%0 Journal Article %J Am J Respir Crit Care Med %D 2004 %T Sleep apnea and markers of vascular endothelial function in a large community sample of older adults. %A Nieto, F Javier %A Herrington, David M %A Redline, Susan %A Benjamin, Emelia J %A Robbins, John A %K Age Factors %K Aged %K Aged, 80 and over %K Biomarkers %K Body Mass Index %K Brachial Artery %K Cardiovascular Diseases %K Cohort Studies %K Comorbidity %K Endothelium, Vascular %K Female %K Humans %K Hypertension %K Linear Models %K Male %K Polysomnography %K Prevalence %K Probability %K Residence Characteristics %K Risk Assessment %K Sampling Studies %K Severity of Illness Index %K Sleep Apnea Syndromes %K Ultrasonography, Doppler %X

Clinical studies have suggested that sleep apnea is associated with impaired brachial artery flow-mediated dilation, a surrogate of endothelial dysfunction. We examined this question among older participants in the baseline examination of the Sleep Heart Health/Cardiovascular Health Study cohort (n = 1,037, age 68 years or older, 56% female). Indices of sleep apnea, derived from 12-channel home polysomnography, were the apnea-hypopnea index (average number of apneas/hypopneas per hour) and the hypoxemia index (percentage of time below 90% O2 saturation). Baseline arterial diameter and percentage of flow-mediated dilation were measured by ultrasound. Sleep apnea measures were associated with baseline diameter and the percentage of flow-mediated dilation, although these associations were weakened after adjustment for other cardiovascular risk factors, particularly body mass index. However, a statistically significant linear association between the hypoxemia index and baseline diameter was observed even after adjustment for body mass index and other confounders (p < 0.01). The associations were stronger among participants who were younger than 80 years and among those who with hypertension. This study adds to the growing body of evidence linking sleep apnea with vascular dysfunction in older subjects. Whether these relationships are entirely independent of obesity is unclear. This association might be one of the mechanisms explaining the relationship between sleep apnea, hypertension, and cardiovascular disease.

%B Am J Respir Crit Care Med %V 169 %P 354-60 %8 2004 Feb 01 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/14551166?dopt=Abstract %R 10.1164/rccm.200306-756OC %0 Journal Article %J Am J Respir Crit Care Med %D 2006 %T Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. %A Mehra, Reena %A Benjamin, Emelia J %A Shahar, Eyal %A Gottlieb, Daniel J %A Nawabit, Rawan %A Kirchner, H Lester %A Sahadevan, Jayakumar %A Redline, Susan %K Aged %K Aged, 80 and over %K Arrhythmias, Cardiac %K Circadian Rhythm %K Electrocardiography %K Female %K Follow-Up Studies %K Humans %K Male %K Middle Aged %K Odds Ratio %K Polysomnography %K Prevalence %K Retrospective Studies %K Risk Factors %K Severity of Illness Index %K Sleep %K Sleep Apnea, Obstructive %X

RATIONALE: Sleep-disordered breathing recurrent intermittent hypoxia and sympathetic nervous system activity surges provide the milieu for cardiac arrhythmia development.

OBJECTIVE: We postulate that the prevalence of nocturnal cardiac arrhythmias is higher among subjects with than without sleep-disordered breathing.

METHODS: The prevalence of arrhythmias was compared in two samples of participants from the Sleep Heart Health Study frequency-matched on age, sex, race/ethnicity, and body mass index: (1) 228 subjects with sleep-disordered breathing (respiratory disturbance index>or=30) and (2) 338 subjects without sleep-disordered breathing (respiratory disturbance index<5).

RESULTS: Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy (nonsustained ventricular tachycardia or bigeminy or trigeminy or quadrigeminy) were more common in subjects with sleep-disordered breathing compared with those without sleep-disordered breathing: 4.8 versus 0.9% (p=0.003) for atrial fibrillation; 5.3 versus 1.2% (p=0.004) for nonsustained ventricular tachycardia; 25.0 versus 14.5% (p=0.002) for complex ventricular ectopy. Compared with those without sleep-disordered breathing and adjusting for age, sex, body mass index, and prevalent coronary heart disease, individuals with sleep-disordered breathing had four times the odds of atrial fibrillation (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.03-15.74), three times the odds of nonsustained ventricular tachycardia (OR, 3.40; 95% CI, 1.03-11.20), and almost twice the odds of complex ventricular ectopy (OR, 1.74; 95% CI, 1.11-2.74). A significant relation was also observed between sleep-disordered breathing and ventricular ectopic beats/h (p<0.0003) considered as a continuous outcome.

CONCLUSIONS: Individuals with severe sleep-disordered breathing have two- to fourfold higher odds of complex arrhythmias than those without sleep-disordered breathing even after adjustment for potential confounders.

%B Am J Respir Crit Care Med %V 173 %P 910-6 %8 2006 Apr 15 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/16424443?dopt=Abstract %R 10.1164/rccm.200509-1442OC %0 Journal Article %J Sleep %D 2006 %T Obstructive sleep apnea and plasma natriuretic peptide levels in a community-based sample. %A Patwardhan, Anjali A %A Larson, Martin G %A Levy, Daniel %A Benjamin, Emelia J %A Leip, Eric P %A Keyes, Michelle J %A Wang, Thomas J %A Gottlieb, Daniel J %A Vasan, Ramachandran S %K Atrial Fibrillation %K Body Mass Index %K Cohort Studies %K Female %K Humans %K Hypertension %K Male %K Middle Aged %K Myocardial Infarction %K Natriuretic Peptides %K Obesity %K Polysomnography %K Prevalence %K Residence Characteristics %K Severity of Illness Index %K Sleep Apnea, Obstructive %X

STUDY OBJECTIVES: We hypothesized that alterations in cardiac hemodynamics associated with obstructive sleep apnea-hypopnea (OSAH) would be reflected in higher natriuretic peptide levels. We examined the association of OSAH with natriuretic peptides in a community-based sample.

DESIGN: Cross-sectional, retrospective, observational study.

SETTING: Framingham Heart Study Offspring Cohort and Sleep Heart Health Study.

PARTICIPANTS: Community-based sample of 623 individuals.

MEASUREMENTS: Full-montage home polysomnography was used to determine apnea-hypopnea index (AHI) and percentage of time with an oxyhemoglobin saturation < 90% (PctLt90). Sensitive immunoradiometric assays were used to measure plasma B-type (BNP) and N-terminal pro-atrial natriuretic peptide (NT-ANP). Multivariable regression was used to examine the relations between natriuretic peptides and indicators of OSAH, adjusting for age, sex, body mass index, and clinical covariates.

RESULTS: No statistically significant relations between OSAH indices and BNP were observed in the multivariable model. Compared with an AHI < 5, relative levels of 1.20, 0.88, and 0.91 were observed forAHI categories 5-15, 15-30, >30 events per hour, respectively. For NT-ANP, no significant relations were seen with AHI in the multivariable model (relative levels of 0.98, 0.91, and 0.90). An inverse association was observed between NT-ANP and PctLt90 in age- and sex-adjusted models (relative levels of 0.93, 0.87, and 0.80), although this association became statistically nonsignificant after adjusting for body mass index.

CONCLUSION: Lack of association of natriuretic peptides with OSAH indices suggests that undiagnosed OSAH may not be associated with major alterations in left ventricular function, as reflected in morning natriuretic peptide levels.

%B Sleep %V 29 %P 1301-6 %8 2006 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/17068983?dopt=Abstract %R 10.1093/sleep/29.10.1301 %0 Journal Article %J Circulation %D 2008 %T Left ventricular morphology and systolic function in sleep-disordered breathing: the Sleep Heart Health Study. %A Chami, Hassan A %A Devereux, Richard B %A Gottdiener, John S %A Mehra, Reena %A Roman, Mary J %A Benjamin, Emelia J %A Gottlieb, Daniel J %K Aged %K Echocardiography %K Female %K Humans %K Hypertrophy, Left Ventricular %K Hypoxia %K Male %K Middle Aged %K Odds Ratio %K Sleep Apnea Syndromes %K Systole %K Ventricular Dysfunction, Left %X

BACKGROUND: Whether sleep-disordered breathing (SDB) is a risk factor for left ventricular (LV) hypertrophy and dysfunction is controversial. We assessed the relation of SDB to LV morphology and systolic function in a community-based sample of middle-aged and older adults.

