@article {6818, title = {Genes from a translational analysis support a multifactorial nature of white matter hyperintensities.}, journal = {Stroke}, volume = {46}, year = {2015}, month = {2015 Feb}, pages = {341-7}, abstract = {

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative.

METHODS: We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE.

RESULTS: Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7{\texttimes}10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE{\textquoteright}s genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1).

CONCLUSIONS: Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer{\textquoteright}s disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia.

}, keywords = {Aged, Alzheimer Disease, Animals, Brain, Causality, Dementia, Female, Genome-Wide Association Study, Humans, Leukoencephalopathies, Male, Polymorphism, Single Nucleotide, Rats, Rats, Inbred SHR, Rats, Wistar, Risk Factors, Translational Medical Research, White Matter}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.114.007649}, author = {Lopez, Lorna M and Hill, W David and Harris, Sarah E and Valdes Hernandez, Maria and Munoz Maniega, Susana and Bastin, Mark E and Bailey, Emma and Smith, Colin and McBride, Martin and McClure, John and Graham, Delyth and Dominiczak, Anna and Yang, Qiong and Fornage, Myriam and Ikram, M Arfan and Debette, Stephanie and Launer, Lenore and Bis, Joshua C and Schmidt, Reinhold and Seshadri, Sudha and Porteous, David J and Starr, John and Deary, Ian J and Wardlaw, Joanna M} } @article {7796, title = {Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.}, journal = {Stroke}, year = {2018}, month = {2018 Jul 12}, abstract = {

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.

METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.

RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6{\texttimes}10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5{\texttimes}10) partially independent of known common signal (=1.4{\texttimes}10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9{\texttimes}10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8{\texttimes}10).

CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.118.020689}, author = {Jian, Xueqiu and Satizabal, Claudia L and Smith, Albert V and Wittfeld, Katharina and Bis, Joshua C and Smith, Jennifer A and Hsu, Fang-Chi and Nho, Kwangsik and Hofer, Edith and Hagenaars, Saskia P and Nyquist, Paul A and Mishra, Aniket and Adams, Hieab H H and Li, Shuo and Teumer, Alexander and Zhao, Wei and Freedman, Barry I and Saba, Yasaman and Yanek, Lisa R and Chauhan, Ganesh and van Buchem, Mark A and Cushman, Mary and Royle, Natalie A and Bryan, R Nick and Niessen, Wiro J and Windham, Beverly G and DeStefano, Anita L and Habes, Mohamad and Heckbert, Susan R and Palmer, Nicholette D and Lewis, Cora E and Eiriksdottir, Gudny and Maillard, Pauline and Mathias, Rasika A and Homuth, Georg and Vald{\'e}s-Hern{\'a}ndez, Maria Del C and Divers, Jasmin and Beiser, Alexa S and Langner, S{\"o}nke and Rice, Kenneth M and Bastin, Mark E and Yang, Qiong and Maldjian, Joseph A and Starr, John M and Sidney, Stephen and Risacher, Shannon L and Uitterlinden, Andr{\'e} G and Gudnason, Vilmundur G and Nauck, Matthias and Rotter, Jerome I and Schreiner, Pamela J and Boerwinkle, Eric and van Duijn, Cornelia M and Mazoyer, Bernard and von Sarnowski, Bettina and Gottesman, Rebecca F and Levy, Daniel and Sigurdsson, Sigurdur and Vernooij, Meike W and Turner, Stephen T and Schmidt, Reinhold and Wardlaw, Joanna M and Psaty, Bruce M and Mosley, Thomas H and DeCarli, Charles S and Saykin, Andrew J and Bowden, Donald W and Becker, Diane M and Deary, Ian J and Schmidt, Helena and Kardia, Sharon L R and Ikram, M Arfan and Debette, Stephanie and Grabe, Hans J and Longstreth, W T and Seshadri, Sudha and Launer, Lenore J and Fornage, Myriam} } @article {7849, title = {Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Sep 26}, pages = {3945}, abstract = {

