Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities

Nicola J. Armstrong; Karen A. Mather; Muralidharan Sargurupremraj; Maria J. Knol; Rainer Malik; Claudia L. Satizabal; Lisa R. Yanek; Wei Wen; Vilmundur G. Gudnason; Nicole D. Dueker; Lloyd T. Elliott; Edith Hofer; Joshua Bis; Neda Jahanshad; Shuo Li; Mark A. Logue; Michelle Luciano; Markus Scholz; Albert V. Smith; Stella Trompet; Dina Vojinovic; Rui Xia; Fidel Alfaro-Almagro; David Ames; Najaf Amin; Philippe Amouyel; Alexa S. Beiser; Henry Brodaty; Ian J. Deary; Christine Fennema-Notestine; Piyush G. Gampawar; Rebecca Gottesman; Ludovica Griffanti; Clifford R. Jack; Mark Jenkinson; Jiyang Jiang; Brian G. Kral; John B. Kwok; Leonie Lampe; David C.M. Liewald; Pauline Maillard; Jonathan Marchini; Mark E. Bastin; Bernard Mazoyer; Lukas Pirpamer; José Rafael Romero; Gennady V. Roshchupkin; Peter R. Schofield; Matthias L. Schroeter; David J. Stott; Anbupalam Thalamuthu; Julian Trollor; Christophe Tzourio; Jeroen van der Grond; Meike W. Vernooij; Veronica A. Witte; Margaret J. Wright; Qiong Yang; Zoe Morris; Siggi Siggurdsson; Bruce Psaty; Arno Villringer; Helena Schmidt; Asta K. Haberg; Cornelia M. van Duijn; J. Wouter Jukema; Martin Dichgans; Ralph L. Sacco; Clinton B. Wright; William S. Kremen; Lewis C. Becker; Paul M. Thompson; Thomas H. Mosley; Joanna M. Wardlaw; M. Arfan Ikram; Hieab H.H. Adams; Sudha Seshadri; Perminder S. Sachdev; Stephen M. Smith; Lenore Launer; William Longstreth; Charles DeCarli; Reinhold Schmidt; Myriam Fornage; Stephanie Debette; Paul A. Nyquist

doi:10.1161/STROKEAHA.119.027544

Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities

Nicola J. Armstrong, Karen A. Mather, Muralidharan Sargurupremraj, Maria J. Knol, Rainer Malik, Claudia L. Satizabal, Lisa R. Yanek, Wei Wen, Vilmundur G. Gudnason, Nicole D. Dueker, Lloyd T. Elliott, Edith Hofer, Joshua Bis, Neda Jahanshad, Shuo Li, Mark A. Logue, Michelle Luciano, Markus Scholz, Albert V. Smith, Stella TrompetDina Vojinovic, Rui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S. Beiser, Henry Brodaty, Ian J. Deary, Christine Fennema-Notestine, Piyush G. Gampawar, Rebecca Gottesman, Ludovica Griffanti, Clifford R. Jack, Mark Jenkinson, Jiyang Jiang, Brian G. Kral, John B. Kwok, Leonie Lampe, David C.M. Liewald, Pauline Maillard, Jonathan Marchini, Mark E. Bastin, Bernard Mazoyer, Lukas Pirpamer, José Rafael Romero, Gennady V. Roshchupkin, Peter R. Schofield, Matthias L. Schroeter, David J. Stott, Anbupalam Thalamuthu, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W. Vernooij, Veronica A. Witte, Margaret J. Wright, Qiong Yang, Zoe Morris, Siggi Siggurdsson, Bruce Psaty, Arno Villringer, Helena Schmidt, Asta K. Haberg, Cornelia M. van Duijn, J. Wouter Jukema, Martin Dichgans, Ralph L. Sacco, Clinton B. Wright, William S. Kremen, Lewis C. Becker, Paul M. Thompson, Thomas H. Mosley, Joanna M. Wardlaw, M. Arfan Ikram, Hieab H.H. Adams, Sudha Seshadri, Perminder S. Sachdev, Stephen M. Smith, Lenore Launer, William Longstreth, Charles DeCarli, Reinhold Schmidt, Myriam Fornage, Stephanie Debette, Paul A. Nyquist