METHODS AND RESULTS: The present study was a cross-sectional observational study of 2058 Sleep Heart Health Study participants (mean age 65+/-12 years; 58% women; 44% ethnic minorities) who had technically adequate echocardiograms. A polysomnographically derived apnea-hypopnea index (AHI) and hypoxemia index (percent of sleep time with oxyhemoglobin saturation < 90%) were used to quantify SDB severity. LV mass index was significantly associated with both AHI and hypoxemia index after adjustment for age, sex, ethnicity, study site, body mass index, current and prior smoking, alcohol consumption, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and prevalent myocardial infarction. Adjusted LV mass index was 41.3 (SD 9.90) g/m(2.7) in participants with AHI < 5 (n=957) and 44.1 (SD 9.90) g/m(2.7) in participants with AHI > or = 30 (n=84) events per hour. Compared with participants with AHI < 5, those with AHI > or = 30 had an adjusted odds ratio of 1.78 (95% confidence interval 1.14 to 2.79) for LV hypertrophy. A higher AHI and higher hypoxemia index were also associated with larger LV diastolic dimension and lower LV ejection fraction, with a trend toward lower LV fractional shortening. LV wall thickness was significantly associated with the hypoxemia index but not with AHI. Left atrial diameter was not associated with either SDB measure.

CONCLUSIONS: In a community-based cohort, SDB is associated with echocardiographic evidence of increased LV mass and reduced LV systolic function.

%B Circulation %V 117 %P 2599-607 %8 2008 May 20 %G eng %N 20 %1 https://www.ncbi.nlm.nih.gov/pubmed/18458174?dopt=Abstract %R 10.1161/CIRCULATIONAHA.107.717892 %0 Journal Article %J Vasc Med %D 2009 %T Brachial artery diameter, blood flow and flow-mediated dilation in sleep-disordered breathing. %A Chami, Hassan A %A Keyes, Michelle J %A Vita, Joseph A %A Mitchell, Gary F %A Larson, Martin G %A Fan, Shuxia %A Vasan, Ramachandran S %A O'Connor, George T %A Benjamin, Emelia J %A Gottlieb, Daniel J %K Adult %K Aged %K Aged, 80 and over %K Blood Flow Velocity %K Brachial Artery %K Cross-Sectional Studies %K Female %K Humans %K Hyperemia %K Hypoxia %K Laser-Doppler Flowmetry %K Male %K Middle Aged %K Polysomnography %K Regional Blood Flow %K Severity of Illness Index %K Sleep Apnea Syndromes %K Ultrasonography %K Vasodilation %X

Clinic-based, case-control studies linked sleep-disordered breathing (SDB) to markers of endothelial dysfunction. We attempted to validate this association in a large community-based sample, and evaluate the relation of SDB to arterial diameter and peripheral blood flow. This community-based, cross-sectional observational study included 327 men and 355 women, aged 42-83 years, from the Framingham Heart Study site of the Sleep Heart Health Study. The polysomnographically derived apnea-hypopnea index and the hypoxemia index (percent sleep time with oxyhemoglobin saturation below 90%) were used to quantify the severity of SDB. Brachial artery ultrasound measurements included baseline diameter, percent flow-mediated dilation, and baseline and hyperemic flow velocity and volume. The baseline brachial artery diameter was significantly associated with both the apnea-hypopnea index and the hypoxemia index. The association was diminished by adjustment for body mass index, but remained significant for the apnea-hypopnea index. Age-, sex-, race- and body mass index-adjusted mean diameters were 4.32, 4.33, 4.33, 4.56, 4.53 mm for those with apnea-hypopnea index < 1.5, 1.5-4.9, 5-14.9, 15-29.9, >/= 30, respectively; p = 0.03. Baseline flow measures were associated with the apnea-hypopnea index but this association was non-significant after adjusting for body mass index. No significant association was observed between measures of SDB and percent flow-mediated dilation or hyperemic flow in any model. In conclusion, this study supports a moderate association of SDB and larger baseline brachial artery diameter, which may reflect SDB-induced vascular remodeling. This study does not support a link between SDB and endothelial dysfunction as measured by brachial artery flow-mediated dilation.

%B Vasc Med %V 14 %P 351-60 %8 2009 Nov %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/19808720?dopt=Abstract %R 10.1177/1358863X09105132 %0 Journal Article %J JAMA %D 2009 %T Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. %A Vasan, Ramachandran S %A Glazer, Nicole L %A Felix, Janine F %A Lieb, Wolfgang %A Wild, Philipp S %A Felix, Stephan B %A Watzinger, Norbert %A Larson, Martin G %A Smith, Nicholas L %A Dehghan, Abbas %A Grosshennig, Anika %A Schillert, Arne %A Teumer, Alexander %A Schmidt, Reinhold %A Kathiresan, Sekar %A Lumley, Thomas %A Aulchenko, Yurii S %A König, Inke R %A Zeller, Tanja %A Homuth, Georg %A Struchalin, Maksim %A Aragam, Jayashri %A Bis, Joshua C %A Rivadeneira, Fernando %A Erdmann, Jeanette %A Schnabel, Renate B %A Dörr, Marcus %A Zweiker, Robert %A Lind, Lars %A Rodeheffer, Richard J %A Greiser, Karin Halina %A Levy, Daniel %A Haritunians, Talin %A Deckers, Jaap W %A Stritzke, Jan %A Lackner, Karl J %A Völker, Uwe %A Ingelsson, Erik %A Kullo, Iftikhar %A Haerting, Johannes %A O'Donnell, Christopher J %A Heckbert, Susan R %A Stricker, Bruno H %A Ziegler, Andreas %A Reffelmann, Thorsten %A Redfield, Margaret M %A Werdan, Karl %A Mitchell, Gary F %A Rice, Kenneth %A Arnett, Donna K %A Hofman, Albert %A Gottdiener, John S %A Uitterlinden, André G %A Meitinger, Thomas %A Blettner, Maria %A Friedrich, Nele %A Wang, Thomas J %A Psaty, Bruce M %A van Duijn, Cornelia M %A Wichmann, H-Erich %A Munzel, Thomas F %A Kroemer, Heyo K %A Benjamin, Emelia J %A Rotter, Jerome I %A Witteman, Jacqueline C %A Schunkert, Heribert %A Schmidt, Helena %A Völzke, Henry %A Blankenberg, Stefan %K Adult %K Aged %K Aged, 80 and over %K Aorta %K Cardiovascular Diseases %K Echocardiography %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart Atria %K Heart Ventricles %K Humans %K Male %K Middle Aged %K Organ Size %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K Ventricular Dysfunction, Left %K Ventricular Function, Left %X

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

%B JAMA %V 302 %P 168-78 %8 2009 Jul 08 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/19584346?dopt=Abstract %R 10.1001/jama.2009.978-a %0 Journal Article %J Nat Genet %D 2009 %T Genome-wide association study of blood pressure and hypertension. %A Levy, Daniel %A Ehret, Georg B %A Rice, Kenneth %A Verwoert, Germaine C %A Launer, Lenore J %A Dehghan, Abbas %A Glazer, Nicole L %A Morrison, Alanna C %A Johnson, Andrew D %A Aspelund, Thor %A Aulchenko, Yurii %A Lumley, Thomas %A Köttgen, Anna %A Vasan, Ramachandran S %A Rivadeneira, Fernando %A Eiriksdottir, Gudny %A Guo, Xiuqing %A Arking, Dan E %A Mitchell, Gary F %A Mattace-Raso, Francesco U S %A Smith, Albert V %A Taylor, Kent %A Scharpf, Robert B %A Hwang, Shih-Jen %A Sijbrands, Eric J G %A Bis, Joshua %A Harris, Tamara B %A Ganesh, Santhi K %A O'Donnell, Christopher J %A Hofman, Albert %A Rotter, Jerome I %A Coresh, Josef %A Benjamin, Emelia J %A Uitterlinden, André G %A Heiss, Gerardo %A Fox, Caroline S %A Witteman, Jacqueline C M %A Boerwinkle, Eric %A Wang, Thomas J %A Gudnason, Vilmundur %A Larson, Martin G %A Chakravarti, Aravinda %A Psaty, Bruce M %A van Duijn, Cornelia M %K Blood Pressure %K Cell Line %K Chromosome Mapping %K Chromosomes, Human %K Diastole %K Gene Expression Regulation %K Genetic Association Studies %K Genome-Wide Association Study %K Humans %K Hypertension %K Liver %K Lymphocytes %K Meta-Analysis as Topic %K Odds Ratio %K Phenotype %K Prevalence %K Risk Assessment %K Systole %X

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

%B Nat Genet %V 41 %P 677-87 %8 2009 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19430479?dopt=Abstract %R 10.1038/ng.384 %0 Journal Article %J Nat Genet %D 2009 %T Multiple loci associated with indices of renal function and chronic kidney disease. %A Köttgen, Anna %A Glazer, Nicole L %A Dehghan, Abbas %A Hwang, Shih-Jen %A Katz, Ronit %A Li, Man %A Yang, Qiong %A Gudnason, Vilmundur %A Launer, Lenore J %A Harris, Tamara B %A Smith, Albert V %A Arking, Dan E %A Astor, Brad C %A Boerwinkle, Eric %A Ehret, Georg B %A Ruczinski, Ingo %A Scharpf, Robert B %A Chen, Yii-Der Ida %A de Boer, Ian H %A Haritunians, Talin %A Lumley, Thomas %A Sarnak, Mark %A Siscovick, David %A Benjamin, Emelia J %A Levy, Daniel %A Upadhyay, Ashish %A Aulchenko, Yurii S %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A van Duijn, Cornelia M %A Chasman, Daniel I %A Paré, Guillaume %A Ridker, Paul M %A Kao, W H Linda %A Witteman, Jacqueline C %A Coresh, Josef %A Shlipak, Michael G %A Fox, Caroline S %K Chromosome Mapping %K Cohort Studies %K Genetic Variation %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Meta-Analysis as Topic %K Mucoproteins %K Netherlands %K Polymorphism, Single Nucleotide %K Prevalence %K Uromodulin %X

