Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

Benjamin F J Verhaaren, Stéphanie Debette, Joshua C. Bis, Jennifer A. Smith, M. Kamran Ikram, Hieab H. Adams, Ashley H. Beecham, Kumar B. Rajan, Lorna M. Lopez, Sandra Barral, Mark A. Van Buchem, Jeroen Van Der Grond, Albert V. Smith, Katrin Hegenscheid, Neelum T. Aggarwal, Mariza De Andrade, Elizabeth J. Atkinson, Marian Beekman, Alexa S. Beiser, Susan H. BlantonEric Boerwinkle, Adam M. Brickman, R. Nick Bryan, Ganesh Chauhan, Christopher P L H Chen, Vincent Chouraki, Anton J M De Craen, Fabrice Crivello, Ian J. Deary, Joris Deelen, Philip L. De Jager, Carole Dufouil, Mitchell S V Elkind, Denis A. Evans, Paul Freudenberger, Rebecca F. Gottesman, Vilmundur Gunason, Mohamad Habes, Susan R. Heckbert, Gerardo Heiss, Saima Hilal, Edith Hofer, Albert Hofman, Carla A. Ibrahim-Verbaas, David S Knopman, Cora E. Lewis, Jiemin Liao, David C M Liewald, Michelle Luciano, Aad Van Der Lugt, Oliver O. Martinez, Richard Mayeux, Bernard Mazoyer, Mike Nalls, Matthias Nauck, Wiro J. Niessen, Ben A. Oostra, Bruce M. Psaty, Kenneth M. Rice, Jerome I. Rotter, Bettina Von Sarnowski, Helena Schmidt, Pamela J. Schreiner, Maaike Schuur, Stephen S. Sidney, Sigurdur Sigurdsson, P. Eline Slagboom, David J M Stott, John C. Van Swieten, Alexander Teumer, Anna Maria Töglhofer, Matthew Traylor, Stella Trompet, Stephen T Turner, Christophe Tzourio, Hae Won Uh, André G. Uitterlinden, Meike W. Vernooij, Jing J. Wang, Tien Y. Wong, Joanna M. Wardlaw, B. Gwen Windham, Katharina Wittfeld, Christiane Wolf, Clinton B. Wright, Qiong Yang, Wei Zhao, Alex Zijdenbos, J. Wouter Jukema, Ralph L. Sacco, Sharon L R Kardia, Philippe Amouyel, Thomas H. Mosley, W. T. Longstreth, Charles C. DeCarli, Cornelia M. Van Duijn, Reinhold Schmidt, Lenore J. Launer, Hans J. Grabe, Sudha S. Seshadri, M. Arfan Ikram, Myriam Fornage

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Background-The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results-We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10-19) and identified novel loci on chr10q24 (P=1.6×10-9) and chr2p21 (P=4.4×10-8). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10-8) and chr2p16 (P=1.5×10-8). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions-We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

Original languageEnglish (US)
Pages (from-to)398-409
Number of pages12
JournalCirculation: Cardiovascular Genetics
Volume8
Issue number2
DOIs
StatePublished - Apr 4 2015

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Dementia
Linear Models
Stroke
Genetic Loci
Cerebral Hemorrhage
Hispanic Americans
Ethnic Groups
Glioma
Neuroglia
Single Nucleotide Polymorphism
White Matter
Alzheimer Disease
Genotype
Genome
Population
Genes

Keywords

  • cerebral small vessel diseases
  • cerebrovascular disorders
  • genome-wide association study
  • hypertension
  • leukoencephalopathies
  • polymorphisms, single nucleotide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Verhaaren, B. F. J., Debette, S., Bis, J. C., Smith, J. A., Ikram, M. K., Adams, H. H., ... Fornage, M. (2015). Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI. Circulation: Cardiovascular Genetics, 8(2), 398-409. https://doi.org/10.1161/CIRCGENETICS.114.000858

Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI. / Verhaaren, Benjamin F J; Debette, Stéphanie; Bis, Joshua C.; Smith, Jennifer A.; Ikram, M. Kamran; Adams, Hieab H.; Beecham, Ashley H.; Rajan, Kumar B.; Lopez, Lorna M.; Barral, Sandra; Van Buchem, Mark A.; Van Der Grond, Jeroen; Smith, Albert V.; Hegenscheid, Katrin; Aggarwal, Neelum T.; De Andrade, Mariza; Atkinson, Elizabeth J.; Beekman, Marian; Beiser, Alexa S.; Blanton, Susan H.; Boerwinkle, Eric; Brickman, Adam M.; Bryan, R. Nick; Chauhan, Ganesh; Chen, Christopher P L H; Chouraki, Vincent; De Craen, Anton J M; Crivello, Fabrice; Deary, Ian J.; Deelen, Joris; De Jager, Philip L.; Dufouil, Carole; Elkind, Mitchell S V; Evans, Denis A.; Freudenberger, Paul; Gottesman, Rebecca F.; Gunason, Vilmundur; Habes, Mohamad; Heckbert, Susan R.; Heiss, Gerardo; Hilal, Saima; Hofer, Edith; Hofman, Albert; Ibrahim-Verbaas, Carla A.; Knopman, David S; Lewis, Cora E.; Liao, Jiemin; Liewald, David C M; Luciano, Michelle; Van Der Lugt, Aad; Martinez, Oliver O.; Mayeux, Richard; Mazoyer, Bernard; Nalls, Mike; Nauck, Matthias; Niessen, Wiro J.; Oostra, Ben A.; Psaty, Bruce M.; Rice, Kenneth M.; Rotter, Jerome I.; Von Sarnowski, Bettina; Schmidt, Helena; Schreiner, Pamela J.; Schuur, Maaike; Sidney, Stephen S.; Sigurdsson, Sigurdur; Slagboom, P. Eline; Stott, David J M; Van Swieten, John C.; Teumer, Alexander; Töglhofer, Anna Maria; Traylor, Matthew; Trompet, Stella; Turner, Stephen T; Tzourio, Christophe; Uh, Hae Won; Uitterlinden, André G.; Vernooij, Meike W.; Wang, Jing J.; Wong, Tien Y.; Wardlaw, Joanna M.; Windham, B. Gwen; Wittfeld, Katharina; Wolf, Christiane; Wright, Clinton B.; Yang, Qiong; Zhao, Wei; Zijdenbos, Alex; Jukema, J. Wouter; Sacco, Ralph L.; Kardia, Sharon L R; Amouyel, Philippe; Mosley, Thomas H.; Longstreth, W. T.; DeCarli, Charles C.; Van Duijn, Cornelia M.; Schmidt, Reinhold; Launer, Lenore J.; Grabe, Hans J.; Seshadri, Sudha S.; Ikram, M. Arfan; Fornage, Myriam.

In: Circulation: Cardiovascular Genetics, Vol. 8, No. 2, 04.04.2015, p. 398-409.

