White matter lesion progression: genome-wide search for genetic influences

Edith Hofer; Margherita Cavalieri; Joshua C Bis; Charles DeCarli; Myriam Fornage; Sigurdur Sigurdsson; Velandai Srikanth; Stella Trompet; Benjamin F J Verhaaren; Christiane Wolf; Qiong Yang; Hieab H H Adams; Philippe Amouyel; Alexa Beiser; Brendan M Buckley; Michele Callisaya; Ganesh Chauhan; Anton J M de Craen; Carole Dufouil; Cornelia M van Duijn; Ian Ford; Paul Freudenberger; Rebecca F Gottesman; Vilmundur Gudnason; Gerardo Heiss; Albert Hofman; Thomas Lumley; Oliver Martinez; Bernard Mazoyer; Chris Moran; Wiro J. Niessen; Thanh Phan; Bruce M Psaty; Claudia L Satizabal; Naveed Sattar; Sabrina Schilling; Dean K Shibata; P Eline Slagboom; Albert Smith; David J Stott; Kent D Taylor; Russell Thomson; Anna M Töglhofer; Christophe Tzourio; Mark van Buchem; Jing Wang; Rudi G. J. Westendorp; B Gwen Windham; Meike W Vernooij; Alex Zijdenbos; Richard Beare; Stéphanie Debette; M Arfan Ikram; J Wouter Jukema; Lenore J Launer; W T Longstreth; Thomas H Mosley; Sudha Seshadri; Helena Schmidt; Reinhold Schmidt

doi:10.1161/STROKEAHA.115.009252

White matter lesion progression: genome-wide search for genetic influences

Edith Hofer, Margherita Cavalieri, Joshua C Bis, Charles DeCarli, Myriam Fornage, Sigurdur Sigurdsson, Velandai Srikanth, Stella Trompet, Benjamin F J Verhaaren, Christiane Wolf, Qiong Yang, Hieab H H Adams, Philippe Amouyel, Alexa Beiser, Brendan M Buckley, Michele Callisaya, Ganesh Chauhan, Anton J M de Craen, Carole Dufouil, Cornelia M van DuijnIan Ford, Paul Freudenberger, Rebecca F Gottesman, Vilmundur Gudnason, Gerardo Heiss, Albert Hofman, Thomas Lumley, Oliver Martinez, Bernard Mazoyer, Chris Moran, Wiro J. Niessen, Thanh Phan, Bruce M Psaty, Claudia L Satizabal, Naveed Sattar, Sabrina Schilling, Dean K Shibata, P Eline Slagboom, Albert Smith, David J Stott, Kent D Taylor, Russell Thomson, Anna M Töglhofer, Christophe Tzourio, Mark van Buchem, Jing Wang, Rudi G. J. Westendorp, B Gwen Windham, Meike W Vernooij, Alex Zijdenbos, Richard Beare, Stéphanie Debette, M Arfan Ikram, J Wouter Jukema, Lenore J Launer, W T Longstreth, Thomas H Mosley, Sudha Seshadri, Helena Schmidt, Reinhold Schmidt

17 Citations (Scopus)

Abstract

Background and Purpose-White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results-A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10^-8). Four loci were suggestive (P<1×10^-5) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10^-6); 12q13.13 (rs4761974, P=8.71×10^-7); 20p12.1 (rs6135309, P=3.69×10^-6); and 4p15.31 (rs7664442, P=2.26×10^-6). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. Conclusions-Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

Original language	English
Journal	Stroke
Volume	46
Pages (from-to)	3048-3057
Number of pages	10
ISSN	0039-2499
DOIs	https://doi.org/10.1161/STROKEAHA.115.009252
Publication status	Published - 1 Nov 2015

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Hofer, E., Cavalieri, M., Bis, J. C., DeCarli, C., Fornage, M., Sigurdsson, S., Srikanth, V., Trompet, S., Verhaaren, B. F. J., Wolf, C., Yang, Q., Adams, H. H. H., Amouyel, P., Beiser, A., Buckley, B. M., Callisaya, M., Chauhan, G., de Craen, A. J. M., Dufouil, C., ... Schmidt, R. (2015). White matter lesion progression: genome-wide search for genetic influences. Stroke, 46, 3048-3057. https://doi.org/10.1161/STROKEAHA.115.009252

Hofer, E, Cavalieri, M, Bis, JC, DeCarli, C, Fornage, M, Sigurdsson, S, Srikanth, V, Trompet, S, Verhaaren, BFJ, Wolf, C, Yang, Q, Adams, HHH, Amouyel, P, Beiser, A, Buckley, BM, Callisaya, M, Chauhan, G, de Craen, AJM, Dufouil, C, van Duijn, CM, Ford, I, Freudenberger, P, Gottesman, RF, Gudnason, V, Heiss, G, Hofman, A, Lumley, T, Martinez, O, Mazoyer, B, Moran, C, Niessen, WJ, Phan, T, Psaty, BM, Satizabal, CL, Sattar, N, Schilling, S, Shibata, DK, Slagboom, PE, Smith, A, Stott, DJ, Taylor, KD, Thomson, R, Töglhofer, AM, Tzourio, C, van Buchem, M, Wang, J, Westendorp, RGJ, Windham, BG, Vernooij, MW, Zijdenbos, A, Beare, R, Debette, S, Ikram, MA, Jukema, JW, Launer, LJ, Longstreth, WT, Mosley, TH, Seshadri, S, Schmidt, H & Schmidt, R 2015, 'White matter lesion progression: genome-wide search for genetic influences', Stroke, vol. 46, pp. 3048-3057. https://doi.org/10.1161/STROKEAHA.115.009252