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

%B Nat Genet %V 41 %P 712-7 %8 2009 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19430482?dopt=Abstract %R 10.1038/ng.377 %0 Journal Article %J Nat Genet %D 2009 %T Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. %A Benjamin, Emelia J %A Rice, Kenneth M %A Arking, Dan E %A Pfeufer, Arne %A van Noord, Charlotte %A Smith, Albert V %A Schnabel, Renate B %A Bis, Joshua C %A Boerwinkle, Eric %A Sinner, Moritz F %A Dehghan, Abbas %A Lubitz, Steven A %A D'Agostino, Ralph B %A Lumley, Thomas %A Ehret, Georg B %A Heeringa, Jan %A Aspelund, Thor %A Newton-Cheh, Christopher %A Larson, Martin G %A Marciante, Kristin D %A Soliman, Elsayed Z %A Rivadeneira, Fernando %A Wang, Thomas J %A Eiriksdottir, Gudny %A Levy, Daniel %A Psaty, Bruce M %A Li, Man %A Chamberlain, Alanna M %A Hofman, Albert %A Vasan, Ramachandran S %A Harris, Tamara B %A Rotter, Jerome I %A Kao, W H Linda %A Agarwal, Sunil K %A Stricker, Bruno H Ch %A Wang, Ke %A Launer, Lenore J %A Smith, Nicholas L %A Chakravarti, Aravinda %A Uitterlinden, André G %A Wolf, Philip A %A Sotoodehnia, Nona %A Köttgen, Anna %A van Duijn, Cornelia M %A Meitinger, Thomas %A Mueller, Martina %A Perz, Siegfried %A Steinbeck, Gerhard %A Wichmann, H-Erich %A Lunetta, Kathryn L %A Heckbert, Susan R %A Gudnason, Vilmundur %A Alonso, Alvaro %A Kääb, Stefan %A Ellinor, Patrick T %A Witteman, Jacqueline C M %K Atrial Fibrillation %K Chromosomes, Human, Pair 16 %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Homeodomain Proteins %K Humans %K Meta-Analysis as Topic %K Mutation %K Polymorphism, Single Nucleotide %K Reproducibility of Results %X

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

%B Nat Genet %V 41 %P 879-81 %8 2009 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/19597492?dopt=Abstract %R 10.1038/ng.416 %0 Journal Article %J Circ Cardiovasc Genet %D 2010 %T Candidate gene association resource (CARe): design, methods, and proof of concept. %A Musunuru, Kiran %A Lettre, Guillaume %A Young, Taylor %A Farlow, Deborah N %A Pirruccello, James P %A Ejebe, Kenechi G %A Keating, Brendan J %A Yang, Qiong %A Chen, Ming-Huei %A Lapchyk, Nina %A Crenshaw, Andrew %A Ziaugra, Liuda %A Rachupka, Anthony %A Benjamin, Emelia J %A Cupples, L Adrienne %A Fornage, Myriam %A Fox, Ervin R %A Heckbert, Susan R %A Hirschhorn, Joel N %A Newton-Cheh, Christopher %A Nizzari, Marcia M %A Paltoo, Dina N %A Papanicolaou, George J %A Patel, Sanjay R %A Psaty, Bruce M %A Rader, Daniel J %A Redline, Susan %A Rich, Stephen S %A Rotter, Jerome I %A Taylor, Herman A %A Tracy, Russell P %A Vasan, Ramachandran S %A Wilson, James G %A Kathiresan, Sekar %A Fabsitz, Richard R %A Boerwinkle, Eric %A Gabriel, Stacey B %K African Americans %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Databases, Genetic %K European Continental Ancestry Group %K Genetic Association Studies %K Genotype %K Humans %K Phenotype %K Pilot Projects %K Polymorphism, Single Nucleotide %K Research Design %K Triglycerides %X

BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

%B Circ Cardiovasc Genet %V 3 %P 267-75 %8 2010 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20400780?dopt=Abstract %R 10.1161/CIRCGENETICS.109.882696 %0 Journal Article %J Nat Genet %D 2010 %T Common variants in KCNN3 are associated with lone atrial fibrillation. %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Glazer, Nicole L %A Pfeufer, Arne %A Alonso, Alvaro %A Chung, Mina K %A Sinner, Moritz F %A de Bakker, Paul I W %A Mueller, Martina %A Lubitz, Steven A %A Fox, Ervin %A Darbar, Dawood %A Smith, Nicholas L %A Smith, Jonathan D %A Schnabel, Renate B %A Soliman, Elsayed Z %A Rice, Kenneth M %A Van Wagoner, David R %A Beckmann, Britt-M %A van Noord, Charlotte %A Wang, Ke %A Ehret, Georg B %A Rotter, Jerome I %A Hazen, Stanley L %A Steinbeck, Gerhard %A Smith, Albert V %A Launer, Lenore J %A Harris, Tamara B %A Makino, Seiko %A Nelis, Mari %A Milan, David J %A Perz, Siegfried %A Esko, Tõnu %A Köttgen, Anna %A Moebus, Susanne %A Newton-Cheh, Christopher %A Li, Man %A Möhlenkamp, Stefan %A Wang, Thomas J %A Kao, W H Linda %A Vasan, Ramachandran S %A Nöthen, Markus M %A MacRae, Calum A %A Stricker, Bruno H Ch %A Hofman, Albert %A Uitterlinden, André G %A Levy, Daniel %A Boerwinkle, Eric %A Metspalu, Andres %A Topol, Eric J %A Chakravarti, Aravinda %A Gudnason, Vilmundur %A Psaty, Bruce M %A Roden, Dan M %A Meitinger, Thomas %A Wichmann, H-Erich %A Witteman, Jacqueline C M %A Barnard, John %A Arking, Dan E %A Benjamin, Emelia J %A Heckbert, Susan R %A Kääb, Stefan %K Adolescent %K Adult %K Aged %K Atrial Fibrillation %K Case-Control Studies %K Cohort Studies %K Female %K Genome-Wide Association Study %K Humans %K Introns %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Small-Conductance Calcium-Activated Potassium Channels %K Young Adult %X

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

%B Nat Genet %V 42 %P 240-4 %8 2010 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20173747?dopt=Abstract %R 10.1038/ng.537 %0 Journal Article %J Circulation %D 2010 %T European ancestry as a risk factor for atrial fibrillation in African Americans. %A Marcus, Gregory M %A Alonso, Alvaro %A Peralta, Carmen A %A Lettre, Guillaume %A Vittinghoff, Eric %A Lubitz, Steven A %A Fox, Ervin R %A Levitzky, Yamini S %A Mehra, Reena %A Kerr, Kathleen F %A Deo, Rajat %A Sotoodehnia, Nona %A Akylbekova, Meggie %A Ellinor, Patrick T %A Paltoo, Dina N %A Soliman, Elsayed Z %A Benjamin, Emelia J %A Heckbert, Susan R %K African Americans %K Aged %K Atrial Fibrillation %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Risk Factors %X

BACKGROUND: Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF.

METHODS AND RESULTS: We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results.

CONCLUSIONS: European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.

%B Circulation %V 122 %P 2009-15 %8 2010 Nov 16 %G eng %N 20 %1 http://www.ncbi.nlm.nih.gov/pubmed/21098467?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.958306 %0 Journal Article %J Nat Genet %D 2010 %T Genome-wide association study of PR interval. %A Pfeufer, Arne %A van Noord, Charlotte %A Marciante, Kristin D %A Arking, Dan E %A Larson, Martin G %A Smith, Albert Vernon %A Tarasov, Kirill V %A Müller, Martina %A Sotoodehnia, Nona %A Sinner, Moritz F %A Verwoert, Germaine C %A Li, Man %A Kao, W H Linda %A Köttgen, Anna %A Coresh, Josef %A Bis, Joshua C %A Psaty, Bruce M %A Rice, Kenneth %A Rotter, Jerome I %A Rivadeneira, Fernando %A Hofman, Albert %A Kors, Jan A %A Stricker, Bruno H C %A Uitterlinden, André G %A van Duijn, Cornelia M %A Beckmann, Britt M %A Sauter, Wiebke %A Gieger, Christian %A Lubitz, Steven A %A Newton-Cheh, Christopher %A Wang, Thomas J %A Magnani, Jared W %A Schnabel, Renate B %A Chung, Mina K %A Barnard, John %A Smith, Jonathan D %A Van Wagoner, David R %A Vasan, Ramachandran S %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Launer, Lenore J %A Najjar, Samer S %A Lakatta, Edward %A Schlessinger, David %A Uda, Manuela %A Abecasis, Goncalo R %A Müller-Myhsok, Bertram %A Ehret, Georg B %A Boerwinkle, Eric %A Chakravarti, Aravinda %A Soliman, Elsayed Z %A Lunetta, Kathryn L %A Perz, Siegfried %A Wichmann, H-Erich %A Meitinger, Thomas %A Levy, Daniel %A Gudnason, Vilmundur %A Ellinor, Patrick T %A Sanna, Serena %A Kääb, Stefan %A Witteman, Jacqueline C M %A Alonso, Alvaro %A Benjamin, Emelia J %A Heckbert, Susan R %K Aged %K Atrial Fibrillation %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heart Conduction System %K Humans %K Male %K Meta-Analysis as Topic %X

