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

Abstract / Description of output

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 genome-wide 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 genome-wide 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
Journal	Stroke
DOIs	https://doi.org/10.1161/STROKEAHA.119.027544
Publication status	Published - 10 Jun 2020

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10.1161/STROKEAHA.119.027544

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https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.027544

The Disconnected Mind Phase 3
Cox, S. & Deary, I.
UK-based charities
1/04/16 → 31/03/23
Project: Research
Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III
Wardlaw, J., Bastin, M. & Deary, I.
MRC
1/05/15 → 30/04/19
Project: Research
Brain White mater imaging and cognitive ageing in the Lothian Birth Cohort of 1936:II
Deary, I., Bastin, M., Penke, L., Starr, J. & Wardlaw, J.
MRC
8/06/11 → 7/03/15
Project: Research

Mark Bastin
- Deanery of Clinical Sciences - Personal Chair of Brain Imaging
- Centre for Clinical Brain Sciences
- Euan MacDonald Centre for Motor Neuron Disease Research
- Edinburgh Neuroscience
- Edinburgh Imaging
Person: Academic: Research Active

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. https://doi.org/10.1161/STROKEAHA.119.027544

@article{937e4bbeb6b44d339121cbd64a03b4b4,

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 genome-wide 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 genome-wide 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.",

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 {C.m. Liewald}, David and Pauline Maillard and Jonathan Marchini and Bastin, {Mark E.} and Bernard Mazoyer and Lukas Pirpamer and {Rafael Romero}, Jos{\'e} 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 Jukema, {J. Wouter} 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.}",

year = "2020",

month = jun,

day = "10",

doi = "10.1161/STROKEAHA.119.027544",

language = "English",

journal = "Stroke",

issn = "0039-2499",

publisher = "Lippincott Williams & Wilkins",

}

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, C.m. Liewald, D, Maillard, P, Marchini, J, Bastin, ME, Mazoyer, B, Pirpamer, L, Rafael Romero, J, 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, Jukema, JW, 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. 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 - C.m. Liewald, David

AU - Maillard, Pauline

AU - Marchini, Jonathan

AU - Bastin, Mark E.

AU - Mazoyer, Bernard

AU - Pirpamer, Lukas

AU - Rafael Romero, José

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 - Jukema, J. Wouter

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.

PY - 2020/6/10

Y1 - 2020/6/10

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 genome-wide 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 genome-wide 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 genome-wide 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 genome-wide 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.

U2 - 10.1161/STROKEAHA.119.027544

DO - 10.1161/STROKEAHA.119.027544

M3 - Article

SN - 0039-2499

JO - Stroke

JF - Stroke

ER -

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities

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The Disconnected Mind Phase 3

Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III

Brain White mater imaging and cognitive ageing in the Lothian Birth Cohort of 1936:II

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Mark Bastin

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