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

47 Scopus citations

Abstract

BACKGROUND AND PURPOSE: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genomewide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genomewide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Original language	English
Pages (from-to)	2112-2121
Number of pages	10
Journal	Stroke
Volume	51
Issue number	7
DOIs	https://doi.org/10.1161/STROKEAHA.119.027544
State	Published - Jul 2020
Externally published	Yes

Keywords

Brain
Genome-wide association study
Neuroimaging
Risk factors
White matter

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10.1161/STROKEAHA.119.027544

Cite this

Armstrong, N. J., Mather, K. A., Sargurupremraj, M., Knol, M. J., Malik, R., Satizabal, C. L., Yanek, L. R., Wen, W., Gudnason, V. G., Dueker, N. D., Elliott, L. T., Hofer, E., Bis, J., Jahanshad, N., Li, S., Logue, M. A., Luciano, M., Scholz, M., Smith, A. V., ... Nyquist, P. A. (2020). Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities. Stroke, 51(7), 2112-2121. https://doi.org/10.1161/STROKEAHA.119.027544

@article{4f03a5962d6f4137baaf9f083a94dfd4,

title = "Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities",

abstract = "BACKGROUND AND PURPOSE: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genomewide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genomewide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.",

keywords = "Brain, Genome-wide association study, Neuroimaging, Risk factors, White matter",

author = "Armstrong, {Nicola J.} and Mather, {Karen A.} and Muralidharan Sargurupremraj and Knol, {Maria J.} and Rainer Malik and Satizabal, {Claudia L.} and Yanek, {Lisa R.} and Wei Wen and Gudnason, {Vilmundur G.} and Dueker, {Nicole D.} and Elliott, {Lloyd T.} and Edith Hofer and Joshua Bis and Neda Jahanshad and Shuo Li and Logue, {Mark A.} and Michelle Luciano and Markus Scholz and Smith, {Albert V.} and Stella Trompet and Dina Vojinovic and Rui Xia and Fidel Alfaro-Almagro and David Ames and Najaf Amin and Philippe Amouyel and Beiser, {Alexa S.} and Henry Brodaty and Deary, {Ian J.} and Christine Fennema-Notestine and Gampawar, {Piyush G.} and Rebecca Gottesman and Ludovica Griffanti and Jack, {Clifford R.} and Mark Jenkinson and Jiyang Jiang and Kral, {Brian G.} and Kwok, {John B.} and Leonie Lampe and Liewald, {David C.M.} and Pauline Maillard and Jonathan Marchini and Bastin, {Mark E.} and Bernard Mazoyer and Lukas Pirpamer and Romero, {Jos{\'e} Rafael} and Roshchupkin, {Gennady V.} and Schofield, {Peter R.} and Schroeter, {Matthias L.} and Stott, {David J.} and Anbupalam Thalamuthu and Julian Trollor and Christophe Tzourio and {van der Grond}, Jeroen and Vernooij, {Meike W.} and Witte, {Veronica A.} and Wright, {Margaret J.} and Qiong Yang and Zoe Morris and Siggi Siggurdsson and Bruce Psaty and Arno Villringer and Helena Schmidt and Haberg, {Asta K.} and {van Duijn}, {Cornelia M.} and {Wouter Jukema}, J. and Martin Dichgans and Sacco, {Ralph L.} and Wright, {Clinton B.} and Kremen, {William S.} and Becker, {Lewis C.} and Thompson, {Paul M.} and Mosley, {Thomas H.} and Wardlaw, {Joanna M.} and Ikram, {M. Arfan} and Adams, {Hieab H.H.} and Sudha Seshadri and Sachdev, {Perminder S.} and Smith, {Stephen M.} and Lenore Launer and William Longstreth and Charles DeCarli and Reinhold Schmidt and Myriam Fornage and Stephanie Debette and Nyquist, {Paul A.}",