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

%B Nat Genet %V 42 %P 153-9 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20062060?dopt=Abstract %R 10.1038/ng.517 %0 Journal Article %J Circ Cardiovasc Genet %D 2010 %T Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium. %A Morrison, Alanna C %A Felix, Janine F %A Cupples, L Adrienne %A Glazer, Nicole L %A Loehr, Laura R %A Dehghan, Abbas %A Demissie, Serkalem %A Bis, Joshua C %A Rosamond, Wayne D %A Aulchenko, Yurii S %A Wang, Ying A %A Haritunians, Talin %A Folsom, Aaron R %A Rivadeneira, Fernando %A Benjamin, Emelia J %A Lumley, Thomas %A Couper, David %A Stricker, Bruno H %A O'Donnell, Christopher J %A Rice, Kenneth M %A Chang, Patricia P %A Hofman, Albert %A Levy, Daniel %A Rotter, Jerome I %A Fox, Ervin R %A Uitterlinden, André G %A Wang, Thomas J %A Psaty, Bruce M %A Willerson, James T %A van Duijn, Cornelia M %A Boerwinkle, Eric %A Witteman, Jacqueline C M %A Vasan, Ramachandran S %A Smith, Nicholas L %K African Americans %K Aged %K Aged, 80 and over %K Chemokines %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart Failure %K Humans %K Introns %K Male %K MARVEL Domain-Containing Proteins %K Membrane Proteins %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.

CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

%B Circ Cardiovasc Genet %V 3 %P 248-55 %8 2010 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20400778?dopt=Abstract %R 10.1161/CIRCGENETICS.109.895995 %0 Journal Article %J Circulation %D 2010 %T Independent susceptibility markers for atrial fibrillation on chromosome 4q25. %A Lubitz, Steven A %A Sinner, Moritz F %A Lunetta, Kathryn L %A Makino, Seiko %A Pfeufer, Arne %A Rahman, Rosanna %A Veltman, Caroline E %A Barnard, John %A Bis, Joshua C %A Danik, Stephan P %A Sonni, Akshata %A Shea, Marisa A %A Del Monte, Federica %A Perz, Siegfried %A Müller, Martina %A Peters, Annette %A Greenberg, Steven M %A Furie, Karen L %A van Noord, Charlotte %A Boerwinkle, Eric %A Stricker, Bruno H C %A Witteman, Jacqueline %A Smith, Jonathan D %A Chung, Mina K %A Heckbert, Susan R %A Benjamin, Emelia J %A Rosand, Jonathan %A Arking, Dan E %A Alonso, Alvaro %A Kääb, Stefan %A Ellinor, Patrick T %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Chromosome Mapping %K Chromosomes, Human, Pair 4 %K European Continental Ancestry Group %K Female %K Genetic Markers %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

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.

%B Circulation %V 122 %P 976-84 %8 2010 Sep 07 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/20733104?dopt=Abstract %R 10.1161/CIRCULATIONAHA.109.886440 %0 Journal Article %J Hum Mol Genet %D 2010 %T Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. %A Barbalic, Maja %A Dupuis, Josée %A Dehghan, Abbas %A Bis, Joshua C %A Hoogeveen, Ron C %A Schnabel, Renate B %A Nambi, Vijay %A Bretler, Monique %A Smith, Nicholas L %A Peters, Annette %A Lu, Chen %A Tracy, Russell P %A Aleksic, Nena %A Heeriga, Jan %A Keaney, John F %A Rice, Kenneth %A Lip, Gregory Y H %A Vasan, Ramachandran S %A Glazer, Nicole L %A Larson, Martin G %A Uitterlinden, André G %A Yamamoto, Jennifer %A Durda, Peter %A Haritunians, Talin %A Psaty, Bruce M %A Boerwinkle, Eric %A Hofman, Albert %A Koenig, Wolfgang %A Jenny, Nancy S %A Witteman, Jacqueline C %A Ballantyne, Christie %A Benjamin, Emelia J %K ABO Blood-Group System %K Blood Platelets %K Enzyme-Linked Immunosorbent Assay %K European Continental Ancestry Group %K Fluorescence %K Genome-Wide Association Study %K Humans %K Intercellular Adhesion Molecule-1 %K P-Selectin %X

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

%B Hum Mol Genet %V 19 %P 1863-72 %8 2010 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/20167578?dopt=Abstract %R 10.1093/hmg/ddq061 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2010 %T A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. %A Newman, Anne B %A Walter, Stefan %A Lunetta, Kathryn L %A Garcia, Melissa E %A Slagboom, P Eline %A Christensen, Kaare %A Arnold, Alice M %A Aspelund, Thor %A Aulchenko, Yurii S %A Benjamin, Emelia J %A Christiansen, Lene %A D'Agostino, Ralph B %A Fitzpatrick, Annette L %A Franceschini, Nora %A Glazer, Nicole L %A Gudnason, Vilmundur %A Hofman, Albert %A Kaplan, Robert %A Karasik, David %A Kelly-Hayes, Margaret %A Kiel, Douglas P %A Launer, Lenore J %A Marciante, Kristin D %A Massaro, Joseph M %A Miljkovic, Iva %A Nalls, Michael A %A Hernandez, Dena %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome %A Seshadri, Sudha %A Smith, Albert V %A Taylor, Kent D %A Tiemeier, Henning %A Uh, Hae-Won %A Uitterlinden, André G %A Vaupel, James W %A Walston, Jeremy %A Westendorp, Rudi G J %A Harris, Tamara B %A Lumley, Thomas %A van Duijn, Cornelia M %A Murabito, Joanne M %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Alleles %K Cohort Studies %K Confidence Intervals %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Longevity %K Male %K Middle Aged %K Odds Ratio %K Polymorphism, Single Nucleotide %X

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.

METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

%B J Gerontol A Biol Sci Med Sci %V 65 %P 478-87 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20304771?dopt=Abstract %R 10.1093/gerona/glq028 %0 Journal Article %J Arch Intern Med %D 2010 %T Validation of an atrial fibrillation risk algorithm in whites and African Americans. %A Schnabel, Renate B %A Aspelund, Thor %A Li, Guo %A Sullivan, Lisa M %A Suchy-Dicey, Astrid %A Harris, Tamara B %A Pencina, Michael J %A D'Agostino, Ralph B %A Levy, Daniel %A Kannel, William B %A Wang, Thomas J %A Kronmal, Richard A %A Wolf, Philip A %A Burke, Gregory L %A Launer, Lenore J %A Vasan, Ramachandran S %A Psaty, Bruce M %A Benjamin, Emelia J %A Gudnason, Vilmundur %A Heckbert, Susan R %K African Continental Ancestry Group %K Age Factors %K Aged %K Aged, 80 and over %K Algorithms %K Atrial Fibrillation %K Blood Pressure %K Body Mass Index %K Cohort Studies %K Electrocardiography %K Europe %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Hypertension %K Incidence %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Proportional Hazards Models %K Risk Factors %K Sex Factors %K Systole %K United States %X

BACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.

METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.

RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.

CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.

%B Arch Intern Med %V 170 %P 1909-17 %8 2010 Nov 22 %G eng %N 21 %1 http://www.ncbi.nlm.nih.gov/pubmed/21098350?dopt=Abstract %R 10.1001/archinternmed.2010.434 %0 Journal Article %J PLoS Genet %D 2011 %T Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. %A Paré, Guillaume %A Ridker, Paul M %A Rose, Lynda %A Barbalic, Maja %A Dupuis, Josée %A Dehghan, Abbas %A Bis, Joshua C %A Benjamin, Emelia J %A Shiffman, Dov %A Parker, Alexander N %A Chasman, Daniel I %K ABO Blood-Group System %K Cohort Studies %K Female %K Gene Frequency %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K I-kappa B Kinase %K Intercellular Adhesion Molecule-1 %K Lipase %K Membrane Proteins %K Models, Genetic %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %K Proteins %K Transcription Factor RelA %X

Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P  =  5.8 × 10(-9)), RELA (rs1049728, P =  2.7 × 10(-16)), and SH2B3 (rs3184504, P =  2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.

