@article {1092, title = {Genomewide association studies of stroke.}, journal = {N Engl J Med}, volume = {360}, year = {2009}, month = {2009 Apr 23}, pages = {1718-28}, abstract = {

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95\% confidence interval [CI], 1.19 to 1.42) and 1.33 (95\% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11\% and 12\% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95\% CI, 1.01 to 1.79; P=0.04) and 1.42 (95\% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95\% CI, 1.01 to 1.37; P=0.03) and 1.19 (95\% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

}, keywords = {African Continental Ancestry Group, Aged, Chromosomes, Human, Pair 12, Cohort Studies, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Stroke}, issn = {1533-4406}, doi = {10.1056/NEJMoa0900094}, author = {Ikram, M Arfan and Seshadri, Sudha and Bis, Joshua C and Fornage, Myriam and DeStefano, Anita L and Aulchenko, Yurii S and Debette, Stephanie and Lumley, Thomas and Folsom, Aaron R and van den Herik, Evita G and Bos, Michiel J and Beiser, Alexa and Cushman, Mary and Launer, Lenore J and Shahar, Eyal and Struchalin, Maksim and Du, Yangchun and Glazer, Nicole L and Rosamond, Wayne D and Rivadeneira, Fernando and Kelly-Hayes, Margaret and Lopez, Oscar L and Coresh, Josef and Hofman, Albert and DeCarli, Charles and Heckbert, Susan R and Koudstaal, Peter J and Yang, Qiong and Smith, Nicholas L and Kase, Carlos S and Rice, Kenneth and Haritunians, Talin and Roks, Gerwin and de Kort, Paul L M and Taylor, Kent D and de Lau, Lonneke M and Oostra, Ben A and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Boerwinkle, Eric and Psaty, Bruce M and Mosley, Thomas H and van Duijn, Cornelia M and Breteler, Monique M B and Longstreth, W T and Wolf, Philip A} } @article {1156, title = {Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.}, journal = {Stroke}, volume = {41}, year = {2010}, month = {2010 Feb}, pages = {210-7}, abstract = {

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4\% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20\%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95\% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

}, keywords = {African Americans, Aged, Brain, Brain Infarction, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.109.569194}, author = {Debette, Stephanie and Bis, Joshua C and Fornage, Myriam and Schmidt, Helena and Ikram, M Arfan and Sigurdsson, Sigurdur and Heiss, Gerardo and Struchalin, Maksim and Smith, Albert V and van der Lugt, Aad and DeCarli, Charles and Lumley, Thomas and Knopman, David S and Enzinger, Christian and Eiriksdottir, Gudny and Koudstaal, Peter J and DeStefano, Anita L and Psaty, Bruce M and Dufouil, Carole and Catellier, Diane J and Fazekas, Franz and Aspelund, Thor and Aulchenko, Yurii S and Beiser, Alexa and Rotter, Jerome I and Tzourio, Christophe and Shibata, Dean K and Tscherner, Maria and Harris, Tamara B and Rivadeneira, Fernando and Atwood, Larry D and Rice, Kenneth and Gottesman, Rebecca F and van Buchem, Mark A and Uitterlinden, Andr{\'e} G and Kelly-Hayes, Margaret and Cushman, Mary and Zhu, Yicheng and Boerwinkle, Eric and Gudnason, Vilmundur and Hofman, Albert and Romero, Jose R and Lopez, Oscar and van Duijn, Cornelia M and Au, Rhoda and Heckbert, Susan R and Wolf, Philip A and Mosley, Thomas H and Seshadri, Sudha and Breteler, Monique M B and Schmidt, Reinhold and Launer, Lenore J and Longstreth, W T} } @article {1226, title = {Independent susceptibility markers for atrial fibrillation on chromosome 4q25.}, journal = {Circulation}, volume = {122}, year = {2010}, month = {2010 Sep 07}, pages = {976-84}, abstract = {

BACKGROUND: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.

METHODS AND RESULTS: Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95\% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals.

CONCLUSIONS: We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.

}, keywords = {Aged, Aged, 80 and over, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.109.886440}, author = {Lubitz, Steven A and Sinner, Moritz F and Lunetta, Kathryn L and Makino, Seiko and Pfeufer, Arne and Rahman, Rosanna and Veltman, Caroline E and Barnard, John and Bis, Joshua C and Danik, Stephan P and Sonni, Akshata and Shea, Marisa A and Del Monte, Federica and Perz, Siegfried and M{\"u}ller, Martina and Peters, Annette and Greenberg, Steven M and Furie, Karen L and van Noord, Charlotte and Boerwinkle, Eric and Stricker, Bruno H C and Witteman, Jacqueline and Smith, Jonathan D and Chung, Mina K and Heckbert, Susan R and Benjamin, Emelia J and Rosand, Jonathan and Arking, Dan E and Alonso, Alvaro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T} } @article {6820, title = {Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.}, journal = {J Am Coll Cardiol}, volume = {63}, year = {2014}, month = {2014 Apr 1}, pages = {1200-10}, abstract = {

OBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.

BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.

METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).

RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.

CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

}, keywords = {Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, Europe, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Polymorphism, Single Nucleotide, Transcription Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2013.12.015}, author = {Lubitz, Steven A and Lunetta, Kathryn L and Lin, Honghuang and Arking, Dan E and Trompet, Stella and Li, Guo and Krijthe, Bouwe P and Chasman, Daniel I and Barnard, John and Kleber, Marcus E and D{\"o}rr, Marcus and Ozaki, Kouichi and Smith, Albert V and M{\"u}ller-Nurasyid, Martina and Walter, Stefan and Agarwal, Sunil K and Bis, Joshua C and Brody, Jennifer A and Chen, Lin Y and Everett, Brendan M and Ford, Ian and Franco, Oscar H and Harris, Tamara B and Hofman, Albert and K{\"a}{\"a}b, Stefan and Mahida, Saagar and Kathiresan, Sekar and Kubo, Michiaki and Launer, Lenore J and Macfarlane, Peter W and Magnani, Jared W and McKnight, Barbara and McManus, David D and Peters, Annette and Psaty, Bruce M and Rose, Lynda M and Rotter, Jerome I and Silbernagel, Guenther and Smith, Jonathan D and Sotoodehnia, Nona and Stott, David J and Taylor, Kent D and Tomaschitz, Andreas and Tsunoda, Tatsuhiko and Uitterlinden, Andr{\'e} G and Van Wagoner, David R and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Murabito, Joanne M and Sinner, Moritz F and Gudnason, Vilmundur and Felix, Stephan B and M{\"a}rz, Winfried and Chung, Mina and Albert, Christine M and Stricker, Bruno H and Tanaka, Toshihiro and Heckbert, Susan R and Jukema, J Wouter and Alonso, Alvaro and Benjamin, Emelia J and Ellinor, Patrick T} }