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6 results on '"Grewal, Raji P"'

1. Multi-ethnic genome-wide association study for atrial fibrillation

Author

Roselli, Carolina, Chaffin, Mark D, Weng, Lu-Chen, Aeschbacher, Stefanie, Ahlberg, Gustav, Albert, Christine M, Almgren, Peter, Alonso, Alvaro, Anderson, Christopher D, Aragam, Krishna G, Arking, Dan E, Barnard, John, Bartz, Traci M, Benjamin, Emelia J, Bihlmeyer, Nathan A, Bis, Joshua C, Bloom, Heather L, Boerwinkle, Eric, Bottinger, Erwin B, Brody, Jennifer A, Calkins, Hugh, Campbell, Archie, Cappola, Thomas P, Carlquist, John, Chasman, Daniel I, Chen, Lin Y, Chen, Yii-Der Ida, Choi, Eue-Keun, Choi, Seung Hoan, Christophersen, Ingrid E, Chung, Mina K, Cole, John W, Conen, David, Cook, James, Crijns, Harry J, Cutler, Michael J, Damrauer, Scott M, Daniels, Brian R, Darbar, Dawood, Delgado, Graciela, Denny, Joshua C, Dichgans, Martin, Dörr, Marcus, Dudink, Elton A, Dudley, Samuel C, Esa, Nada, Esko, Tonu, Eskola, Markku, Fatkin, Diane, Felix, Stephan B, Ford, Ian, Franco, Oscar H, Geelhoed, Bastiaan, Grewal, Raji P, Gudnason, Vilmundur, Guo, Xiuqing, Gupta, Namrata, Gustafsson, Stefan, Gutmann, Rebecca, Hamsten, Anders, Harris, Tamara B, Hayward, Caroline, Heckbert, Susan R, Hernesniemi, Jussi, Hocking, Lynne J, Hofman, Albert, Horimoto, Andrea RVR, Huang, Jie, Huang, Paul L, Huffman, Jennifer, Ingelsson, Erik, Ipek, Esra Gucuk, Ito, Kaoru, Jimenez-Conde, Jordi, Johnson, Renee, Jukema, J Wouter, Kääb, Stefan, Kähönen, Mika, Kamatani, Yoichiro, Kane, John P, Kastrati, Adnan, Kathiresan, Sekar, Katschnig-Winter, Petra, Kavousi, Maryam, Kessler, Thorsten, Kietselaer, Bas L, Kirchhof, Paulus, Kleber, Marcus E, Knight, Stacey, Krieger, Jose E, Kubo, Michiaki, Launer, Lenore J, Laurikka, Jari, Lehtimäki, Terho, Leineweber, Kirsten, Lemaitre, Rozenn N, Li, Man, Lim, Hong Euy, Lin, Henry J, and Lin, Honghuang

Subjects
Biological Sciences, Genetics, Heart Disease, Cardiovascular, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Atrial Fibrillation, Case-Control Studies, Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Quantitative Trait Loci, Transcriptome, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Published
2018

2. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei-Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I, Ikram, M Arfan, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei-Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, and Sale, Michele M

Subjects
Biological Sciences, Genetics, Human Genome, Stroke, Clinical Research, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Computational Biology, Databases, Genetic, Epigenesis, Genetic, Female, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, INDEL Mutation, Linkage Disequilibrium, Male, Models, Genetic, Polymorphism, Single Nucleotide, Risk Factors, AFGen Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, International Genomics of Blood Pressure (iGEN-BP) Consortium, INVENT Consortium, STARNET, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium, METASTROKE Consortium, Neurology Working Group of the CHARGE Consortium, NINDS Stroke Genetics Network, UK Young Lacunar DNA Study, MEGASTROKE Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Published
2018

3. Genetic variation at 16q24.2 is associated with small vessel stroke

Author

Traylor, Matthew, Malik, Rainer, Nalls, Mike A, Cotlarciuc, Ioana, Radmanesh, Farid, Thorleifsson, Gudmar, Hanscombe, Ken B, Langefeld, Carl, Saleheen, Danish, Rost, Natalia S, Yet, Idil, Spector, Tim D, Bell, Jordana T, Hannon, Eilis, Mill, Jonathan, Chauhan, Ganesh, Debette, Stephanie, Bis, Joshua C, Longstreth, WT, Ikram, M Arfan, Launer, Lenore J, Seshadri, Sudha, METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium, Hamilton-Bruce, Monica Anne, Jimenez-Conde, Jordi, Cole, John W, Schmidt, Reinhold, Słowik, Agnieszka, Lemmens, Robin, Lindgren, Arne, Melander, Olle, Grewal, Raji P, Sacco, Ralph L, Rundek, Tatjana, Rexrode, Kathryn, Arnett, Donna K, Johnson, Julie A, Benavente, Oscar R, Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Pulit, Sara L, Wong, Quenna, Rich, Stephen S, de Bakker, Paul IW, McArdle, Patrick F, Woo, Daniel, Anderson, Christopher D, Xu, Huichun, Heitsch, Laura, Fornage, Myriam, Jern, Christina, Stefansson, Kari, Thorsteinsdottir, Unnur, Gretarsdottir, Solveig, Lewis, Cathryn M, Sharma, Pankaj, Sudlow, Cathie LM, Rothwell, Peter M, Boncoraglio, Giorgio B, Thijs, Vincent, Levi, Chris, Meschia, James F, Rosand, Jonathan, Kittner, Steven J, Mitchell, Braxton D, Dichgans, Martin, Worrall, Bradford B, Markus, Hugh S, International Stroke Genetics Consortium, Traylor, Matthew [0000-0001-6624-8621], Markus, Hugh [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, Genetic Variation, Zinc Fingers, Middle Aged, Stroke, Genetic Loci, Cerebral Small Vessel Diseases, Stroke, Lacunar, Humans, Female, Chromosomes, Human, Pair 16, Aged, Genome-Wide Association Study
Abstract

OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. METHODS: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10-9 ). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10-5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10-7 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10-6 ). INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394.

