%0 Journal Article %J Ann Neurol %D 2013 %T Ischemic stroke is associated with the ABO locus: the EuroCLOT study. %A Williams, Frances M K %A Carter, Angela M %A Hysi, Pirro G %A Surdulescu, Gabriela %A Hodgkiss, Dylan %A Soranzo, Nicole %A Traylor, Matthew %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M W %A Sudlow, Cathie %A Farrall, Martin %A Silander, Kaisa %A Kaunisto, Mari %A Wagner, Peter %A Saarela, Olli %A Kuulasmaa, Kari %A Virtamo, Jarmo %A Salomaa, Veikko %A Amouyel, Philippe %A Arveiler, Dominique %A Ferrieres, Jean %A Wiklund, Per-Gunnar %A Ikram, M Arfan %A Hofman, Albert %A Boncoraglio, Giorgio B %A Parati, Eugenio A %A Helgadottir, Anna %A Gretarsdottir, Solveig %A Thorsteinsdottir, Unnur %A Thorleifsson, Gudmar %A Stefansson, Kari %A Seshadri, Sudha %A DeStefano, Anita %A Gschwendtner, Andreas %A Psaty, Bruce %A Longstreth, Will %A Mitchell, Braxton D %A Cheng, Yu-Ching %A Clarke, Robert %A Ferrario, Marco %A Bis, Joshua C %A Levi, Christopher %A Attia, John %A Holliday, Elizabeth G %A Scott, Rodney J %A Fornage, Myriam %A Sharma, Pankaj %A Furie, Karen L %A Rosand, Jonathan %A Nalls, Mike %A Meschia, James %A Mosely, Thomas H %A Evans, Alun %A Palotie, Aarno %A Markus, Hugh S %A Grant, Peter J %A Spector, Tim D %K ABO Blood-Group System %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Blood Coagulation %K Brain Ischemia %K Cohort Studies %K Europe %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Stroke %K Young Adult %X

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

%B Ann Neurol %V 73 %P 16-31 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23381943?dopt=Abstract %R 10.1002/ana.23838 %0 Journal Article %J BMC Genet %D 2014 %T Genetic diversity is a predictor of mortality in humans. %A Bihlmeyer, Nathan A %A Brody, Jennifer A %A Smith, Albert Vernon %A Lunetta, Kathryn L %A Nalls, Mike %A Smith, Jennifer A %A Tanaka, Toshiko %A Davies, Gail %A Yu, Lei %A Mirza, Saira Saeed %A Teumer, Alexander %A Coresh, Josef %A Pankow, James S %A Franceschini, Nora %A Scaria, Anish %A Oshima, Junko %A Psaty, Bruce M %A Gudnason, Vilmundur %A Eiriksdottir, Gudny %A Harris, Tamara B %A Li, Hanyue %A Karasik, David %A Kiel, Douglas P %A Garcia, Melissa %A Liu, Yongmei %A Faul, Jessica D %A Kardia, Sharon Lr %A Zhao, Wei %A Ferrucci, Luigi %A Allerhand, Michael %A Liewald, David C %A Redmond, Paul %A Starr, John M %A De Jager, Philip L %A Evans, Denis A %A Direk, Nese %A Ikram, Mohammed Arfan %A Uitterlinden, Andre %A Homuth, Georg %A Lorbeer, Roberto %A Grabe, Hans J %A Launer, Lenore %A Murabito, Joanne M %A Singleton, Andrew B %A Weir, David R %A Bandinelli, Stefania %A Deary, Ian J %A Bennett, David A %A Tiemeier, Henning %A Kocher, Thomas %A Lumley, Thomas %A Arking, Dan E %K Genome-Wide Association Study %K Heterozygote %K Humans %K Mortality %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %X

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

%B BMC Genet %V 15 %P 159 %8 2014 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract %R 10.1186/s12863-014-0159-7 %0 Journal Article %J Stroke %D 2014 %T Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. %A Ibrahim-Verbaas, Carla A %A Fornage, Myriam %A Bis, Joshua C %A Choi, Seung Hoan %A Psaty, Bruce M %A Meigs, James B %A Rao, Madhu %A Nalls, Mike %A Fontes, João D %A O'Donnell, Christopher J %A Kathiresan, Sekar %A Ehret, Georg B %A Fox, Caroline S %A Malik, Rainer %A Dichgans, Martin %A Schmidt, Helena %A Lahti, Jari %A Heckbert, Susan R %A Lumley, Thomas %A Rice, Kenneth %A Rotter, Jerome I %A Taylor, Kent D %A Folsom, Aaron R %A Boerwinkle, Eric %A Rosamond, Wayne D %A Shahar, Eyal %A Gottesman, Rebecca F %A Koudstaal, Peter J %A Amin, Najaf %A Wieberdink, Renske G %A Dehghan, Abbas %A Hofman, Albert %A Uitterlinden, André G %A DeStefano, Anita L %A Debette, Stephanie %A Xue, Luting %A Beiser, Alexa %A Wolf, Philip A %A DeCarli, Charles %A Ikram, M Arfan %A Seshadri, Sudha %A Mosley, Thomas H %A Longstreth, W T %A van Duijn, Cornelia M %A Launer, Lenore J %K Age Factors %K Aged %K Aged, 80 and over %K Area Under Curve %K Case-Control Studies %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Regression Analysis %K Risk Factors %K ROC Curve %K Sex Factors %K Stroke %X

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

%B Stroke %V 45 %P 403-12 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract %R 10.1161/STROKEAHA.113.003044 %0 Journal Article %J Stroke %D 2015 %T Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. %A Carty, Cara L %A Keene, Keith L %A Cheng, Yu-Ching %A Meschia, James F %A Chen, Wei-Min %A Nalls, Mike %A Bis, Joshua C %A Kittner, Steven J %A Rich, Stephen S %A Tajuddin, Salman %A Zonderman, Alan B %A Evans, Michele K %A Langefeld, Carl D %A Gottesman, Rebecca %A Mosley, Thomas H %A Shahar, Eyal %A Woo, Daniel %A Yaffe, Kristine %A Liu, Yongmei %A Sale, Michèle M %A Dichgans, Martin %A Malik, Rainer %A Longstreth, W T %A Mitchell, Braxton D %A Psaty, Bruce M %A Kooperberg, Charles %A Reiner, Alexander %A Worrall, Bradford B %A Fornage, Myriam %K African Americans %K Case-Control Studies %K Cohort Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %X

BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations.

METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations.

RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS.

CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

%B Stroke %V 46 %P 2063-8 %8 2015 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/26089329?dopt=Abstract %R 10.1161/STROKEAHA.115.009044 %0 Journal Article %J Circ Cardiovasc Genet %D 2015 %T Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. %A Verhaaren, Benjamin F J %A Debette, Stephanie %A Bis, Joshua C %A Smith, Jennifer A %A Ikram, M Kamran %A Adams, Hieab H %A Beecham, Ashley H %A Rajan, Kumar B %A Lopez, Lorna M %A Barral, Sandra %A van Buchem, Mark A %A van der Grond, Jeroen %A Smith, Albert V %A Hegenscheid, Katrin %A Aggarwal, Neelum T %A de Andrade, Mariza %A Atkinson, Elizabeth J %A Beekman, Marian %A Beiser, Alexa S %A Blanton, Susan H %A Boerwinkle, Eric %A Brickman, Adam M %A Bryan, R Nick %A Chauhan, Ganesh %A Chen, Christopher P L H %A Chouraki, Vincent %A de Craen, Anton J M %A Crivello, Fabrice %A Deary, Ian J %A Deelen, Joris %A De Jager, Philip L %A Dufouil, Carole %A Elkind, Mitchell S V %A Evans, Denis A %A Freudenberger, Paul %A Gottesman, Rebecca F %A Guðnason, Vilmundur %A Habes, Mohamad %A Heckbert, Susan R %A Heiss, Gerardo %A Hilal, Saima %A Hofer, Edith %A Hofman, Albert %A Ibrahim-Verbaas, Carla A %A Knopman, David S %A Lewis, Cora E %A Liao, Jiemin %A Liewald, David C M %A Luciano, Michelle %A van der Lugt, Aad %A Martinez, Oliver O %A Mayeux, Richard %A Mazoyer, Bernard %A Nalls, Mike %A Nauck, Matthias %A Niessen, Wiro J %A Oostra, Ben A %A Psaty, Bruce M %A Rice, Kenneth M %A Rotter, Jerome I %A von Sarnowski, Bettina %A Schmidt, Helena %A Schreiner, Pamela J %A Schuur, Maaike %A Sidney, Stephen S %A Sigurdsson, Sigurdur %A Slagboom, P Eline %A Stott, David J M %A van Swieten, John C %A Teumer, Alexander %A Töglhofer, Anna Maria %A Traylor, Matthew %A Trompet, Stella %A Turner, Stephen T %A Tzourio, Christophe %A Uh, Hae-Won %A Uitterlinden, André G %A Vernooij, Meike W %A Wang, Jing J %A Wong, Tien Y %A Wardlaw, Joanna M %A Windham, B Gwen %A Wittfeld, Katharina %A Wolf, Christiane %A Wright, Clinton B %A Yang, Qiong %A Zhao, Wei %A Zijdenbos, Alex %A Jukema, J Wouter %A Sacco, Ralph L %A Kardia, Sharon L R %A Amouyel, Philippe %A Mosley, Thomas H %A Longstreth, W T %A DeCarli, Charles C %A van Duijn, Cornelia M %A Schmidt, Reinhold %A Launer, Lenore J %A Grabe, Hans J %A Seshadri, Sudha S %A Ikram, M Arfan %A Fornage, Myriam %K Aged %K Aged, 80 and over %K Chromosomes, Human %K Continental Population Groups %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Models, Genetic %K Stroke %K White Matter %X

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.

%B Circ Cardiovasc Genet %V 8 %P 398-409 %8 2015 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract %R 10.1161/CIRCGENETICS.114.000858 %0 Journal Article %J JAMA Neurol %D 2015 %T Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. %A Auer, Paul L %A Nalls, Mike %A Meschia, James F %A Worrall, Bradford B %A Longstreth, W T %A Seshadri, Sudha %A Kooperberg, Charles %A Burger, Kathleen M %A Carlson, Christopher S %A Carty, Cara L %A Chen, Wei-Min %A Cupples, L Adrienne %A DeStefano, Anita L %A Fornage, Myriam %A Hardy, John %A Hsu, Li %A Jackson, Rebecca D %A Jarvik, Gail P %A Kim, Daniel S %A Lakshminarayan, Kamakshi %A Lange, Leslie A %A Manichaikul, Ani %A Quinlan, Aaron R %A Singleton, Andrew B %A Thornton, Timothy A %A Nickerson, Deborah A %A Peters, Ulrike %A Rich, Stephen S %K Aged %K Brain Ischemia %K Exome %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Muscle Proteins %K National Heart, Lung, and Blood Institute (U.S.) %K Nuclear Proteins %K Open Reading Frames %K Palmitoyl-CoA Hydrolase %K Stroke %K United States %X

IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

%B JAMA Neurol %V 72 %P 781-8 %8 2015 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/25961151?dopt=Abstract %R 10.1001/jamaneurol.2015.0582