Research output: Contribution to journalArticle

Verhaaren, BFJ, Debette, S, Bis, JC, Smith, JA, Ikram, MK, Adams, HH, Beecham, AH, Rajan, KB, Lopez, LM, Barral, S, Van Buchem, MA, Van Der Grond, J, Smith, AV, Hegenscheid, K, Aggarwal, NT, De Andrade, M, Atkinson, EJ, Beekman, M, Beiser, AS, Blanton, SH, Boerwinkle, E, Brickman, AM, Bryan, RN, Chauhan, G, Chen, CPLH, Chouraki, V, De Craen, AJM, Crivello, F, Deary, IJ, Deelen, J, De Jager, PL, Dufouil, C, Elkind, MSV, Evans, DA, Freudenberger, P, Gottesman, RF, Gunason, V, Habes, M, Heckbert, SR, Heiss, G, Hilal, S, Hofer, E, Hofman, A, Ibrahim-Verbaas, CA, Knopman, DS, Lewis, CE, Liao, J, Liewald, DCM, Luciano, M, Van Der Lugt, A, Martinez, OO, Mayeux, R, Mazoyer, B, Nalls, M, Nauck, M, Niessen, WJ, Oostra, BA, Psaty, BM, Rice, KM, Rotter, JI, Von Sarnowski, B, Schmidt, H, Schreiner, PJ, Schuur, M, Sidney, SS, Sigurdsson, S, Slagboom, PE, Stott, DJM, Van Swieten, JC, Teumer, A, Töglhofer, AM, Traylor, M, Trompet, S, Turner, ST, Tzourio, C, Uh, HW, Uitterlinden, AG, Vernooij, MW, Wang, JJ, Wong, TY, Wardlaw, JM, Windham, BG, Wittfeld, K, Wolf, C, Wright, CB, Yang, Q, Zhao, W, Zijdenbos, A, Jukema, JW, Sacco, RL, Kardia, SLR, Amouyel, P, Mosley, TH, Longstreth, WT, DeCarli, CC, Van Duijn, CM, Schmidt, R, Launer, LJ, Grabe, HJ, Seshadri, SS, Ikram, MA & Fornage, M 2015, 'Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI', Circulation: Cardiovascular Genetics, vol. 8, no. 2, pp. 398-409. https://doi.org/10.1161/CIRCGENETICS.114.000858
Verhaaren, Benjamin F J ; Debette, Stéphanie ; Bis, Joshua C. ; Smith, Jennifer A. ; Ikram, M. Kamran ; Adams, Hieab H. ; Beecham, Ashley H. ; Rajan, Kumar B. ; Lopez, Lorna M. ; Barral, Sandra ; Van Buchem, Mark A. ; Van Der Grond, Jeroen ; Smith, Albert V. ; Hegenscheid, Katrin ; Aggarwal, Neelum T. ; De Andrade, Mariza ; Atkinson, Elizabeth J. ; Beekman, Marian ; Beiser, Alexa S. ; Blanton, Susan H. ; Boerwinkle, Eric ; Brickman, Adam M. ; Bryan, R. Nick ; Chauhan, Ganesh ; Chen, Christopher P L H ; Chouraki, Vincent ; De Craen, Anton J M ; Crivello, Fabrice ; Deary, Ian J. ; Deelen, Joris ; De Jager, Philip L. ; Dufouil, Carole ; Elkind, Mitchell S V ; Evans, Denis A. ; Freudenberger, Paul ; Gottesman, Rebecca F. ; Gunason, Vilmundur ; Habes, Mohamad ; Heckbert, Susan R. ; Heiss, Gerardo ; Hilal, Saima ; Hofer, Edith ; Hofman, Albert ; Ibrahim-Verbaas, Carla A. ; Knopman, David S ; Lewis, Cora E. ; Liao, Jiemin ; Liewald, David C M ; Luciano, Michelle ; Van Der Lugt, Aad ; Martinez, Oliver O. ; Mayeux, Richard ; Mazoyer, Bernard ; Nalls, Mike ; Nauck, Matthias ; Niessen, Wiro J. ; Oostra, Ben A. ; Psaty, Bruce M. ; Rice, Kenneth M. ; Rotter, Jerome I. ; Von Sarnowski, Bettina ; Schmidt, Helena ; Schreiner, Pamela J. ; Schuur, Maaike ; Sidney, Stephen S. ; Sigurdsson, Sigurdur ; Slagboom, P. Eline ; Stott, David J M ; Van Swieten, John C. ; Teumer, Alexander ; Töglhofer, Anna Maria ; Traylor, Matthew ; Trompet, Stella ; Turner, Stephen T ; Tzourio, Christophe ; Uh, Hae Won ; Uitterlinden, André G. ; Vernooij, Meike W. ; Wang, Jing J. ; Wong, Tien Y. ; Wardlaw, Joanna M. ; Windham, B. Gwen ; Wittfeld, Katharina ; Wolf, Christiane ; Wright, Clinton B. ; Yang, Qiong ; Zhao, Wei ; Zijdenbos, Alex ; Jukema, J. Wouter ; Sacco, Ralph L. ; Kardia, Sharon L R ; Amouyel, Philippe ; Mosley, Thomas H. ; Longstreth, W. T. ; DeCarli, Charles C. ; Van Duijn, Cornelia M. ; Schmidt, Reinhold ; Launer, Lenore J. ; Grabe, Hans J. ; Seshadri, Sudha S. ; Ikram, M. Arfan ; Fornage, Myriam. / Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI. In: Circulation: Cardiovascular Genetics. 2015 ; Vol. 8, No. 2. pp. 398-409.
