@article {1323, title = {Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 11}, pages = {940-7}, abstract = {

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 {\texttimes} 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

}, keywords = {Adult, Aged, Aging, Atherosclerosis, Carotid Intima-Media Thickness, Cohort Studies, Coronary Artery Disease, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Heart, Humans, Middle Aged, Phenotype, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.920}, author = {Bis, Joshua C and Kavousi, Maryam and Franceschini, Nora and Isaacs, Aaron and Abecasis, Goncalo R and Schminke, Ulf and Post, Wendy S and Smith, Albert V and Cupples, L Adrienne and Markus, Hugh S and Schmidt, Reinhold and Huffman, Jennifer E and Lehtim{\"a}ki, Terho and Baumert, Jens and M{\"u}nzel, Thomas and Heckbert, Susan R and Dehghan, Abbas and North, Kari and Oostra, Ben and Bevan, Steve and Stoegerer, Eva-Maria and Hayward, Caroline and Raitakari, Olli and Meisinger, Christa and Schillert, Arne and Sanna, Serena and V{\"o}lzke, Henry and Cheng, Yu-Ching and Thorsson, Bolli and Fox, Caroline S and Rice, Kenneth and Rivadeneira, Fernando and Nambi, Vijay and Halperin, Eran and Petrovic, Katja E and Peltonen, Leena and Wichmann, H Erich and Schnabel, Renate B and D{\"o}rr, Marcus and Parsa, Afshin and Aspelund, Thor and Demissie, Serkalem and Kathiresan, Sekar and Reilly, Muredach P and Taylor, Kent and Uitterlinden, Andre and Couper, David J and Sitzer, Matthias and K{\"a}h{\"o}nen, Mika and Illig, Thomas and Wild, Philipp S and Orr{\`u}, Marco and L{\"u}demann, Jan and Shuldiner, Alan R and Eiriksdottir, Gudny and White, Charles C and Rotter, Jerome I and Hofman, Albert and Seissler, Jochen and Zeller, Tanja and Usala, Gianluca and Ernst, Florian and Launer, Lenore J and D{\textquoteright}Agostino, Ralph B and O{\textquoteright}Leary, Daniel H and Ballantyne, Christie and Thiery, Joachim and Ziegler, Andreas and Lakatta, Edward G and Chilukoti, Ravi Kumar and Harris, Tamara B and Wolf, Philip A and Psaty, Bruce M and Polak, Joseph F and Li, Xia and Rathmann, Wolfgang and Uda, Manuela and Boerwinkle, Eric and Klopp, Norman and Schmidt, Helena and Wilson, James F and Viikari, Jorma and Koenig, Wolfgang and Blankenberg, Stefan and Newman, Anne B and Witteman, Jacqueline and Heiss, Gerardo and Duijn, Cornelia van and Scuteri, Angelo and Homuth, Georg and Mitchell, Braxton D and Gudnason, Vilmundur and O{\textquoteright}Donnell, Christopher J} } @article {6297, title = {Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Feb}, pages = {394-402}, abstract = {

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

}, keywords = {Adult, Aged, Aged, 80 and over, Atrial Fibrillation, Blood Pressure, Brain Ischemia, Case-Control Studies, Cohort Studies, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Multilocus Sequence Typing, Polymorphism, Single Nucleotide, Population, Prospective Studies, Reproducibility of Results, Risk Assessment, Risk Factors, Sex Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.113.002938}, author = {Malik, Rainer and Bevan, Steve and Nalls, Michael A and Holliday, Elizabeth G and Devan, William J and Cheng, Yu-Ching and Ibrahim-Verbaas, Carla A and Verhaaren, Benjamin F J and Bis, Joshua C and Joon, Aron Y and de Stefano, Anita L and Fornage, Myriam and Psaty, Bruce M and Ikram, M Arfan and Launer, Lenore J and van Duijn, Cornelia M and Sharma, Pankaj and Mitchell, Braxton D and Rosand, Jonathan and Meschia, James F and Levi, Christopher and Rothwell, Peter M and Sudlow, Cathie and Markus, Hugh S and Seshadri, Sudha and Dichgans, Martin} }