note = "Funding Information: This work is supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, R01AG059874, P41EB015922, R56AG058854, U54 EB020403, R01AG022381, U54EB020403, R01AG059874, and R01NS115845. Medical Research Council, Age UK, Scottish Funding Council, Row Fogo Trust, The Welcome Trust, Age UK, Cross Council Lifelong Health and Wellbeing Initiative, Leverhulme Trust, National Institute for Health Research, Biotechnology and Biological Sciences Research Council, UK Medical Research Council, Icelandic Heart Association, and the Althingi, Austrian Science Fund (FWF), Australian National Health and Medical Research Council, Austrian National Bank, Anniversary Fund, European Commission FP6 STRP, European Community{\textquoteright}s 5th and 7th Framework Program, Netherlands Organization for Scientific Research, Netherlands Consortium for Healthy Aging, Russian Foundation for Basic Research, Russian Federal Agency of Scientific Organizations, Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, Norwegian National Advisory Unit for functional magnetic resonance imaging (MRI), Leipzig Research Center for Civilization Diseases (LIFE), Bristol-Myers Squibb, Netherlands Heart Foundation, French National Research Agency (ANR), Foundation Leducq, Joint Programme of Neurodegenerative Disease research, Bordeaux University, Institut Pasteur de Lille, the labex DISTALZ and the Centre National de G{\'e}notypage. Deutsche Forschungsgesellschaft (DFG) no. WI 3342/3-1 and grants from European Union, European Regional Development Fund, Free State of Saxony within the framework of the excellence initiative, LIFE-Leipzig Research Center for Civilization Diseases no. 100329290, 713-241202, 14505/2470, 14575/2470. Max Planck Society, State of Saxony, Brain Foundation, Bristol-Myers Squibb, National Health and Medical Research Council (NHMRC) of Australia, NHMRC of Australia, Parkinson{\textquoteright}s UK; Medical Research Council - Dementias Platform UK, National Institute on Aging, Bethesda, MD, P30 AG 010129 Full details of funding support for each cohort are detailed in the Data Supplement. Funding Information: Dr Marchini is an employee of, and owns stock and stock options for, Regen-eron Pharmaceuticals; Dr Sachdev received personal fees from Biogen; Henry Brodaty, Advisory Board member, Nutricia Australia; Philippe Amouyel, advisor for Foundation Alzheimer non-profit organization and for Genoscreen Biotech company; Christine Fennema-Notestine, received finding from National Institutes of Health Grants R01AG022381; Dr Gottesman, American Academy of Neurology, Associate Editor, Neurology; Drs Thompson and Jahanshad received grant support from Biogen Inc for work unrelated to the contents of this manuscript. Dr DeCarli, consultant to Novartis; Markus Scholz disclosed Pfizer, Inc, grants; Ralph Sacco, grant support from Boehringer Ingelheim, National Institute of Neurological Disorders and Stroke Grants; Dr Wardlaw, grant support from the Medical Research Council, Age UK, Scottish Funding Council, and Row Fogo Trust during the conduct of the study and grant support from Fondation Leducq, Wellcome Trust, Engineering and Physical Sciences Research Council, Chest Heart Stroke Scotland, British Heart Foundation, Stroke Association, Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK outside the submitted work. The other authors report no conflicts. Funding Information: This work is supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, R01AG059874, P41EB015922, R56AG058854, U54 EB020403, R01AG022381, U54EB020403, R01AG059874, and R01NS115845. Medical Research Council, Age UK, Scottish Funding Council, Row Fogo Trust, The Welcome Trust, Age UK, Cross Council Lifelong Health and Wellbeing Initiative, Leverhulme Trust, National Institute for Health Research, Biotechnology and Biological Sciences Research Council, UK Medical Research Council, Icelandic Heart Association, and the Althingi, Austrian Science Fund (FWF), Australian National Health and Medical Research Council, Austrian National Bank, Anniversary Fund, European Commission FP6 STRP, European Community{\textquoteright}s 5th and 7th Framework Program, Netherlands Organization for Scientific Research, Netherlands Consortium for Healthy Aging, Russian Foundation for Basic Research, Russian Federal Agency of Scientific Organizations, Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, Norwegian National Advisory Unit for functional magnetic resonance imaging (MRI), Leipzig Research Center for Civilization Diseases (LIFE), Bristol-Myers Squibb, Netherlands Heart Foundation, French National Research Agency (ANR), Foundation Leducq, Joint Programme of Neurodegenerative Disease research, Bordeaux University, Institut Pasteur de Lille, the labex DIS-TALZ and the Centre National de G{\'e}notypage. Deutsche Forschungsgesell-schaft (DFG) no. WI 3342/3-1 and grants from European Union, European Regional Development Fund, Free State of Saxony within the framework of the excellence initiative, LIFE-Leipzig Research Center for Civilization Diseases no. 100329290, 713-241202, 14505/2470, 14575/2470. Max Planck Society, State of Saxony, Brain Foundation, Bristol-Myers Squibb, National Health and Medical Research Council (NHMRC) of Australia, NHMRC of Australia, Parkinson{\textquoteright}s UK; Medical Research Council - Dementias Platform UK, National Institute on Aging, Bethesda, MD, P30 AG 010129 Full details of funding support for each cohort are detailed in the Data Supplement. Publisher Copyright: {\textcopyright} 2020 American Heart Association, Inc.",