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 {\texttimes} 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-06234-w}, author = {Vojinovic, Dina and Adams, Hieab H and Jian, Xueqiu and Yang, Qiong and Smith, Albert Vernon and Bis, Joshua C and Teumer, Alexander and Scholz, Markus and Armstrong, Nicola J and Hofer, Edith and Saba, Yasaman and Luciano, Michelle and Bernard, Manon and Trompet, Stella and Yang, Jingyun and Gillespie, Nathan A and van der Lee, Sven J and Neumann, Alexander and Ahmad, Shahzad and Andreassen, Ole A and Ames, David and Amin, Najaf and Arfanakis, Konstantinos and Bastin, Mark E and Becker, Diane M and Beiser, Alexa S and Beyer, Frauke and Brodaty, Henry and Bryan, R Nick and B{\"u}low, Robin and Dale, Anders M and De Jager, Philip L and Deary, Ian J and DeCarli, Charles and Fleischman, Debra A and Gottesman, Rebecca F and van der Grond, Jeroen and Gudnason, Vilmundur and Harris, Tamara B and Homuth, Georg and Knopman, David S and Kwok, John B and Lewis, Cora E and Li, Shuo and Loeffler, Markus and Lopez, Oscar L and Maillard, Pauline and El Marroun, Hanan and Mather, Karen A and Mosley, Thomas H and Muetzel, Ryan L and Nauck, Matthias and Nyquist, Paul A and Panizzon, Matthew S and Pausova, Zdenka and Psaty, Bruce M and Rice, Ken and Rotter, Jerome I and Royle, Natalie and Satizabal, Claudia L and Schmidt, Reinhold and Schofield, Peter R and Schreiner, Pamela J and Sidney, Stephen and Stott, David J and Thalamuthu, Anbupalam and Uitterlinden, Andr{\'e} G and Vald{\'e}s Hern{\'a}ndez, Maria C and Vernooij, Meike W and Wen, Wei and White, Tonya and Witte, A Veronica and Wittfeld, Katharina and Wright, Margaret J and Yanek, Lisa R and Tiemeier, Henning and Kremen, William S and Bennett, David A and Jukema, J Wouter and Paus, Tom{\'a}{\v s} and Wardlaw, Joanna M and Schmidt, Helena and Sachdev, Perminder S and Villringer, Arno and Grabe, Hans J{\"o}rgen and Longstreth, W T and van Duijn, Cornelia M and Launer, Lenore J and Seshadri, Sudha and Ikram, M Arfan and Fornage, Myriam} } @article {8206, title = {Genetic architecture of subcortical brain structures in 38,851 individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Nov}, pages = {1624-1636}, abstract = {