%B PLoS Genet %V 7 %P e1001374 %8 2011 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21533024?dopt=Abstract %R 10.1371/journal.pgen.1001374 %0 Journal Article %J Neurobiol Aging %D 2011 %T A genome-wide association study of aging. %A Walter, Stefan %A Atzmon, Gil %A Demerath, Ellen W %A Garcia, Melissa E %A Kaplan, Robert C %A Kumari, Meena %A Lunetta, Kathryn L %A Milaneschi, Yuri %A Tanaka, Toshiko %A Tranah, Gregory J %A Völker, Uwe %A Yu, Lei %A Arnold, Alice %A Benjamin, Emelia J %A Biffar, Reiner %A Buchman, Aron S %A Boerwinkle, Eric %A Couper, David %A De Jager, Philip L %A Evans, Denis A %A Harris, Tamara B %A Hoffmann, Wolfgang %A Hofman, Albert %A Karasik, David %A Kiel, Douglas P %A Kocher, Thomas %A Kuningas, Maris %A Launer, Lenore J %A Lohman, Kurt K %A Lutsey, Pamela L %A Mackenbach, Johan %A Marciante, Kristin %A Psaty, Bruce M %A Reiman, Eric M %A Rotter, Jerome I %A Seshadri, Sudha %A Shardell, Michelle D %A Smith, Albert V %A van Duijn, Cornelia %A Walston, Jeremy %A Zillikens, M Carola %A Bandinelli, Stefania %A Baumeister, Sebastian E %A Bennett, David A %A Ferrucci, Luigi %A Gudnason, Vilmundur %A Kivimaki, Mika %A Liu, Yongmei %A Murabito, Joanne M %A Newman, Anne B %A Tiemeier, Henning %A Franceschini, Nora %K Aging %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Longevity %X

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

%B Neurobiol Aging %V 32 %P 2109.e15-28 %8 2011 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21782286?dopt=Abstract %R 10.1016/j.neurobiolaging.2011.05.026 %0 Journal Article %J Circ Cardiovasc Genet %D 2011 %T Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project. %A Schnabel, Renate B %A Kerr, Kathleen F %A Lubitz, Steven A %A Alkylbekova, Ermeg L %A Marcus, Gregory M %A Sinner, Moritz F %A Magnani, Jared W %A Wolf, Philip A %A Deo, Rajat %A Lloyd-Jones, Donald M %A Lunetta, Kathryn L %A Mehra, Reena %A Levy, Daniel %A Fox, Ervin R %A Arking, Dan E %A Mosley, Thomas H %A Müller-Nurasyid, Martina %A Young, Taylor R %A Wichmann, H-Erich %A Seshadri, Sudha %A Farlow, Deborah N %A Rotter, Jerome I %A Soliman, Elsayed Z %A Glazer, Nicole L %A Wilson, James G %A Breteler, Monique M B %A Sotoodehnia, Nona %A Newton-Cheh, Christopher %A Kääb, Stefan %A Ellinor, Patrick T %A Alonso, Alvaro %A Benjamin, Emelia J %A Heckbert, Susan R %K African Americans %K Aged %K Alleles %K Atrial Fibrillation %K Chromosomes, Human, Pair 4 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Humans %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %K Risk Factors %K Stroke %K United States %X

BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16-1.69; P=0.0005).

CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.

%B Circ Cardiovasc Genet %V 4 %P 557-64 %8 2011 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21846873?dopt=Abstract %R 10.1161/CIRCGENETICS.110.959197 %0 Journal Article %J Circulation %D 2011 %T Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. %A Dehghan, Abbas %A Dupuis, Josée %A Barbalic, Maja %A Bis, Joshua C %A Eiriksdottir, Gudny %A Lu, Chen %A Pellikka, Niina %A Wallaschofski, Henri %A Kettunen, Johannes %A Henneman, Peter %A Baumert, Jens %A Strachan, David P %A Fuchsberger, Christian %A Vitart, Veronique %A Wilson, James F %A Paré, Guillaume %A Naitza, Silvia %A Rudock, Megan E %A Surakka, Ida %A de Geus, Eco J C %A Alizadeh, Behrooz Z %A Guralnik, Jack %A Shuldiner, Alan %A Tanaka, Toshiko %A Zee, Robert Y L %A Schnabel, Renate B %A Nambi, Vijay %A Kavousi, Maryam %A Ripatti, Samuli %A Nauck, Matthias %A Smith, Nicholas L %A Smith, Albert V %A Sundvall, Jouko %A Scheet, Paul %A Liu, Yongmei %A Ruokonen, Aimo %A Rose, Lynda M %A Larson, Martin G %A Hoogeveen, Ron C %A Freimer, Nelson B %A Teumer, Alexander %A Tracy, Russell P %A Launer, Lenore J %A Buring, Julie E %A Yamamoto, Jennifer F %A Folsom, Aaron R %A Sijbrands, Eric J G %A Pankow, James %A Elliott, Paul %A Keaney, John F %A Sun, Wei %A Sarin, Antti-Pekka %A Fontes, João D %A Badola, Sunita %A Astor, Brad C %A Hofman, Albert %A Pouta, Anneli %A Werdan, Karl %A Greiser, Karin H %A Kuss, Oliver %A Meyer zu Schwabedissen, Henriette E %A Thiery, Joachim %A Jamshidi, Yalda %A Nolte, Ilja M %A Soranzo, Nicole %A Spector, Timothy D %A Völzke, Henry %A Parker, Alexander N %A Aspelund, Thor %A Bates, David %A Young, Lauren %A Tsui, Kim %A Siscovick, David S %A Guo, Xiuqing %A Rotter, Jerome I %A Uda, Manuela %A Schlessinger, David %A Rudan, Igor %A Hicks, Andrew A %A Penninx, Brenda W %A Thorand, Barbara %A Gieger, Christian %A Coresh, Joe %A Willemsen, Gonneke %A Harris, Tamara B %A Uitterlinden, André G %A Jarvelin, Marjo-Riitta %A Rice, Kenneth %A Radke, Dörte %A Salomaa, Veikko %A Willems van Dijk, Ko %A Boerwinkle, Eric %A Vasan, Ramachandran S %A Ferrucci, Luigi %A Gibson, Quince D %A Bandinelli, Stefania %A Snieder, Harold %A Boomsma, Dorret I %A Xiao, Xiangjun %A Campbell, Harry %A Hayward, Caroline %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Peltonen, Leena %A Psaty, Bruce M %A Gudnason, Vilmundur %A Ridker, Paul M %A Homuth, Georg %A Koenig, Wolfgang %A Ballantyne, Christie M %A Witteman, Jacqueline C M %A Benjamin, Emelia J %A Perola, Markus %A Chasman, Daniel I %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Risk Factors %K Vasculitis %X

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

%B Circulation %V 123 %P 731-8 %8 2011 Feb 22 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21300955?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.948570 %0 Journal Article %J Eur Heart J %D 2012 %T Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies. %A Grallert, Harald %A Dupuis, Josée %A Bis, Joshua C %A Dehghan, Abbas %A Barbalic, Maja %A Baumert, Jens %A Lu, Chen %A Smith, Nicholas L %A Uitterlinden, André G %A Roberts, Robert %A Khuseyinova, Natalie %A Schnabel, Renate B %A Rice, Kenneth M %A Rivadeneira, Fernando %A Hoogeveen, Ron C %A Fontes, João Daniel %A Meisinger, Christa %A Keaney, John F %A Lemaitre, Rozenn %A Aulchenko, Yurii S %A Vasan, Ramachandran S %A Ellis, Stephen %A Hazen, Stanley L %A van Duijn, Cornelia M %A Nelson, Jeanenne J %A März, Winfried %A Schunkert, Heribert %A McPherson, Ruth M %A Stirnadel-Farrant, Heide A %A Psaty, Bruce M %A Gieger, Christian %A Siscovick, David %A Hofman, Albert %A Illig, Thomas %A Cushman, Mary %A Yamamoto, Jennifer F %A Rotter, Jerome I %A Larson, Martin G %A Stewart, Alexandre F R %A Boerwinkle, Eric %A Witteman, Jacqueline C M %A Tracy, Russell P %A Koenig, Wolfgang %A Benjamin, Emelia J %A Ballantyne, Christie M %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Coronary Artery Disease %K Coronary Disease %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Phospholipases A2 %K Polymorphism, Single Nucleotide %X

AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.

CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

%B Eur Heart J %V 33 %P 238-51 %8 2012 Jan %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22003152?dopt=Abstract %R 10.1093/eurheartj/ehr372 %0 Journal Article %J Nat Genet %D 2012 %T Meta-analysis identifies six new susceptibility loci for atrial fibrillation. %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Albert, Christine M %A Glazer, Nicole L %A Ritchie, Marylyn D %A Smith, Albert V %A Arking, Dan E %A Müller-Nurasyid, Martina %A Krijthe, Bouwe P %A Lubitz, Steven A %A Bis, Joshua C %A Chung, Mina K %A Dörr, Marcus %A Ozaki, Kouichi %A Roberts, Jason D %A Smith, J Gustav %A Pfeufer, Arne %A Sinner, Moritz F %A Lohman, Kurt %A Ding, Jingzhong %A Smith, Nicholas L %A Smith, Jonathan D %A Rienstra, Michiel %A Rice, Kenneth M %A Van Wagoner, David R %A Magnani, Jared W %A Wakili, Reza %A Clauss, Sebastian %A Rotter, Jerome I %A Steinbeck, Gerhard %A Launer, Lenore J %A Davies, Robert W %A Borkovich, Matthew %A Harris, Tamara B %A Lin, Honghuang %A Völker, Uwe %A Völzke, Henry %A Milan, David J %A Hofman, Albert %A Boerwinkle, Eric %A Chen, Lin Y %A Soliman, Elsayed Z %A Voight, Benjamin F %A Li, Guo %A Chakravarti, Aravinda %A Kubo, Michiaki %A Tedrow, Usha B %A Rose, Lynda M %A Ridker, Paul M %A Conen, David %A Tsunoda, Tatsuhiko %A Furukawa, Tetsushi %A Sotoodehnia, Nona %A Xu, Siyan %A Kamatani, Naoyuki %A Levy, Daniel %A Nakamura, Yusuke %A Parvez, Babar %A Mahida, Saagar %A Furie, Karen L %A Rosand, Jonathan %A Muhammad, Raafia %A Psaty, Bruce M %A Meitinger, Thomas %A Perz, Siegfried %A Wichmann, H-Erich %A Witteman, Jacqueline C M %A Kao, W H Linda %A Kathiresan, Sekar %A Roden, Dan M %A Uitterlinden, André G %A Rivadeneira, Fernando %A McKnight, Barbara %A Sjögren, Marketa %A Newman, Anne B %A Liu, Yongmei %A Gollob, Michael H %A Melander, Olle %A Tanaka, Toshihiro %A Stricker, Bruno H Ch %A Felix, Stephan B %A Alonso, Alvaro %A Darbar, Dawood %A Barnard, John %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Gudnason, Vilmundur %A Kääb, Stefan %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Atrial Fibrillation %K Child %K Child, Preschool %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Infant %K Infant, Newborn %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K Young Adult %X

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

%B Nat Genet %V 44 %P 670-5 %8 2012 Apr 29 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22544366?dopt=Abstract %R 10.1038/ng.2261 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. %A Butler, Anne M %A Yin, Xiaoyan %A Evans, Daniel S %A Nalls, Michael A %A Smith, Erin N %A Tanaka, Toshiko %A Li, Guo %A Buxbaum, Sarah G %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Benjamin, Emelia J %A Berenson, Gerald S %A Bis, Josh C %A Chen, Wei %A Deo, Rajat %A Ellinor, Patrick T %A Heckbert, Susan R %A Heiss, Gerardo %A Hsueh, Wen-Chi %A Keating, Brendan J %A Kerr, Kathleen F %A Li, Yun %A Limacher, Marian C %A Liu, Yongmei %A Lubitz, Steven A %A Marciante, Kristin D %A Mehra, Reena %A Meng, Yan A %A Newman, Anne B %A Newton-Cheh, Christopher %A North, Kari E %A Palmer, Cameron D %A Psaty, Bruce M %A Quibrera, P Miguel %A Redline, Susan %A Reiner, Alex P %A Rotter, Jerome I %A Schnabel, Renate B %A Schork, Nicholas J %A Singleton, Andrew B %A Smith, J Gustav %A Soliman, Elsayed Z %A Srinivasan, Sathanur R %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Ferrucci, Luigi %A Murray, Sarah S %A Evans, Michele K %A Sotoodehnia, Nona %A Magnani, Jared W %A Avery, Christy L %K Adult %K African Americans %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

%B Circ Cardiovasc Genet %V 5 %P 639-46 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract %R 10.1161/CIRCGENETICS.112.963991 %0 Journal Article %J Hum Mol Genet %D 2013 %T Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. %A Reiner, Alexander P %A Hartiala, Jaana %A Zeller, Tanja %A Bis, Joshua C %A Dupuis, Josée %A Fornage, Myriam %A Baumert, Jens %A Kleber, Marcus E %A Wild, Philipp S %A Baldus, Stephan %A Bielinski, Suzette J %A Fontes, João D %A Illig, Thomas %A Keating, Brendan J %A Lange, Leslie A %A Ojeda, Francisco %A Müller-Nurasyid, Martina %A Munzel, Thomas F %A Psaty, Bruce M %A Rice, Kenneth %A Rotter, Jerome I %A Schnabel, Renate B %A Tang, W H Wilson %A Thorand, Barbara %A Erdmann, Jeanette %A Jacobs, David R %A Wilson, James G %A Koenig, Wolfgang %A Tracy, Russell P %A Blankenberg, Stefan %A März, Winfried %A Gross, Myron D %A Benjamin, Emelia J %A Hazen, Stanley L %A Allayee, Hooman %K Adult %K African Americans %K Aged %K Case-Control Studies %K Complement Factor H %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Gene Expression Regulation, Enzymologic %K Genetic Association Studies %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Peroxidase %K Polymorphism, Single Nucleotide %K Young Adult %X

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.

%B Hum Mol Genet %V 22 %P 3381-93 %8 2013 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/23620142?dopt=Abstract %R 10.1093/hmg/ddt189 %0 Journal Article %J Circ Cardiovasc Genet %D 2013 %T Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study. %A Fox, Ervin R %A Musani, Solomon K %A Barbalic, Maja %A Lin, Honghuang %A Yu, Bing %A Ogunyankin, Kofo O %A Smith, Nicholas L %A Kutlar, Abdullah %A Glazer, Nicole L %A Post, Wendy S %A Paltoo, Dina N %A Dries, Daniel L %A Farlow, Deborah N %A Duarte, Christine W %A Kardia, Sharon L %A Meyers, Kristin J %A Sun, Yan V %A Arnett, Donna K %A Patki, Amit A %A Sha, Jin %A Cui, Xiangqui %A Samdarshi, Tandaw E %A Penman, Alan D %A Bibbins-Domingo, Kirsten %A Bůzková, Petra %A Benjamin, Emelia J %A Bluemke, David A %A Morrison, Alanna C %A Heiss, Gerardo %A Carr, J Jeffrey %A Tracy, Russell P %A Mosley, Thomas H %A Taylor, Herman A %A Psaty, Bruce M %A Heckbert, Susan R %A Cappola, Thomas P %A Vasan, Ramachandran S %K African Americans %K Aged %K Cohort Studies %K Diastole %K Echocardiography %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart %K Humans %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Systole %X

BACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.

METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.

CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

%B Circ Cardiovasc Genet %V 6 %P 37-46 %8 2013 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23275298?dopt=Abstract %R 10.1161/CIRCGENETICS.111.962365 %0 Journal Article %J Biol Psychiatry %D 2013 %T A genome-wide association study of depressive symptoms. %A Hek, Karin %A Demirkan, Ayse %A Lahti, Jari %A Terracciano, Antonio %A Teumer, Alexander %A Cornelis, Marilyn C %A Amin, Najaf %A Bakshis, Erin %A Baumert, Jens %A Ding, Jingzhong %A Liu, Yongmei %A Marciante, Kristin %A Meirelles, Osorio %A Nalls, Michael A %A Sun, Yan V %A Vogelzangs, Nicole %A Yu, Lei %A Bandinelli, Stefania %A Benjamin, Emelia J %A Bennett, David A %A Boomsma, Dorret %A Cannas, Alessandra %A Coker, Laura H %A de Geus, Eco %A De Jager, Philip L %A Diez-Roux, Ana V %A Purcell, Shaun %A Hu, Frank B %A Rimma, Eric B %A Hunter, David J %A Jensen, Majken K %A Curhan, Gary %A Rice, Kenneth %A Penman, Alan D %A Rotter, Jerome I %A Sotoodehnia, Nona %A Emeny, Rebecca %A Eriksson, Johan G %A Evans, Denis A %A Ferrucci, Luigi %A Fornage, Myriam %A Gudnason, Vilmundur %A Hofman, Albert %A Illig, Thomas %A Kardia, Sharon %A Kelly-Hayes, Margaret %A Koenen, Karestan %A Kraft, Peter %A Kuningas, Maris %A Massaro, Joseph M %A Melzer, David %A Mulas, Antonella %A Mulder, Cornelis L %A Murray, Anna %A Oostra, Ben A %A Palotie, Aarno %A Penninx, Brenda %A Petersmann, Astrid %A Pilling, Luke C %A Psaty, Bruce %A Rawal, Rajesh %A Reiman, Eric M %A Schulz, Andrea %A Shulman, Joshua M %A Singleton, Andrew B %A Smith, Albert V %A Sutin, Angelina R %A Uitterlinden, André G %A Völzke, Henry %A Widen, Elisabeth %A Yaffe, Kristine %A Zonderman, Alan B %A Cucca, Francesco %A Harris, Tamara %A Ladwig, Karl-Heinz %A Llewellyn, David J %A Räikkönen, Katri %A Tanaka, Toshiko %A van Duijn, Cornelia M %A Grabe, Hans J %A Launer, Lenore J %A Lunetta, Kathryn L %A Mosley, Thomas H %A Newman, Anne B %A Tiemeier, Henning %A Murabito, Joanne %K Aged %K Aged, 80 and over %K Chromosomes, Human, Pair 5 %K Depression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.

METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.

RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).

CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

%B Biol Psychiatry %V 73 %P 667-78 %8 2013 Apr 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23290196?dopt=Abstract %R 10.1016/j.biopsych.2012.09.033 %0 Journal Article %J J Am Heart Assoc %D 2013 %T Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. %A Alonso, Alvaro %A Krijthe, Bouwe P %A Aspelund, Thor %A Stepas, Katherine A %A Pencina, Michael J %A Moser, Carlee B %A Sinner, Moritz F %A Sotoodehnia, Nona %A Fontes, João D %A Janssens, A Cecile J W %A Kronmal, Richard A %A Magnani, Jared W %A Witteman, Jacqueline C %A Chamberlain, Alanna M %A Lubitz, Steven A %A Schnabel, Renate B %A Agarwal, Sunil K %A McManus, David D %A Ellinor, Patrick T %A Larson, Martin G %A Burke, Gregory L %A Launer, Lenore J %A Hofman, Albert %A Levy, Daniel %A Gottdiener, John S %A Kääb, Stefan %A Couper, David %A Harris, Tamara B %A Soliman, Elsayed Z %A Stricker, Bruno H C %A Gudnason, Vilmundur %A Heckbert, Susan R %A Benjamin, Emelia J %K African Americans %K Age Factors %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Cohort Studies %K Diabetes Mellitus %K European Continental Ancestry Group %K Female %K Heart Failure %K Humans %K Hypertension %K Iceland %K Incidence %K Male %K Middle Aged %K Myocardial Infarction %K Netherlands %K Proportional Hazards Models %K Risk Assessment %K Smoking %K United States %X

BACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.

METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate.

CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.

%B J Am Heart Assoc %V 2 %P e000102 %8 2013 Mar 18 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23537808?dopt=Abstract %R 10.1161/JAHA.112.000102 %0 Journal Article %J Europace %D 2014 %T B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. %A Sinner, Moritz F %A Stepas, Katherine A %A Moser, Carlee B %A Krijthe, Bouwe P %A Aspelund, Thor %A Sotoodehnia, Nona %A Fontes, João D %A Janssens, A Cecile J W %A Kronmal, Richard A %A Magnani, Jared W %A Witteman, Jacqueline C %A Chamberlain, Alanna M %A Lubitz, Steven A %A Schnabel, Renate B %A Vasan, Ramachandran S %A Wang, Thomas J %A Agarwal, Sunil K %A McManus, David D %A Franco, Oscar H %A Yin, Xiaoyan %A Larson, Martin G %A Burke, Gregory L %A Launer, Lenore J %A Hofman, Albert %A Levy, Daniel %A Gottdiener, John S %A Kääb, Stefan %A Couper, David %A Harris, Tamara B %A Astor, Brad C %A Ballantyne, Christie M %A Hoogeveen, Ron C %A Arai, Andrew E %A Soliman, Elsayed Z %A Ellinor, Patrick T %A Stricker, Bruno H C %A Gudnason, Vilmundur %A Heckbert, Susan R %A Pencina, Michael J %A Benjamin, Emelia J %A Alonso, Alvaro %K Aged %K Atrial Fibrillation %K Biomarkers %K C-Reactive Protein %K Europe %K Female %K Humans %K Incidence %K Male %K Natriuretic Peptide, Brain %K Peptide Fragments %K Predictive Value of Tests %K Risk Assessment %K Risk Factors %K United States %X

AIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.

METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.

CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.

%B Europace %V 16 %P 1426-33 %8 2014 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25037055?dopt=Abstract %R 10.1093/europace/euu175 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine. %A Lüneburg, Nicole %A Lieb, Wolfgang %A Zeller, Tanja %A Chen, Ming-Huei %A Maas, Renke %A Carter, Angela M %A Xanthakis, Vanessa %A Glazer, Nicole L %A Schwedhelm, Edzard %A Seshadri, Sudha %A Ikram, Mohammad Arfan %A Longstreth, William T %A Fornage, Myriam %A König, Inke R %A Loley, Christina %A Ojeda, Francisco M %A Schillert, Arne %A Wang, Thomas J %A Sticht, Heinrich %A Kittel, Anja %A König, Jörg %A Benjamin, Emelia J %A Sullivan, Lisa M %A Bernges, Isabel %A Anderssohn, Maike %A Ziegler, Andreas %A Gieger, Christian %A Illig, Thomas %A Meisinger, Christa %A Wichmann, H-Erich %A Wild, Philipp S %A Schunkert, Heribert %A Psaty, Bruce M %A Wiggins, Kerri L %A Heckbert, Susan R %A Smith, Nicholas %A Lackner, Karl %A Lunetta, Kathryn L %A Blankenberg, Stefan %A Erdmann, Jeanette %A Münzel, Thomas %A Grant, Peter J %A Vasan, Ramachandran S %A Böger, Rainer H %K Adult %K Aged %K Amidohydrolases %K Arginine %K Binding Sites %K Cohort Studies %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K HEK293 Cells %K Humans %K Male %K Mediator Complex %K Middle Aged %K Polymorphism, Single Nucleotide %K Protein Structure, Tertiary %K Risk Factors %K Stroke %K Substrate Specificity %K Transaminases %X

BACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.

METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.

%B Circ Cardiovasc Genet %V 7 %P 864-72 %8 2014 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25245031?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000264 %0 Journal Article %J Circulation %D 2014 %T Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. %A Sinner, Moritz F %A Tucker, Nathan R %A Lunetta, Kathryn L %A Ozaki, Kouichi %A Smith, J Gustav %A Trompet, Stella %A Bis, Joshua C %A Lin, Honghuang %A Chung, Mina K %A Nielsen, Jonas B %A Lubitz, Steven A %A Krijthe, Bouwe P %A Magnani, Jared W %A Ye, Jiangchuan %A Gollob, Michael H %A Tsunoda, Tatsuhiko %A Müller-Nurasyid, Martina %A Lichtner, Peter %A Peters, Annette %A Dolmatova, Elena %A Kubo, Michiaki %A Smith, Jonathan D %A Psaty, Bruce M %A Smith, Nicholas L %A Jukema, J Wouter %A Chasman, Daniel I %A Albert, Christine M %A Ebana, Yusuke %A Furukawa, Tetsushi %A Macfarlane, Peter W %A Harris, Tamara B %A Darbar, Dawood %A Dörr, Marcus %A Holst, Anders G %A Svendsen, Jesper H %A Hofman, Albert %A Uitterlinden, André G %A Gudnason, Vilmundur %A Isobe, Mitsuaki %A Malik, Rainer %A Dichgans, Martin %A Rosand, Jonathan %A Van Wagoner, David R %A Benjamin, Emelia J %A Milan, David J %A Melander, Olle %A Heckbert, Susan R %A Ford, Ian %A Liu, Yongmei %A Barnard, John %A Olesen, Morten S %A Stricker, Bruno H C %A Tanaka, Toshihiro %A Kääb, Stefan %A Ellinor, Patrick T %K Aged %K Animals %K Atrial Fibrillation %K Chromosome Mapping %K Connexin 43 %K Europe %K Female %K Gene Knockdown Techniques %K Genetic Loci %K Genetic Predisposition to Disease %K Genotype %K Homeodomain Proteins %K Humans %K Japan %K Male %K Middle Aged %K Muscle Proteins %K Nuclear Proteins %K Quantitative Trait Loci %K Repressor Proteins %K T-Box Domain Proteins %K Transcription Factors %K Ubiquitin-Protein Ligases %K Zebrafish %K Zebrafish Proteins %X

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.

METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively).

CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

%B Circulation %V 130 %P 1225-35 %8 2014 Oct 7 %G eng %N 15 %1 http://www.ncbi.nlm.nih.gov/pubmed/25124494?dopt=Abstract %R 10.1161/CIRCULATIONAHA.114.009892 %0 Journal Article %J Hum Genet %D 2014 %T Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans. %A Ellis, Jaclyn %A Lange, Ethan M %A Li, Jin %A Dupuis, Josée %A Baumert, Jens %A Walston, Jeremy D %A Keating, Brendan J %A Durda, Peter %A Fox, Ervin R %A Palmer, Cameron D %A Meng, Yan A %A Young, Taylor %A Farlow, Deborah N %A Schnabel, Renate B %A Marzi, Carola S %A Larkin, Emma %A Martin, Lisa W %A Bis, Joshua C %A Auer, Paul %A Ramachandran, Vasan S %A Gabriel, Stacey B %A Willis, Monte S %A Pankow, James S %A Papanicolaou, George J %A Rotter, Jerome I %A Ballantyne, Christie M %A Gross, Myron D %A Lettre, Guillaume %A Wilson, James G %A Peters, Ulrike %A Koenig, Wolfgang %A Tracy, Russell P %A Redline, Susan %A Reiner, Alex P %A Benjamin, Emelia J %A Lange, Leslie A %K Adult %K African Americans %K Aged %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K CD36 Antigens %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10(-6); CRP, p = 4.2 × 10(-71); APOE, p = 1.6 × 10(-6)). The fourth significant locus, CD36 (p = 1.6 × 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10(-6); CD36, p = 1.4 × 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.

