%0 Journal Article %1 Armstrong2020-tz %A Armstrong, Nicola J %A Mather, Karen A %A Sargurupremraj, Muralidharan %A Knol, Maria J %A Malik, Rainer %A Satizabal, Claudia L %A Yanek, Lisa R %A Wen, Wei %A Gudnason, Vilmundur G %A Dueker, Nicole D %A Elliott, Lloyd T %A Hofer, Edith %A Bis, Joshua %A Jahanshad, Neda %A Li, Shuo %A Logue, Mark A %A Luciano, Michelle %A Scholz, Markus %A Smith, Albert V %A Trompet, Stella %A Vojinovic, Dina %A Xia, Rui %A Alfaro-Almagro, Fidel %A Ames, David %A Amin, Najaf %A Amouyel, Philippe %A Beiser, Alexa S %A Brodaty, Henry %A Deary, Ian J %A Fennema-Notestine, Christine %A Gampawar, Piyush G %A Gottesman, Rebecca %A Griffanti, Ludovica %A Jack, Jr, Clifford R %A Jenkinson, Mark %A Jiang, Jiyang %A Kral, Brian G %A Kwok, John B %A Lampe, Leonie %A C M Liewald, David %A Maillard, Pauline %A Marchini, Jonathan %A Bastin, Mark E %A Mazoyer, Bernard %A Pirpamer, Lukas %A Rafael Romero, José %A Roshchupkin, Gennady V %A Schofield, Peter R %A Schroeter, Matthias L %A Stott, David J %A Thalamuthu, Anbupalam %A Trollor, Julian %A Tzourio, Christophe %A van der Grond, Jeroen %A Vernooij, Meike W %A Witte, Veronica A %A Wright, Margaret J %A Yang, Qiong %A Morris, Zoe %A Siggurdsson, Siggi %A Psaty, Bruce %A Villringer, Arno %A Schmidt, Helena %A Haberg, Asta K %A van Duijn, Cornelia M %A Jukema, J Wouter %A Dichgans, Martin %A Sacco, Ralph L %A Wright, Clinton B %A Kremen, William S %A Becker, Lewis C %A Thompson, Paul M %A Mosley, Thomas H %A Wardlaw, Joanna M %A Ikram, M Arfan %A Adams, Hieab H H %A Seshadri, Sudha %A Sachdev, Perminder S %A Smith, Stephen M %A Launer, Lenore %A Longstreth, William %A DeCarli, Charles %A Schmidt, Reinhold %A Fornage, Myriam %A Debette, Stephanie %A Nyquist, Paul A %D 2020 %I Ovid Technologies (Wolters Kluwer Health) %J Stroke %K association brain; factors; genome-wide matter neuroimaging; risk study; topic_lifescience white %N 7 %P 2111--2121 %T Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities %V 51 %X 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.

@article{Armstrong2020-tz, 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.}, added-at = {2024-09-10T11:54:51.000+0200}, author = {Armstrong, Nicola J and Mather, Karen A and Sargurupremraj, Muralidharan and Knol, Maria J and Malik, Rainer and Satizabal, Claudia L and Yanek, Lisa R and Wen, Wei and Gudnason, Vilmundur G and Dueker, Nicole D and Elliott, Lloyd T and Hofer, Edith and Bis, Joshua and Jahanshad, Neda and Li, Shuo and Logue, Mark A and Luciano, Michelle and Scholz, Markus and Smith, Albert V and Trompet, Stella and Vojinovic, Dina and Xia, Rui and Alfaro-Almagro, Fidel and Ames, David and Amin, Najaf and Amouyel, Philippe and Beiser, Alexa S and Brodaty, Henry and Deary, Ian J and Fennema-Notestine, Christine and Gampawar, Piyush G and Gottesman, Rebecca and Griffanti, Ludovica and {Jack, Jr}, Clifford R and Jenkinson, Mark and Jiang, Jiyang and Kral, Brian G and Kwok, John B and Lampe, Leonie and C M Liewald, David and Maillard, Pauline and Marchini, Jonathan and Bastin, Mark E and Mazoyer, Bernard and Pirpamer, Lukas and Rafael Romero, Jos{\'e} and Roshchupkin, Gennady V and Schofield, Peter R and Schroeter, Matthias L and Stott, David J and Thalamuthu, Anbupalam and Trollor, Julian and Tzourio, Christophe and van der Grond, Jeroen and Vernooij, Meike W and Witte, Veronica A and Wright, Margaret J and Yang, Qiong and Morris, Zoe and Siggurdsson, Siggi and Psaty, Bruce and Villringer, Arno and Schmidt, Helena and Haberg, Asta K and van Duijn, Cornelia M and Jukema, J Wouter and Dichgans, Martin 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 Seshadri, Sudha and Sachdev, Perminder S and Smith, Stephen M and Launer, Lenore and Longstreth, William and DeCarli, Charles and Schmidt, Reinhold and Fornage, Myriam and Debette, Stephanie and Nyquist, Paul A}, biburl = {https://puma.scadsai.uni-leipzig.de/bibtex/215badd2411109ed3867a42842194b709/scadsfct}, interhash = {86b692ed3443e80c38917fdb0fa718c9}, intrahash = {15badd2411109ed3867a42842194b709}, journal = {Stroke}, keywords = {association brain; factors; genome-wide matter neuroimaging; risk study; topic_lifescience white}, language = {en}, month = jul, number = 7, pages = {2111--2121}, publisher = {Ovid Technologies (Wolters Kluwer Health)}, timestamp = {2024-09-10T12:00:15.000+0200}, title = {Common genetic variation indicates separate causes for periventricular and deep white matter hyperintensities}, volume = 51, year = 2020 }