year = "2020",

month = jul,

doi = "10.1161/STROKEAHA.119.027544",

language = "English",

volume = "51",

pages = "2112--2121",

journal = "Stroke",

issn = "0039-2499",

publisher = "American Heart Association",

number = "7",

}

Armstrong, NJ, Mather, KA, Sargurupremraj, M, Knol, MJ, Malik, R, Satizabal, CL, Yanek, LR, Wen, W, Gudnason, VG, Dueker, ND, Elliott, LT, Hofer, E, Bis, J, Jahanshad, N, Li, S, Logue, MA, Luciano, M, Scholz, M, Smith, AV, Trompet, S, Vojinovic, D, Xia, R, Alfaro-Almagro, F, Ames, D, Amin, N, Amouyel, P, Beiser, AS, Brodaty, H, Deary, IJ, Fennema-Notestine, C, Gampawar, PG, Gottesman, R, Griffanti, L, Jack, CR, Jenkinson, M, Jiang, J, Kral, BG, Kwok, JB, Lampe, L, Liewald, DCM, Maillard, P, Marchini, J, Bastin, ME, Mazoyer, B, Pirpamer, L, Romero, JR, Roshchupkin, GV, Schofield, PR, Schroeter, ML, Stott, DJ, Thalamuthu, A, Trollor, J, Tzourio, C, van der Grond, J, Vernooij, MW, Witte, VA, Wright, MJ, Yang, Q, Morris, Z, Siggurdsson, S, Psaty, B, Villringer, A, Schmidt, H, Haberg, AK, van Duijn, CM, Wouter Jukema, J, Dichgans, M, Sacco, RL, Wright, CB, Kremen, WS, Becker, LC, Thompson, PM, Mosley, TH, Wardlaw, JM, Ikram, MA, Adams, HHH, Seshadri, S, Sachdev, PS, Smith, SM, Launer, L, Longstreth, W, DeCarli, C, Schmidt, R, Fornage, M, Debette, S & Nyquist, PA 2020, 'Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities', Stroke, vol. 51, no. 7, pp. 2112-2121. https://doi.org/10.1161/STROKEAHA.119.027544

TY - JOUR

T1 - Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities

AU - Armstrong, Nicola J.

AU - Mather, Karen A.

AU - Sargurupremraj, Muralidharan

AU - Knol, Maria J.

AU - Malik, Rainer

AU - Satizabal, Claudia L.

AU - Yanek, Lisa R.

AU - Wen, Wei

AU - Gudnason, Vilmundur G.

AU - Dueker, Nicole D.

AU - Elliott, Lloyd T.

AU - Hofer, Edith

AU - Bis, Joshua

AU - Jahanshad, Neda

AU - Li, Shuo

AU - Logue, Mark A.

AU - Luciano, Michelle

AU - Scholz, Markus

AU - Smith, Albert V.

AU - Trompet, Stella

AU - Vojinovic, Dina

AU - Xia, Rui

AU - Alfaro-Almagro, Fidel

AU - Ames, David

AU - Amin, Najaf

AU - Amouyel, Philippe

AU - Beiser, Alexa S.