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abstract = "Background-The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results-We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10-19) and identified novel loci on chr10q24 (P=1.6×10-9) and chr2p21 (P=4.4×10-8). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10-8) and chr2p16 (P=1.5×10-8). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions-We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.",
keywords = "cerebral small vessel diseases, cerebrovascular disorders, genome-wide association study, hypertension, leukoencephalopathies, polymorphisms, single nucleotide",
author = "Verhaaren, {Benjamin F J} and St{\'e}phanie Debette and Bis, {Joshua C.} and Smith, {Jennifer A.} and Ikram, {M. Kamran} and Adams, {Hieab H.} and Beecham, {Ashley H.} and Rajan, {Kumar B.} and Lopez, {Lorna M.} and Sandra Barral and {Van Buchem}, {Mark A.} and {Van Der Grond}, Jeroen and Smith, {Albert V.} and Katrin Hegenscheid and Aggarwal, {Neelum T.} and {De Andrade}, Mariza and Atkinson, {Elizabeth J.} and Marian Beekman and Beiser, {Alexa S.} and Blanton, {Susan H.} and Eric Boerwinkle and Brickman, {Adam M.} and Bryan, {R. Nick} and Ganesh Chauhan and Chen, {Christopher P L H} and Vincent Chouraki and {De Craen}, {Anton J M} and Fabrice Crivello and Deary, {Ian J.} and Joris Deelen and {De Jager}, {Philip L.} and Carole Dufouil and Elkind, {Mitchell S V} and Evans, {Denis A.} and Paul Freudenberger and Gottesman, {Rebecca F.} and Vilmundur Gunason and Mohamad Habes and Heckbert, {Susan R.} and Gerardo Heiss and Saima Hilal and Edith Hofer and Albert Hofman and Ibrahim-Verbaas, {Carla A.} and Knopman, {David S} and Lewis, {Cora E.} and Jiemin Liao and Liewald, {David C M} and Michelle Luciano and {Van Der Lugt}, Aad and Martinez, {Oliver O.} and Richard Mayeux and Bernard Mazoyer and Mike Nalls and Matthias Nauck and Niessen, {Wiro J.} and Oostra, {Ben A.} and Psaty, {Bruce M.} and Rice, {Kenneth M.} and Rotter, {Jerome I.} and {Von Sarnowski}, Bettina and Helena Schmidt and Schreiner, {Pamela J.} and Maaike Schuur and Sidney, {Stephen S.} and Sigurdur Sigurdsson and Slagboom, {P. Eline} and Stott, {David J M} and {Van Swieten}, {John C.} and Alexander Teumer and T{\"o}glhofer, {Anna Maria} and Matthew Traylor and Stella Trompet and Turner, {Stephen T} and Christophe Tzourio and Uh, {Hae Won} and Uitterlinden, {Andr{\'e} G.} and Vernooij, {Meike W.} and Wang, {Jing J.} and Wong, {Tien Y.} and Wardlaw, {Joanna M.} and Windham, {B. Gwen} and Katharina Wittfeld and Christiane Wolf and Wright, {Clinton B.} and Qiong Yang and Wei Zhao and Alex Zijdenbos and Jukema, {J. Wouter} and Sacco, {Ralph L.} and Kardia, {Sharon L R} and Philippe Amouyel and Mosley, {Thomas H.} and Longstreth, {W. T.} and DeCarli, {Charles C.} and {Van Duijn}, {Cornelia M.} and Reinhold Schmidt and Launer, {Lenore J.} and Grabe, {Hans J.} and Seshadri, {Sudha S.} and Ikram, {M. Arfan} and Myriam Fornage",
year = "2015",
month = "4",
day = "4",
doi = "10.1161/CIRCGENETICS.114.000858",
language = "English (US)",
volume = "8",
pages = "398--409",
journal = "Circulation. Genomic and precision medicine",
issn = "1942-325X",
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TY - JOUR