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0511-y}, author = {Satizabal, Claudia L and Adams, Hieab H H and Hibar, Derrek P and White, Charles C and Knol, Maria J and Stein, Jason L and Scholz, Markus and Sargurupremraj, Muralidharan and Jahanshad, Neda and Roshchupkin, Gennady V and Smith, Albert V and Bis, Joshua C and Jian, Xueqiu and Luciano, Michelle and Hofer, Edith and Teumer, Alexander and van der Lee, Sven J and Yang, Jingyun and Yanek, Lisa R and Lee, Tom V and Li, Shuo and Hu, Yanhui and Koh, Jia Yu and Eicher, John D and Desrivi{\`e}res, Sylvane and Arias-Vasquez, Alejandro and Chauhan, Ganesh and Athanasiu, Lavinia and Renter{\'\i}a, Miguel E and Kim, Sungeun and Hoehn, David and Armstrong, Nicola J and Chen, Qiang and Holmes, Avram J and den Braber, Anouk and Kloszewska, Iwona and Andersson, Micael and Espeseth, Thomas and Grimm, Oliver and Abramovic, Lucija and Alhusaini, Saud and Milaneschi, Yuri and Papmeyer, Martina and Axelsson, Tomas and Ehrlich, Stefan and Roiz-Santia{\~n}ez, Roberto and Kraemer, Bernd and H{\r a}berg, Asta K and Jones, Hannah J and Pike, G Bruce and Stein, Dan J and Stevens, Allison and Bralten, Janita and Vernooij, Meike W and Harris, Tamara B and Filippi, Irina and Witte, A Veronica and Guadalupe, Tulio and Wittfeld, Katharina and Mosley, Thomas H and Becker, James T and Doan, Nhat Trung and Hagenaars, Saskia P and Saba, Yasaman and Cuellar-Partida, Gabriel and Amin, Najaf and Hilal, Saima and Nho, Kwangsik and Mirza-Schreiber, Nazanin and Arfanakis, Konstantinos and Becker, Diane M and Ames, David and Goldman, Aaron L and Lee, Phil H and Boomsma, Dorret I and Lovestone, Simon and Giddaluru, Sudheer and Le Hellard, Stephanie and Mattheisen, Manuel and Bohlken, Marc M and Kasperaviciute, Dalia and Schmaal, Lianne and Lawrie, Stephen M and Agartz, Ingrid and Walton, Esther and Tordesillas-Gutierrez, Diana and Davies, Gareth E and Shin, Jean and Ipser, Jonathan C and Vinke, Louis N and Hoogman, Martine and Jia, Tianye and Burkhardt, Ralph and Klein, Marieke and Crivello, Fabrice and Janowitz, Deborah and Carmichael, Owen and Haukvik, Unn K and Aribisala, Benjamin S and Schmidt, Helena and Strike, Lachlan T and Cheng, Ching-Yu and Risacher, Shannon L and P{\"u}tz, Benno and Fleischman, Debra A and Assareh, Amelia A and Mattay, Venkata S and Buckner, Randy L and Mecocci, Patrizia and Dale, Anders M and Cichon, Sven and Boks, Marco P and Matarin, Mar and Penninx, Brenda W J H and Calhoun, Vince D and Chakravarty, M Mallar and Marquand, Andre F and Macare, Christine and Kharabian Masouleh, Shahrzad and Oosterlaan, Jaap and Amouyel, Philippe and Hegenscheid, Katrin and Rotter, Jerome I and Schork, Andrew J and Liewald, David C M and de Zubicaray, Greig I and Wong, Tien Yin and Shen, Li and S{\"a}mann, Philipp G and Brodaty, Henry and Roffman, Joshua L and de Geus, Eco J C and Tsolaki, Magda and Erk, Susanne and van Eijk, Kristel R and Cavalleri, Gianpiero L and van der Wee, Nic J A and McIntosh, Andrew M and Gollub, Randy L and Bulayeva, Kazima B and Bernard, Manon and Richards, Jennifer S and Himali, Jayandra J and Loeffler, Markus and Rommelse, Nanda and Hoffmann, Wolfgang and Westlye, Lars T and Vald{\'e}s Hern{\'a}ndez, Maria C and Hansell, Narelle K and van Erp, Theo G M and Wolf, Christiane and Kwok, John B J and Vellas, Bruno and Heinz, Andreas and Olde Loohuis, Loes M and Delanty, Norman and Ho, Beng-Choon and Ching, Christopher R K and Shumskaya, Elena and Singh, Baljeet and Hofman, Albert and van der Meer, Dennis and Homuth, Georg and Psaty, Bruce M and Bastin, Mark E and Montgomery, Grant W and Foroud, Tatiana M and Reppermund, Simone and Hottenga, Jouke-Jan and Simmons, Andrew and Meyer-Lindenberg, Andreas and Cahn, Wiepke and Whelan, Christopher D and van Donkelaar, Marjolein M J and Yang, Qiong and Hosten, Norbert and Green, Robert C and Thalamuthu, Anbupalam and Mohnke, Sebastian and Hulshoff Pol, Hilleke E and Lin, Honghuang and Jack, Clifford R and Schofield, Peter R and M{\"u}hleisen, Thomas W and Maillard, Pauline and Potkin, Steven G and Wen, Wei and Fletcher, Evan and Toga, Arthur W and Gruber, Oliver and Huentelman, Matthew and Davey Smith, George and Launer, Lenore J and Nyberg, Lars and J{\"o}nsson, Erik G and Crespo-Facorro, Benedicto and Koen, Nastassja and Greve, Douglas N and Uitterlinden, Andr{\'e} G and Weinberger, Daniel R and Steen, Vidar M and Fedko, Iryna O and Groenewold, Nynke A and Niessen, Wiro J and Toro, Roberto and Tzourio, Christophe and Longstreth, William T and Ikram, M Kamran and Smoller, Jordan W and van Tol, Marie-Jose and Sussmann, Jessika E and Paus, Tom{\'a}{\v s} and Lema{\^\i}tre, Herv{\'e} and Schroeter, Matthias L and Mazoyer, Bernard and Andreassen, Ole A and Holsboer, Florian and Depondt, Chantal and Veltman, Dick J and Turner, Jessica A and Pausova, Zdenka and Schumann, Gunter and van Rooij, Daan and Djurovic, Srdjan and Deary, Ian J and McMahon, Katie L and M{\"u}ller-Myhsok, Bertram and Brouwer, Rachel M and Soininen, Hilkka and Pandolfo, Massimo and Wassink, Thomas H and Cheung, Joshua W and Wolfers, Thomas and Martinot, Jean-Luc and Zwiers, Marcel P and Nauck, Matthias and Melle, Ingrid and Martin, Nicholas G and Kanai, Ryota and Westman, Eric and Kahn, Ren{\'e} S and Sisodiya, Sanjay M and White, Tonya and Saremi, Arvin and van Bokhoven, Hans and Brunner, Han G and V{\"o}lzke, Henry and Wright, Margaret J and van {\textquoteright}t Ent, Dennis and N{\"o}then, Markus M and Ophoff, Roel A and Buitelaar, Jan K and Fern{\'a}ndez, Guill{\'e}n and Sachdev, Perminder S and Rietschel, Marcella and van Haren, Neeltje E M and Fisher, Simon E and Beiser, Alexa S and Francks, Clyde and Saykin, Andrew J and Mather, Karen A and Romanczuk-Seiferth, Nina and Hartman, Catharina A and DeStefano, Anita L and Heslenfeld, Dirk J and Weiner, Michael W and Walter, Henrik and Hoekstra, Pieter J and Nyquist, Paul A and Franke, Barbara and Bennett, David A and Grabe, Hans J and Johnson, Andrew D and Chen, Christopher and van Duijn, Cornelia M and Lopez, Oscar L and Fornage, Myriam and Wardlaw, Joanna M and Schmidt, Reinhold and DeCarli, Charles and De Jager, Philip L and Villringer, Arno and Debette, Stephanie and Gudnason, Vilmundur and Medland, Sarah E and Shulman, Joshua M and Thompson, Paul M and Seshadri, Sudha and Ikram, M Arfan} } @article {9184, title = {Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.}, journal = {Brain}, year = {2022}, month = {2022 Aug 09}, abstract = {