@article{ae60886fa26b4b518b9bbbd172cbf73e,

title = "White matter lesion progression: genome-wide search for genetic influences",

abstract = "Background and Purpose-White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results-A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10-8). Four loci were suggestive (P<1×10-5) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10-6); 12q13.13 (rs4761974, P=8.71×10-7); 20p12.1 (rs6135309, P=3.69×10-6); and 4p15.31 (rs7664442, P=2.26×10-6). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. Conclusions-Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.",

author = "Edith Hofer and Margherita Cavalieri and Bis, {Joshua C} and Charles DeCarli and Myriam Fornage and Sigurdur Sigurdsson and Velandai Srikanth and Stella Trompet and Verhaaren, {Benjamin F J} and Christiane Wolf and Qiong Yang and Adams, {Hieab H H} and Philippe Amouyel and Alexa Beiser and Buckley, {Brendan M} and Michele Callisaya and Ganesh Chauhan and {de Craen}, {Anton J M} and Carole Dufouil and {van Duijn}, {Cornelia M} and Ian Ford and Paul Freudenberger and Gottesman, {Rebecca F} and Vilmundur Gudnason and Gerardo Heiss and Albert Hofman and Thomas Lumley and Oliver Martinez and Bernard Mazoyer and Chris Moran and Niessen, {Wiro J.} and Thanh Phan and Psaty, {Bruce M} and Satizabal, {Claudia L} and Naveed Sattar and Sabrina Schilling and Shibata, {Dean K} and Slagboom, {P Eline} and Albert Smith and Stott, {David J} and Taylor, {Kent D} and Russell Thomson and T{\"o}glhofer, {Anna M} and Christophe Tzourio and {van Buchem}, Mark and Jing Wang and Westendorp, {Rudi G. J.} and Windham, {B Gwen} and Vernooij, {Meike W} and Alex Zijdenbos and Richard Beare and St{\'e}phanie Debette and Ikram, {M Arfan} and Jukema, {J Wouter} and Launer, {Lenore J} and Longstreth, {W T} and Mosley, {Thomas H} and Sudha Seshadri and Helena Schmidt and Reinhold Schmidt",

note = "{\textcopyright} 2015 American Heart Association, Inc.",

year = "2015",

month = nov,

day = "1",

doi = "10.1161/STROKEAHA.115.009252",

language = "English",

volume = "46",

pages = "3048--3057",

journal = "Stroke",

issn = "0039-2499",

publisher = "Lippincott Williams & Wilkins",

}

TY - JOUR

T1 - White matter lesion progression

T2 - genome-wide search for genetic influences

AU - Hofer, Edith

AU - Cavalieri, Margherita

AU - Bis, Joshua C

AU - DeCarli, Charles

AU - Fornage, Myriam

AU - Sigurdsson, Sigurdur

AU - Srikanth, Velandai

AU - Trompet, Stella

AU - Verhaaren, Benjamin F J

AU - Wolf, Christiane

AU - Yang, Qiong

AU - Adams, Hieab H H

AU - Amouyel, Philippe

AU - Beiser, Alexa

AU - Buckley, Brendan M

AU - Callisaya, Michele

AU - Chauhan, Ganesh

AU - de Craen, Anton J M

AU - Dufouil, Carole

AU - van Duijn, Cornelia M

AU - Ford, Ian

AU - Freudenberger, Paul

AU - Gottesman, Rebecca F

AU - Gudnason, Vilmundur

AU - Heiss, Gerardo

AU - Hofman, Albert

AU - Lumley, Thomas

AU - Martinez, Oliver

AU - Mazoyer, Bernard

AU - Moran, Chris

AU - Niessen, Wiro J.

AU - Phan, Thanh

AU - Psaty, Bruce M

AU - Satizabal, Claudia L

AU - Sattar, Naveed

AU - Schilling, Sabrina

AU - Shibata, Dean K

AU - Slagboom, P Eline

AU - Smith, Albert

AU - Stott, David J

AU - Taylor, Kent D

AU - Thomson, Russell

AU - Töglhofer, Anna M

AU - Tzourio, Christophe

AU - van Buchem, Mark

AU - Wang, Jing

AU - Westendorp, Rudi G. J.

AU - Windham, B Gwen

AU - Vernooij, Meike W

AU - Zijdenbos, Alex

AU - Beare, Richard

AU - Debette, Stéphanie

AU - Ikram, M Arfan

AU - Jukema, J Wouter

AU - Launer, Lenore J

AU - Longstreth, W T

AU - Mosley, Thomas H

AU - Seshadri, Sudha

AU - Schmidt, Helena

AU - Schmidt, Reinhold

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Background and Purpose-White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results-A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10-8). Four loci were suggestive (P<1×10-5) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10-6); 12q13.13 (rs4761974, P=8.71×10-7); 20p12.1 (rs6135309, P=3.69×10-6); and 4p15.31 (rs7664442, P=2.26×10-6). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. Conclusions-Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

AB - Background and Purpose-White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results-A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10-8). Four loci were suggestive (P<1×10-5) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10-6); 12q13.13 (rs4761974, P=8.71×10-7); 20p12.1 (rs6135309, P=3.69×10-6); and 4p15.31 (rs7664442, P=2.26×10-6). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. Conclusions-Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

U2 - 10.1161/STROKEAHA.115.009252

DO - 10.1161/STROKEAHA.115.009252

M3 - Journal article

C2 - 26451028

SN - 0039-2499

VL - 46

SP - 3048

EP - 3057

JO - Stroke

JF - Stroke

ER -

White matter lesion progression: genome-wide search for genetic influences

Abstract

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