@article {1217, title = {Genome-wide association analysis identifies multiple loci related to resting heart rate.}, journal = {Hum Mol Genet}, volume = {19}, year = {2010}, month = {2010 Oct 01}, pages = {3885-94}, abstract = {

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 {\texttimes} 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7\% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6\%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

}, keywords = {Adult, Aged, Base Pairing, Cohort Studies, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Heart Rate, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Rest}, issn = {1460-2083}, doi = {10.1093/hmg/ddq303}, author = {Eijgelsheim, Mark and Newton-Cheh, Christopher and Sotoodehnia, Nona and de Bakker, Paul I W and M{\"u}ller, Martina and Morrison, Alanna C and Smith, Albert V and Isaacs, Aaron and Sanna, Serena and D{\"o}rr, Marcus and Navarro, Pau and Fuchsberger, Christian and Nolte, Ilja M and de Geus, Eco J C and Estrada, Karol and Hwang, Shih-Jen and Bis, Joshua C and R{\"u}ckert, Ina-Maria and Alonso, Alvaro and Launer, Lenore J and Hottenga, Jouke Jan and Rivadeneira, Fernando and Noseworthy, Peter A and Rice, Kenneth M and Perz, Siegfried and Arking, Dan E and Spector, Tim D and Kors, Jan A and Aulchenko, Yurii S and Tarasov, Kirill V and Homuth, Georg and Wild, Sarah H and Marroni, Fabio and Gieger, Christian and Licht, Carmilla M and Prineas, Ronald J and Hofman, Albert and Rotter, Jerome I and Hicks, Andrew A and Ernst, Florian and Najjar, Samer S and Wright, Alan F and Peters, Annette and Fox, Ervin R and Oostra, Ben A and Kroemer, Heyo K and Couper, David and V{\"o}lzke, Henry and Campbell, Harry and Meitinger, Thomas and Uda, Manuela and Witteman, Jacqueline C M and Psaty, Bruce M and Wichmann, H-Erich and Harris, Tamara B and K{\"a}{\"a}b, Stefan and Siscovick, David S and Jamshidi, Yalda and Uitterlinden, Andr{\'e} G and Folsom, Aaron R and Larson, Martin G and Wilson, James F and Penninx, Brenda W and Snieder, Harold and Pramstaller, Peter P and van Duijn, Cornelia M and Lakatta, Edward G and Felix, Stephan B and Gudnason, Vilmundur and Pfeufer, Arne and Heckbert, Susan R and Stricker, Bruno H Ch and Boerwinkle, Eric and O{\textquoteright}Donnell, Christopher J} } @article {1182, title = {Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Mar 25}, pages = {e9879}, abstract = {

BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.

METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95\% CI 0.74 to 0.98; p<0.01).

CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

}, keywords = {Aged, Alleles, Case-Control Studies, Cohort Studies, Death, Sudden, Cardiac, Ethnic Groups, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glypicans, Heart Diseases, Humans, Male, Middle Aged, Models, Genetic, Oligonucleotide Array Sequence Analysis, Oregon, Polymorphism, Single Nucleotide}, issn = {1932-6203}, doi = {10.1371/journal.pone.0009879}, author = {Arking, Dan E and Reinier, Kyndaron and Post, Wendy and Jui, Jonathan and Hilton, Gina and O{\textquoteright}Connor, Ashley and Prineas, Ronald J and Boerwinkle, Eric and Psaty, Bruce M and Tomaselli, Gordon F and Rea, Thomas and Sotoodehnia, Nona and Siscovick, David S and Burke, Gregory L and Marb{\'a}n, Eduardo and Spooner, Peter M and Chakravarti, Aravinda and Chugh, Sumeet S} } @article {1304, title = {Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jun}, pages = {e1002158}, abstract = {

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (Pā€Š=ā€Š1.8{\texttimes}10(-10)). The risk allele, while ancestral, has a frequency of ~1.4\%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95\% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (Pā€Š=ā€Š0.006).

}, keywords = {Adult, Aged, Alleles, Chromosomes, Human, Pair 2, Death, Sudden, Cardiac, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Contraction, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002158}, author = {Arking, Dan E and Junttila, M Juhani and Goyette, Philippe and Huertas-Vazquez, Adriana and Eijgelsheim, Mark and Blom, Marieke T and Newton-Cheh, Christopher and Reinier, Kyndaron and Teodorescu, Carmen and Uy-Evanado, Audrey and Carter-Monroe, Naima and Kaikkonen, Kari S and Kortelainen, Marja-Leena and Boucher, Gabrielle and Lagac{\'e}, Caroline and Moes, Anna and Zhao, XiaoQing and Kolodgie, Frank and Rivadeneira, Fernando and Hofman, Albert and Witteman, Jacqueline C M and Uitterlinden, Andr{\'e} G and Marsman, Roos F and Pazoki, Raha and Bardai, Abdennasser and Koster, Rudolph W and Dehghan, Abbas and Hwang, Shih-Jen and Bhatnagar, Pallav and Post, Wendy and Hilton, Gina and Prineas, Ronald J and Li, Man and K{\"o}ttgen, Anna and Ehret, Georg and Boerwinkle, Eric and Coresh, Josef and Kao, W H Linda and Psaty, Bruce M and Tomaselli, Gordon F and Sotoodehnia, Nona and Siscovick, David S and Burke, Greg L and Marb{\'a}n, Eduardo and Spooner, Peter M and Cupples, L Adrienne and Jui, Jonathan and Gunson, Karen and Kesaniemi, Y Antero and Wilde, Arthur A M and Tardif, Jean-Claude and O{\textquoteright}Donnell, Christopher J and Bezzina, Connie R and Virmani, Renu and Stricker, Bruno H C H and Tan, Hanno L and Albert, Christine M and Chakravarti, Aravinda and Rioux, John D and Huikuri, Heikki V and Chugh, Sumeet S} }