchang Lu
, Leo Pekka Lyytikaïnen
, Christopher P. Nelson
, Majid Nikpay
, Liming Qu
, Elias Salfati
, Markus Scholz
, Taru Tukiainen
, Christina Willenborg

Hong Hee Won, Lingyao Zeng, Weihua Zhang, Sonia S. Anand, Frank Beutner, Erwin P. Bottinger, Robert Clarke, George Dedoussis, Ron Do, Toñu Esko, Markku Eskola, Martin Farrall, Dominique Gauguier, Vilmantas Giedraitis, Christopher B. Granger, Alistair S. Hall, Anders Hamsten, Stanley L. Hazen, Jie Huang, Mika Kähönen, Theodosios Kyriakou, Reijo Laaksonen, Lars Lind, Cecilia Lindgren, Patrik K.E. Magnusson, Eirini Marouli, Evelin Mihailov, Andrew P. Morris, Kjell Nikus, Nancy Pedersen, Loukianos Rallidis, Veikko Salomaa, Svati H. Shah, Alexandre F.R. Stewart, John R. Thompson, Pierre A. Zalloua, John C. Chambers, Rory Collins, Erik Ingelsson, Carlos Iribarren, Pekka J. Karhunen, Jaspal S. Kooner, Terho Lehtimäki, Ruth J.F. Loos, Winfried März, Ruth McPherson, Andres Metspalu, Muredach P. Reilly, Samuli Ripatti, Dharambir K. Sanghera, Joachim Thiery, Hugh Watkins, Panos Deloukas, Sekar Kathiresan, Nilesh J. Samani, Heribert Schunkert, Jeanette Erdmann, Inke R. König

College of Medicine and Health Sciences

University Hospital Schleswig-Holstein
Partner Site Hamburg/Kiel/Lübeck
University of Tartu
Institute of Molecular and Cell Biology
Stanford School of Medicine
Massachusetts General Hospital
University of Oxford Medical Sciences Division
University of Oxford
Uppsala University
Fimlab Laboratories
Tampere University
Barts and The London School of Medicine and Dentistry
University of Heidelberg
Icahn School of Medicine at Mount Sinai
University of Leicester
Glenfield Hospital
University of Ottawa
University of Pennsylvania
University of Leipzig
LIFE Research Center of Civilization Diseases
Broad Institute
Sungkyunkwan University
Deutsches Herzzentrum München
Imperial College London
Ealing Hospital National Health Service (NHS) Trust
Population Health Research Institute, Ontario
Harokopio University of Athens
Harvard Medical School
Centre de Recherche des Cordeliers
Uppsala Universit
Duke University
University of Leeds, School of Medicine
Karolinska Inst., Novum, KFC, P.
Cleveland Clinic Foundation
Boston VA Research Institute
Tampere University Hospital
Zora Biosciences
Harvard University
University of Liverpool
University General Hospital Attikon
National Institute for Health and Welfare
Imperial College NHS Trust
Kaiser Permanente Northern California
National Heart and Lung Institute
Synlab Academy
Medical University of Graz
University of Pennsylvania Philadelphia
University of Helsinki
University of Oklahoma Health Sciences Center
University of Oklahoma
Oklahoma Center for Neuroscience
Leipzig University Hospital
Wellcome Trust Sanger Institute
King Abdulaziz University

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

Original language	British English
Article number	35278
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep35278
State	Published - 12 Oct 2016

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Loley, C., Alver, M., Assimes, T. L., Bjonnes, A., Goel, A., Gustafsson, S., Hernesniemi, J., Hopewell, J. C., Kanoni, S., Kleber, M. E., Lau, K. W., Lu, Y., Lyytikaïnen, L. P., Nelson, C. P., Nikpay, M., Qu, L., Salfati, E., Scholz, M., Tukiainen, T., ... König, I. R. (2016). No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis. Scientific Reports, 6, Article 35278. https://doi.org/10.1038/srep35278

@article{e63d61b9949b4c0f92684179623d38ef,

title = "No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis",

abstract = "In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.",

author = "Christina Loley and Maris Alver and Assimes, \{Themistocles L.\} and Andrew Bjonnes and Anuj Goel and Stefan Gustafsson and Jussi Hernesniemi and Hopewell, \{Jemma C.\} and Stavroula Kanoni and Kleber, \{Marcus E.\} and Lau, \{King Wai\} and Yingchang Lu and Lyytika{\"i}nen, \{Leo Pekka\} and Nelson, \{Christopher P.\} and Majid Nikpay and Liming Qu and Elias Salfati and Markus Scholz and Taru Tukiainen and Christina Willenborg and Won, \{Hong Hee\} and Lingyao Zeng and Weihua Zhang and Anand, \{Sonia S.\} and Frank Beutner and Bottinger, \{Erwin P.\} and Robert Clarke and George Dedoussis and Ron Do and To{\~n}u Esko and Markku Eskola and Martin Farrall and Dominique Gauguier and Vilmantas Giedraitis and Granger, \{Christopher B.\} and Hall, \{Alistair S.\} and Anders Hamsten and Hazen, \{Stanley L.\} and Jie Huang and Mika K{\"a}h{\"o}nen and Theodosios Kyriakou and Reijo Laaksonen and Lars Lind and Cecilia Lindgren and Magnusson, \{Patrik K.E.\} and Eirini Marouli and Evelin Mihailov and Morris, \{Andrew P.\} and Kjell Nikus and Nancy Pedersen and Loukianos Rallidis and Veikko Salomaa and Shah, \{Svati H.\} and Stewart, \{Alexandre F.R.\} and Thompson, \{John R.\} and Zalloua, \{Pierre A.\} and Chambers, \{John C.\} and Rory Collins and Erik Ingelsson and Carlos Iribarren and Karhunen, \{Pekka J.\} and Kooner, \{Jaspal S.\} and Terho Lehtim{\"a}ki and Loos, \{Ruth J.F.\} and Winfried M{\"a}rz and Ruth McPherson and Andres Metspalu and Reilly, \{Muredach P.\} and Samuli Ripatti and Sanghera, \{Dharambir K.\} and Joachim Thiery and Hugh Watkins and Panos Deloukas and Sekar Kathiresan and Samani, \{Nilesh J.\} and Heribert Schunkert and Jeanette Erdmann and K{\"o}nig, \{Inke R.\}",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = oct,