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 {\texttimes} 10-8), was associated with F2 expression in blood (P = 6.4 {\texttimes} 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.

}, issn = {1460-2156}, doi = {10.1093/brain/awac290}, author = {Yang, Yunju and Knol, Maria J and Wang, Ruiqi and Mishra, Aniket and Liu, Dan and Luciano, Michelle and Teumer, Alexander and Armstrong, Nicola and Bis, Joshua C and Jhun, Min A and Li, Shuo and Adams, Hieab H H and Aziz, Nasir Ahmad and Bastin, Mark E and Bourgey, Mathieu and Brody, Jennifer A and Frenzel, Stefan and Gottesman, Rebecca F and Hosten, Norbert and Hou, Lifang and Kardia, Sharon L R and Lohner, Valerie and Marquis, Pascale and Maniega, Susana Mu{\~n}oz and Satizabal, Claudia L and Sorond, Farzaneh A and Vald{\'e}s Hern{\'a}ndez, Maria C and van Duijn, Cornelia M and Vernooij, Meike W and Wittfeld, Katharina and Yang, Qiong and Zhao, Wei and Boerwinkle, Eric and Levy, Daniel and Deary, Ian J and Jiang, Jiyang and Mather, Karen A and Mosley, Thomas H and Psaty, Bruce M and Sachdev, Perminder S and Smith, Jennifer A and Sotoodehnia, Nona and DeCarli, Charles S and Breteler, Monique M B and Arfan Ikram, M and Grabe, Hans J and Wardlaw, Joanna and Longstreth, W T and Launer, Lenore J and Seshadri, Sudha and Debette, Stephanie and Fornage, Myriam} }