AU - Brodaty, Henry

AU - Deary, Ian J.

AU - Fennema-Notestine, Christine

AU - Gampawar, Piyush G.

AU - Gottesman, Rebecca

AU - Griffanti, Ludovica

AU - Jack, Clifford R.

AU - Jenkinson, Mark

AU - Jiang, Jiyang

AU - Kral, Brian G.

AU - Kwok, John B.

AU - Lampe, Leonie

AU - Liewald, David C.M.

AU - Maillard, Pauline

AU - Marchini, Jonathan

AU - Bastin, Mark E.

AU - Mazoyer, Bernard

AU - Pirpamer, Lukas

AU - Romero, José Rafael

AU - Roshchupkin, Gennady V.

AU - Schofield, Peter R.

AU - Schroeter, Matthias L.

AU - Stott, David J.

AU - Thalamuthu, Anbupalam

AU - Trollor, Julian

AU - Tzourio, Christophe

AU - van der Grond, Jeroen

AU - Vernooij, Meike W.

AU - Witte, Veronica A.

AU - Wright, Margaret J.

AU - Yang, Qiong

AU - Morris, Zoe

AU - Siggurdsson, Siggi

AU - Psaty, Bruce

AU - Villringer, Arno

AU - Schmidt, Helena

AU - Haberg, Asta K.

AU - van Duijn, Cornelia M.

AU - Wouter Jukema, J.

AU - Dichgans, Martin

AU - Sacco, Ralph L.

AU - Wright, Clinton B.

AU - Kremen, William S.

AU - Becker, Lewis C.

AU - Thompson, Paul M.

AU - Mosley, Thomas H.

AU - Wardlaw, Joanna M.

AU - Ikram, M. Arfan

AU - Adams, Hieab H.H.

AU - Seshadri, Sudha

AU - Sachdev, Perminder S.

AU - Smith, Stephen M.

AU - Launer, Lenore

AU - Longstreth, William

AU - DeCarli, Charles

AU - Schmidt, Reinhold

AU - Fornage, Myriam

AU - Debette, Stephanie

AU - Nyquist, Paul A.