day = "12",

doi = "10.1038/srep35278",

language = "British English",

volume = "6",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Research",

}

Loley, C, Alver, M, Assimes, TL, Bjonnes, A, Goel, A, Gustafsson, S, Hernesniemi, J, Hopewell, JC, Kanoni, S, Kleber, ME, Lau, KW, Lu, Y, Lyytikaïnen, LP, Nelson, CP, Nikpay, M, Qu, L, Salfati, E, Scholz, M, Tukiainen, T, Willenborg, C, Won, HH, Zeng, L, Zhang, W, Anand, SS, Beutner, F, Bottinger, EP, Clarke, R, Dedoussis, G, Do, R, Esko, T, Eskola, M, Farrall, M, Gauguier, D, Giedraitis, V, Granger, CB, Hall, AS, Hamsten, A, Hazen, SL, Huang, J, Kähönen, M, Kyriakou, T, Laaksonen, R, Lind, L, Lindgren, C, Magnusson, PKE, Marouli, E, Mihailov, E, Morris, AP, Nikus, K, Pedersen, N, Rallidis, L, Salomaa, V, Shah, SH, Stewart, AFR, Thompson, JR, Zalloua, PA, Chambers, JC, Collins, R, Ingelsson, E, Iribarren, C, Karhunen, PJ, Kooner, JS, Lehtimäki, T, Loos, RJF, März, W, McPherson, R, Metspalu, A, Reilly, MP, Ripatti, S, Sanghera, DK, Thiery, J, Watkins, H, Deloukas, P, Kathiresan, S, Samani, NJ, Schunkert, H, Erdmann, J & König, IR 2016, 'No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis', Scientific Reports, vol. 6, 35278. https://doi.org/10.1038/srep35278

TY - JOUR

T1 - No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis

AU - Loley, Christina

AU - Alver, Maris

AU - Assimes, Themistocles L.

AU - Bjonnes, Andrew

AU - Goel, Anuj

AU - Gustafsson, Stefan

AU - Hernesniemi, Jussi

AU - Hopewell, Jemma C.

AU - Kanoni, Stavroula

AU - Kleber, Marcus E.

AU - Lau, King Wai

AU - Lu, Yingchang

AU - Lyytikaïnen, Leo Pekka

AU - Nelson, Christopher P.

AU - Nikpay, Majid

AU - Qu, Liming

AU - Salfati, Elias

AU - Scholz, Markus

AU - Tukiainen, Taru

AU - Willenborg, Christina

AU - Won, Hong Hee

AU - Zeng, Lingyao

AU - Zhang, Weihua

AU - Anand, Sonia S.

AU - Beutner, Frank

AU - Bottinger, Erwin P.

AU - Clarke, Robert

AU - Dedoussis, George

AU - Do, Ron

AU - Esko, Toñu

AU - Eskola, Markku

AU - Farrall, Martin

AU - Gauguier, Dominique

AU - Giedraitis, Vilmantas

AU - Granger, Christopher B.

AU - Hall, Alistair S.

AU - Hamsten, Anders

AU - Hazen, Stanley L.

AU - Huang, Jie

AU - Kähönen, Mika

AU - Kyriakou, Theodosios

AU - Laaksonen, Reijo

AU - Lind, Lars

AU - Lindgren, Cecilia

AU - Magnusson, Patrik K.E.

AU - Marouli, Eirini

AU - Mihailov, Evelin

AU - Morris, Andrew P.

AU - Nikus, Kjell

AU - Pedersen, Nancy

AU - Rallidis, Loukianos

AU - Salomaa, Veikko

AU - Shah, Svati H.

AU - Stewart, Alexandre F.R.

AU - Thompson, John R.

AU - Zalloua, Pierre A.

AU - Chambers, John C.

AU - Collins, Rory

AU - Ingelsson, Erik

AU - Iribarren, Carlos

AU - Karhunen, Pekka J.

AU - Kooner, Jaspal S.

AU - Lehtimäki, Terho

AU - Loos, Ruth J.F.

AU - März, Winfried

AU - McPherson, Ruth

AU - Metspalu, Andres

AU - Reilly, Muredach P.

AU - Ripatti, Samuli

AU - Sanghera, Dharambir K.

AU - Thiery, Joachim

AU - Watkins, Hugh

AU - Deloukas, Panos

AU - Kathiresan, Sekar

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - König, Inke R.

PY - 2016/10/12

Y1 - 2016/10/12

N2 - In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

AB - In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

UR - https://www.scopus.com/pages/publications/84991063114

U2 - 10.1038/srep35278

DO - 10.1038/srep35278

M3 - Article

C2 - 27731410

AN - SCOPUS:84991063114

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 35278

ER -

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis

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