Published
2017

4. Genetic variation at 16q24.2 is associated with small vessel stroke

Author

Traylor, Matthew, Malik, Rainer, Nalls, Mike A, Cotlarciuc, Ioana, Radmanesh, Farid, Thorleifsson, Gudmar, Hanscombe, Ken B, Langefeld, Carl, Saleheen, Danish, Rost, Natalia S, Yet, Idil, Spector, Tim D, Bell, Jordana T, Hannon, Eilis, Mill, Jonathan, Chauhan, Ganesh, Debette, Stephanie, Bis, Joshua C, Longstreth, WT, Ikram, M Arfan, Launer, Lenore J, Seshadri, Sudha, METASTROKE, UK Young Lacunar DNA Study, Hamilton-Bruce, Monica Anne, Jimenez-Conde, Jordi, Cole, John W, Schmidt, Reinhold, Słowik, Agnieszka, Lemmens, Robin, Lindgren, Arne, Melander, Olle, Grewal, Raji P, Sacco, Ralph L, Rundek, Tatjana, Rexrode, Kathryn, Arnett, Donna K, Johnson, Julie A, Benavente, Oscar R, Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Pulit, Sara L, Wong, Quenna, Rich, Stephen S, De Bakker, Paul IW, McArdle, Patrick F, Woo, Daniel, Anderson, Christopher D, Xu, Huichun, Heitsch, Laura, Fornage, Myriam, Jern, Christina, Stefansson, Kari, Thorsteinsdottir, Unnur, Gretarsdottir, Solveig, Lewis, Cathryn M, Sharma, Pankaj, Sudlow, Cathie LM, Rothwell, Peter M, Boncoraglio, Giorgio B, Thijs, Vincent, Levi, Chris, Meschia, James F, Rosand, Jonathan, Kittner, Steven J, Mitchell, Braxton D, Dichgans, Martin, Worrall, Bradford B, Markus, Hugh S, and International Stroke Genetics Consortium

Subjects
Adult, Aged, 80 and over, Male, Genetic Variation, Zinc Fingers, Middle Aged, 3. Good health, Stroke, Genetic Loci, Cerebral Small Vessel Diseases, Stroke, Lacunar, Humans, Female, Chromosomes, Human, Pair 16, Aged, Genome-Wide Association Study
Abstract

OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. METHODS: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10-9 ). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10-5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10-7 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10-6 ). INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394.

5. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Author

Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, Van Der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei-Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, De Bakker, Paul IW, DeStefano, Anita L, Den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I, Ikram, M Arfan, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei-Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O'Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, Van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil-Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, AFGen Consortium, Cohorts For Heart And Aging Research In Genomic Epidemiology (CHARGE) Consortium, International Genomics Of Blood Pressure (IGEN-BP) Consortium, INVENT Consortium, STARNET, Bis, Joshua C, Pastinen, Tomi, Ruusalepp, Arno, Schadt, Eric E, Koplev, Simon, Björkegren, Johan LM, Codoni, Veronica, Civelek, Mete, Smith, Nicholas L, Trégouët, David A, Christophersen, Ingrid E, Roselli, Carolina, Lubitz, Steven A, Ellinor, Patrick T, Tai, E Shyong, Kooner, Jaspal S, Kato, Norihiro, He, Jiang, Van Der Harst, Pim, Elliott, Paul, Chambers, John C, Takeuchi, Fumihiko, Johnson, Andrew D, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC-CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Consortium (ISGC), METASTROKE Consortium, Neurology Working Group Of The CHARGE Consortium, NINDS Stroke Genetics Network (SiGN), UK Young Lacunar DNA Study, MEGASTROKE Consortium, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Longstreth, WT, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Subjects
Male, Models, Genetic, Computational Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 3. Good health, Epigenesis, Genetic, Stroke, INDEL Mutation, Genetic Loci, Risk Factors, Databases, Genetic, Humans, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

6. Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls

Author

Traylor, Matthew, Anderson, Christopher D, Rutten-Jacobs, Loes CA, Falcone, Guido J, Comeau, Mary E, Ay, Hakan, Sudlow, Cathie LM, Xu, Huichun, Mitchell, Braxton D, Cole, John W, Rexrode, Kathryn, Jimenez-Conde, Jordi, Schmidt, Reinhold, Grewal, Raji P, Sacco, Ralph, Ribases, Marta, Rundek, Tatjana, Rosand, Jonathan, Dichgans, Martin, Lee, Jin-Moo, Langefeld, Carl D, Kittner, Steven J, Markus, Hugh S, Woo, Daniel, Malik, Rainer, and NINDS Stroke Genetics Network (SiGN) And International Stroke Genetics Consortium (ISGC)

Subjects
Aged, 80 and over, Male, cerebral hemorrhage, haplotype, Genotype, Bayes Theorem, Middle Aged, 3. Good health, Europe, Stroke, Genetic Loci, Case-Control Studies, Humans, Female, cardiovascular diseases, chromosome, atherosclerosis, dementia, Aged, Genome-Wide Association Study
Abstract

BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

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