N1 - Funding Information: This work is supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, R01AG059874, P41EB015922, R56AG058854, U54 EB020403, R01AG022381, U54EB020403, R01AG059874, and R01NS115845. Medical Research Council, Age UK, Scottish Funding Council, Row Fogo Trust, The Welcome Trust, Age UK, Cross Council Lifelong Health and Wellbeing Initiative, Leverhulme Trust, National Institute for Health Research, Biotechnology and Biological Sciences Research Council, UK Medical Research Council, Icelandic Heart Association, and the Althingi, Austrian Science Fund (FWF), Australian National Health and Medical Research Council, Austrian National Bank, Anniversary Fund, European Commission FP6 STRP, European Community’s 5th and 7th Framework Program, Netherlands Organization for Scientific Research, Netherlands Consortium for Healthy Aging, Russian Foundation for Basic Research, Russian Federal Agency of Scientific Organizations, Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, Norwegian National Advisory Unit for functional magnetic resonance imaging (MRI), Leipzig Research Center for Civilization Diseases (LIFE), Bristol-Myers Squibb, Netherlands Heart Foundation, French National Research Agency (ANR), Foundation Leducq, Joint Programme of Neurodegenerative Disease research, Bordeaux University, Institut Pasteur de Lille, the labex DISTALZ and the Centre National de Génotypage. Deutsche Forschungsgesellschaft (DFG) no. WI 3342/3-1 and grants from European Union, European Regional Development Fund, Free State of Saxony within the framework of the excellence initiative, LIFE-Leipzig Research Center for Civilization Diseases no. 100329290, 713-241202, 14505/2470, 14575/2470. Max Planck Society, State of Saxony, Brain Foundation, Bristol-Myers Squibb, National Health and Medical Research Council (NHMRC) of Australia, NHMRC of Australia, Parkinson’s UK; Medical Research Council - Dementias Platform UK, National Institute on Aging, Bethesda, MD, P30 AG 010129 Full details of funding support for each cohort are detailed in the Data Supplement. Funding Information: Dr Marchini is an employee of, and owns stock and stock options for, Regen-eron Pharmaceuticals; Dr Sachdev received personal fees from Biogen; Henry Brodaty, Advisory Board member, Nutricia Australia; Philippe Amouyel, advisor for Foundation Alzheimer non-profit organization and for Genoscreen Biotech company; Christine Fennema-Notestine, received finding from National Institutes of Health Grants R01AG022381; Dr Gottesman, American Academy of Neurology, Associate Editor, Neurology; Drs Thompson and Jahanshad received grant support from Biogen Inc for work unrelated to the contents of this manuscript. Dr DeCarli, consultant to Novartis; Markus Scholz disclosed Pfizer, Inc, grants; Ralph Sacco, grant support from Boehringer Ingelheim, National Institute of Neurological Disorders and Stroke Grants; Dr Wardlaw, grant support from the Medical Research Council, Age UK, Scottish Funding Council, and Row Fogo Trust during the conduct of the study and grant support from Fondation Leducq, Wellcome Trust, Engineering and Physical Sciences Research Council, Chest Heart Stroke Scotland, British Heart Foundation, Stroke Association, Alzheimer’s Society and Alzheimer’s Research UK outside the submitted work. The other authors report no conflicts. Funding Information: This work is supported by the National Institute of Neurological Disorders and Stroke, National Institutes of Health, R01AG059874, P41EB015922, R56AG058854, U54 EB020403, R01AG022381, U54EB020403, R01AG059874, and R01NS115845. Medical Research Council, Age UK, Scottish Funding Council, Row Fogo Trust, The Welcome Trust, Age UK, Cross Council Lifelong Health and Wellbeing Initiative, Leverhulme Trust, National Institute for Health Research, Biotechnology and Biological Sciences Research Council, UK Medical Research Council, Icelandic Heart Association, and the Althingi, Austrian Science Fund (FWF), Australian National Health and Medical Research Council, Austrian National Bank, Anniversary Fund, European Commission FP6 STRP, European Community’s 5th and 7th Framework Program, Netherlands Organization for Scientific Research, Netherlands Consortium for Healthy Aging, Russian Foundation for Basic Research, Russian Federal Agency of Scientific Organizations, Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, Norwegian National Advisory Unit for functional magnetic resonance imaging (MRI), Leipzig Research Center for Civilization Diseases (LIFE), Bristol-Myers Squibb, Netherlands Heart Foundation, French National Research Agency (ANR), Foundation Leducq, Joint Programme of Neurodegenerative Disease research, Bordeaux University, Institut Pasteur de Lille, the labex DIS-TALZ and the Centre National de Génotypage. Deutsche Forschungsgesell-schaft (DFG) no. WI 3342/3-1 and grants from European Union, European Regional Development Fund, Free State of Saxony within the framework of the excellence initiative, LIFE-Leipzig Research Center for Civilization Diseases no. 100329290, 713-241202, 14505/2470, 14575/2470. Max Planck Society, State of Saxony, Brain Foundation, Bristol-Myers Squibb, National Health and Medical Research Council (NHMRC) of Australia, NHMRC of Australia, Parkinson’s UK; Medical Research Council - Dementias Platform UK, National Institute on Aging, Bethesda, MD, P30 AG 010129 Full details of funding support for each cohort are detailed in the Data Supplement. Publisher Copyright: © 2020 American Heart Association, Inc.

PY - 2020/7

Y1 - 2020/7

N2 - BACKGROUND AND PURPOSE: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genomewide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genomewide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

AB - BACKGROUND AND PURPOSE: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genomewide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genomewide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

KW - Brain

KW - Genome-wide association study

KW - Neuroimaging

KW - Risk factors

KW - White matter

UR - http://www.scopus.com/inward/record.url?scp=85087342729&partnerID=8YFLogxK

U2 - 10.1161/STROKEAHA.119.027544

DO - 10.1161/STROKEAHA.119.027544

M3 - Article

C2 - 32517579

AN - SCOPUS:85087342729

SN - 0039-2499

VL - 51

SP - 2112

EP - 2121

JO - Stroke

JF - Stroke

IS - 7

ER -

Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities

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