The copy number variation and stroke (CaNVAS) risk and outcome study

John W. Cole; Taiwo Adigun; Rufus Akinyemi; Onoja Matthew Akpa; Steven Bell; Bowang Chen; Jordi Jimenez Conde; Uxue Lazcano Dobao; Israel Fernandez; Myriam Fornage; Cristina Gallego-Fabrega; Christina Jern; Michael Krawczak; Arne Lindgren; Hugh S. Markus; Olle Melander; Mayowa Owolabi; Kristina Schlicht; Martin Söderholm; Vinodh Srinivasasainagendra; Carolina Soriano Tárraga; Martin Stenman; Hemant Tiwari; Margaret Corasaniti; Natalie Fecteau; Beth Guizzardi; Haley Lopez; Kevin Nguyen; Brady Gaynor; Timothy O’Connor; O. Colin Stine; Steven J. Kittner; Patrick McArdle; Braxton D. Mitchell; Huichun Xu; Caspar Grond-Ginsbach

doi:10.1371/journal.pone.0248791

The copy number variation and stroke (CaNVAS) risk and outcome study

John W. Cole, Taiwo Adigun, Rufus Akinyemi, Onoja Matthew Akpa, Steven Bell, Bowang Chen, Jordi Jimenez Conde, Uxue Lazcano Dobao, Israel Fernandez, Myriam Fornage, Cristina Gallego-Fabrega, Christina Jern, Michael Krawczak, Arne Lindgren, Hugh S. Markus, Olle Melander, Mayowa Owolabi, Kristina Schlicht, Martin Söderholm, Vinodh SrinivasasainagendraCarolina Soriano Tárraga, Martin Stenman, Hemant Tiwari, Margaret Corasaniti, Natalie Fecteau, Beth Guizzardi, Haley Lopez, Kevin Nguyen, Brady Gaynor, Timothy O’Connor, O. Colin Stine, Steven J. Kittner, Patrick McArdle, Braxton D. Mitchell, Huichun Xu, Caspar Grond-Ginsbach

Department of Psychiatry

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

2 Scopus citations

Abstract

Background and purpose The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap. Methods Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data. Results The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism. Conclusion The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum.

Original language	English
Article number	e0248791
Journal	PloS one
Volume	16
Issue number	4 April
DOIs	https://doi.org/10.1371/journal.pone.0248791
State	Published - Apr 2021

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Cole, J. W., Adigun, T., Akinyemi, R., Akpa, O. M., Bell, S., Chen, B., Conde, J. J., Dobao, U. L., Fernandez, I., Fornage, M., Gallego-Fabrega, C., Jern, C., Krawczak, M., Lindgren, A., Markus, H. S., Melander, O., Owolabi, M., Schlicht, K., Söderholm, M., ... Grond-Ginsbach, C. (2021). The copy number variation and stroke (CaNVAS) risk and outcome study. PloS one, 16(4 April), Article e0248791. https://doi.org/10.1371/journal.pone.0248791

@article{6e450625c60a46bd95a8a2fc1a5f61ef,

title = "The copy number variation and stroke (CaNVAS) risk and outcome study",

abstract = "Background and purpose The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap. Methods Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data. Results The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism. Conclusion The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum.",

author = "Cole, {John W.} and Taiwo Adigun and Rufus Akinyemi and Akpa, {Onoja Matthew} and Steven Bell and Bowang Chen and Conde, {Jordi Jimenez} and Dobao, {Uxue Lazcano} and Israel Fernandez and Myriam Fornage and Cristina Gallego-Fabrega and Christina Jern and Michael Krawczak and Arne Lindgren and Markus, {Hugh S.} and Olle Melander and Mayowa Owolabi and Kristina Schlicht and Martin S{\"o}derholm and Vinodh Srinivasasainagendra and T{\'a}rraga, {Carolina Soriano} and Martin Stenman and Hemant Tiwari and Margaret Corasaniti and Natalie Fecteau and Beth Guizzardi and Haley Lopez and Kevin Nguyen and Brady Gaynor and Timothy O{\textquoteright}Connor and {Colin Stine}, O. and Kittner, {Steven J.} and Patrick McArdle and Mitchell, {Braxton D.} and Huichun Xu and Caspar Grond-Ginsbach",

note = "Publisher Copyright: Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.",

year = "2021",

month = apr,

doi = "10.1371/journal.pone.0248791",

language = "English",

volume = "16",

journal = "PloS one",

issn = "1932-6203",

number = "4 April",

}

Cole, JW, Adigun, T, Akinyemi, R, Akpa, OM, Bell, S, Chen, B, Conde, JJ, Dobao, UL, Fernandez, I, Fornage, M, Gallego-Fabrega, C, Jern, C, Krawczak, M, Lindgren, A, Markus, HS, Melander, O, Owolabi, M, Schlicht, K, Söderholm, M, Srinivasasainagendra, V, Tárraga, CS, Stenman, M, Tiwari, H, Corasaniti, M, Fecteau, N, Guizzardi, B, Lopez, H, Nguyen, K, Gaynor, B, O’Connor, T, Colin Stine, O, Kittner, SJ, McArdle, P, Mitchell, BD, Xu, H & Grond-Ginsbach, C 2021, 'The copy number variation and stroke (CaNVAS) risk and outcome study', PloS one, vol. 16, no. 4 April, e0248791. https://doi.org/10.1371/journal.pone.0248791

TY - JOUR

T1 - The copy number variation and stroke (CaNVAS) risk and outcome study

AU - Cole, John W.

AU - Adigun, Taiwo

AU - Akinyemi, Rufus

AU - Akpa, Onoja Matthew

AU - Bell, Steven

AU - Chen, Bowang

AU - Conde, Jordi Jimenez

AU - Dobao, Uxue Lazcano

AU - Fernandez, Israel

AU - Fornage, Myriam

AU - Gallego-Fabrega, Cristina

AU - Jern, Christina

AU - Krawczak, Michael

AU - Lindgren, Arne

AU - Markus, Hugh S.

AU - Melander, Olle

AU - Owolabi, Mayowa

AU - Schlicht, Kristina

AU - Söderholm, Martin

AU - Srinivasasainagendra, Vinodh

AU - Tárraga, Carolina Soriano

AU - Stenman, Martin

AU - Tiwari, Hemant

AU - Corasaniti, Margaret

AU - Fecteau, Natalie

AU - Guizzardi, Beth

AU - Lopez, Haley

AU - Nguyen, Kevin

AU - Gaynor, Brady

AU - O’Connor, Timothy

AU - Colin Stine, O.

AU - Kittner, Steven J.

AU - McArdle, Patrick

AU - Mitchell, Braxton D.

AU - Xu, Huichun

AU - Grond-Ginsbach, Caspar

N1 - Publisher Copyright: Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

PY - 2021/4

Y1 - 2021/4

N2 - Background and purpose The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap. Methods Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data. Results The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism. Conclusion The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum.

AB - Background and purpose The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap. Methods Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data. Results The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism. Conclusion The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum.

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U2 - 10.1371/journal.pone.0248791

DO - 10.1371/journal.pone.0248791

M3 - Article

C2 - 33872305

AN - SCOPUS:85104485683

SN - 1932-6203

VL - 16

JO - PloS one

JF - PloS one

IS - 4 April

M1 - e0248791

ER -

The copy number variation and stroke (CaNVAS) risk and outcome study

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