T1 - Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

AU - Verhaaren, Benjamin F J

AU - Debette, Stéphanie

AU - Bis, Joshua C.

AU - Smith, Jennifer A.

AU - Ikram, M. Kamran

AU - Adams, Hieab H.

AU - Beecham, Ashley H.

AU - Rajan, Kumar B.

AU - Lopez, Lorna M.

AU - Barral, Sandra

AU - Van Buchem, Mark A.

AU - Van Der Grond, Jeroen

AU - Smith, Albert V.

AU - Hegenscheid, Katrin

AU - Aggarwal, Neelum T.

AU - De Andrade, Mariza

AU - Atkinson, Elizabeth J.

AU - Beekman, Marian

AU - Beiser, Alexa S.

AU - Blanton, Susan H.

AU - Boerwinkle, Eric

AU - Brickman, Adam M.

AU - Bryan, R. Nick

AU - Chauhan, Ganesh

AU - Chen, Christopher P L H

AU - Chouraki, Vincent

AU - De Craen, Anton J M

AU - Crivello, Fabrice

AU - Deary, Ian J.

AU - Deelen, Joris

AU - De Jager, Philip L.

AU - Dufouil, Carole

AU - Elkind, Mitchell S V

AU - Evans, Denis A.

AU - Freudenberger, Paul

AU - Gottesman, Rebecca F.

AU - Gunason, Vilmundur

AU - Habes, Mohamad

AU - Heckbert, Susan R.

AU - Heiss, Gerardo

AU - Hilal, Saima

AU - Hofer, Edith

AU - Hofman, Albert

AU - Ibrahim-Verbaas, Carla A.

AU - Knopman, David S

AU - Lewis, Cora E.

AU - Liao, Jiemin

AU - Liewald, David C M

AU - Luciano, Michelle

AU - Van Der Lugt, Aad

AU - Martinez, Oliver O.

AU - Mayeux, Richard

AU - Mazoyer, Bernard

AU - Nalls, Mike

AU - Nauck, Matthias

AU - Niessen, Wiro J.

AU - Oostra, Ben A.

AU - Psaty, Bruce M.

AU - Rice, Kenneth M.

AU - Rotter, Jerome I.

AU - Von Sarnowski, Bettina

AU - Schmidt, Helena

AU - Schreiner, Pamela J.

AU - Schuur, Maaike

AU - Sidney, Stephen S.

AU - Sigurdsson, Sigurdur

AU - Slagboom, P. Eline

AU - Stott, David J M

AU - Van Swieten, John C.

AU - Teumer, Alexander

AU - Töglhofer, Anna Maria

AU - Traylor, Matthew

AU - Trompet, Stella

AU - Turner, Stephen T

AU - Tzourio, Christophe

AU - Uh, Hae Won

AU - Uitterlinden, André G.

AU - Vernooij, Meike W.

AU - Wang, Jing J.

AU - Wong, Tien Y.

AU - Wardlaw, Joanna M.

AU - Windham, B. Gwen

AU - Wittfeld, Katharina

AU - Wolf, Christiane

AU - Wright, Clinton B.

AU - Yang, Qiong

AU - Zhao, Wei

AU - Zijdenbos, Alex

AU - Jukema, J. Wouter

AU - Sacco, Ralph L.

AU - Kardia, Sharon L R

AU - Amouyel, Philippe

AU - Mosley, Thomas H.

AU - Longstreth, W. T.

AU - DeCarli, Charles C.

AU - Van Duijn, Cornelia M.

AU - Schmidt, Reinhold

AU - Launer, Lenore J.

AU - Grabe, Hans J.

AU - Seshadri, Sudha S.

AU - Ikram, M. Arfan

AU - Fornage, Myriam

PY - 2015/4/4

Y1 - 2015/4/4

N2 - Background-The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results-We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10-19) and identified novel loci on chr10q24 (P=1.6×10-9) and chr2p21 (P=4.4×10-8). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10-8) and chr2p16 (P=1.5×10-8). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions-We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

AB - Background-The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results-We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10-19) and identified novel loci on chr10q24 (P=1.6×10-9) and chr2p21 (P=4.4×10-8). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10-8) and chr2p16 (P=1.5×10-8). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions-We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

KW - cerebral small vessel diseases

KW - cerebrovascular disorders

KW - genome-wide association study

KW - hypertension

KW - leukoencephalopathies

KW - polymorphisms, single nucleotide

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