%B Hum Genet %V 133 %P 985-95 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24643644?dopt=Abstract %R 10.1007/s00439-014-1439-z %0 Journal Article %J J Am Coll Cardiol %D 2014 %T Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. %A Lubitz, Steven A %A Lunetta, Kathryn L %A Lin, Honghuang %A Arking, Dan E %A Trompet, Stella %A Li, Guo %A Krijthe, Bouwe P %A Chasman, Daniel I %A Barnard, John %A Kleber, Marcus E %A Dörr, Marcus %A Ozaki, Kouichi %A Smith, Albert V %A Müller-Nurasyid, Martina %A Walter, Stefan %A Agarwal, Sunil K %A Bis, Joshua C %A Brody, Jennifer A %A Chen, Lin Y %A Everett, Brendan M %A Ford, Ian %A Franco, Oscar H %A Harris, Tamara B %A Hofman, Albert %A Kääb, Stefan %A Mahida, Saagar %A Kathiresan, Sekar %A Kubo, Michiaki %A Launer, Lenore J %A Macfarlane, Peter W %A Magnani, Jared W %A McKnight, Barbara %A McManus, David D %A Peters, Annette %A Psaty, Bruce M %A Rose, Lynda M %A Rotter, Jerome I %A Silbernagel, Guenther %A Smith, Jonathan D %A Sotoodehnia, Nona %A Stott, David J %A Taylor, Kent D %A Tomaschitz, Andreas %A Tsunoda, Tatsuhiko %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Murabito, Joanne M %A Sinner, Moritz F %A Gudnason, Vilmundur %A Felix, Stephan B %A März, Winfried %A Chung, Mina %A Albert, Christine M %A Stricker, Bruno H %A Tanaka, Toshihiro %A Heckbert, Susan R %A Jukema, J Wouter %A Alonso, Alvaro %A Benjamin, Emelia J %A Ellinor, Patrick T %K Adult %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Atrial Fibrillation %K Chromosome Mapping %K Chromosomes, Human, Pair 4 %K Europe %K European Continental Ancestry Group %K Female %K Genetic Markers %K Genetic Predisposition to Disease %K Homeodomain Proteins %K Humans %K Japan %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Transcription Factors %X

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.

%B J Am Coll Cardiol %V 63 %P 1200-10 %8 2014 Apr 1 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24486271?dopt=Abstract %R 10.1016/j.jacc.2013.12.015 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. %A Magnani, Jared W %A Brody, Jennifer A %A Prins, Bram P %A Arking, Dan E %A Lin, Honghuang %A Yin, Xiaoyan %A Liu, Ching-Ti %A Morrison, Alanna C %A Zhang, Feng %A Spector, Tim D %A Alonso, Alvaro %A Bis, Joshua C %A Heckbert, Susan R %A Lumley, Thomas %A Sitlani, Colleen M %A Cupples, L Adrienne %A Lubitz, Steven A %A Soliman, Elsayed Z %A Pulit, Sara L %A Newton-Cheh, Christopher %A O'Donnell, Christopher J %A Ellinor, Patrick T %A Benjamin, Emelia J %A Muzny, Donna M %A Gibbs, Richard A %A Santibanez, Jireh %A Taylor, Herman A %A Rotter, Jerome I %A Lange, Leslie A %A Psaty, Bruce M %A Jackson, Rebecca %A Rich, Stephen S %A Boerwinkle, Eric %A Jamshidi, Yalda %A Sotoodehnia, Nona %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Conduction System %K Heart Diseases %K Humans %K Male %K Middle Aged %K NAV1.5 Voltage-Gated Sodium Channel %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

BACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.

METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).

CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

%B Circ Cardiovasc Genet %V 7 %P 365-73 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951663?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000098 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Lin, Honghuang %A Wang, Min %A Brody, Jennifer A %A Bis, Joshua C %A Dupuis, Josée %A Lumley, Thomas %A McKnight, Barbara %A Rice, Kenneth M %A Sitlani, Colleen M %A Reid, Jeffrey G %A Bressler, Jan %A Liu, Xiaoming %A Davis, Brian C %A Johnson, Andrew D %A O'Donnell, Christopher J %A Kovar, Christie L %A Dinh, Huyen %A Wu, Yuanqing %A Newsham, Irene %A Chen, Han %A Broka, Andi %A DeStefano, Anita L %A Gupta, Mayetri %A Lunetta, Kathryn L %A Liu, Ching-Ti %A White, Charles C %A Xing, Chuanhua %A Zhou, Yanhua %A Benjamin, Emelia J %A Schnabel, Renate B %A Heckbert, Susan R %A Psaty, Bruce M %A Muzny, Donna M %A Cupples, L Adrienne %A Morrison, Alanna C %A Boerwinkle, Eric %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Research Design %K Sequence Analysis, DNA %X

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.

%B Circ Cardiovasc Genet %V 7 %P 335-43 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951659?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000350 %0 Journal Article %J Heart Rhythm %D 2014 %T Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. %A Lin, Honghuang %A Sinner, Moritz F %A Brody, Jennifer A %A Arking, Dan E %A Lunetta, Kathryn L %A Rienstra, Michiel %A Lubitz, Steven A %A Magnani, Jared W %A Sotoodehnia, Nona %A McKnight, Barbara %A McManus, David D %A Boerwinkle, Eric %A Psaty, Bruce M %A Rotter, Jerome I %A Bis, Joshua C %A Gibbs, Richard A %A Muzny, Donna %A Kovar, Christie L %A Morrison, Alanna C %A Gupta, Mayetri %A Folsom, Aaron R %A Kääb, Stefan %A Heckbert, Susan R %A Alonso, Alvaro %A Ellinor, Patrick T %A Benjamin, Emelia J %K Aged %K Atrial Fibrillation %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Homeodomain Proteins %K Humans %K Linkage Disequilibrium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %X

BACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.

OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.

RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).

CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

%B Heart Rhythm %V 11 %P 452-7 %8 2014 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24239840?dopt=Abstract %R 10.1016/j.hrthm.2013.11.012 %0 Journal Article %J Hum Mol Genet %D 2015 %T Association of exome sequences with plasma C-reactive protein levels in >9000 participants. %A Schick, Ursula M %A Auer, Paul L %A Bis, Joshua C %A Lin, Honghuang %A Wei, Peng %A Pankratz, Nathan %A Lange, Leslie A %A Brody, Jennifer %A Stitziel, Nathan O %A Kim, Daniel S %A Carlson, Christopher S %A Fornage, Myriam %A Haessler, Jeffery %A Hsu, Li %A Jackson, Rebecca D %A Kooperberg, Charles %A Leal, Suzanne M %A Psaty, Bruce M %A Boerwinkle, Eric %A Tracy, Russell %A Ardissino, Diego %A Shah, Svati %A Willer, Cristen %A Loos, Ruth %A Melander, Olle %A McPherson, Ruth %A Hovingh, Kees %A Reilly, Muredach %A Watkins, Hugh %A Girelli, Domenico %A Fontanillas, Pierre %A Chasman, Daniel I %A Gabriel, Stacey B %A Gibbs, Richard %A Nickerson, Deborah A %A Kathiresan, Sekar %A Peters, Ulrike %A Dupuis, Josée %A Wilson, James G %A Rich, Stephen S %A Morrison, Alanna C %A Benjamin, Emelia J %A Gross, Myron D %A Reiner, Alex P %K Adult %K African Americans %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Exome %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hepatocyte Nuclear Factor 1-alpha %K Humans %K Male %K Plasma %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %K Risk Factors %X

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

%B Hum Mol Genet %V 24 %P 559-71 %8 2015 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25187575?dopt=Abstract %R 10.1093/hmg/ddu450 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. %A Broer, Linda %A Buchman, Aron S %A Deelen, Joris %A Evans, Daniel S %A Faul, Jessica D %A Lunetta, Kathryn L %A Sebastiani, Paola %A Smith, Jennifer A %A Smith, Albert V %A Tanaka, Toshiko %A Yu, Lei %A Arnold, Alice M %A Aspelund, Thor %A Benjamin, Emelia J %A De Jager, Philip L %A Eirkisdottir, Gudny %A Evans, Denis A %A Garcia, Melissa E %A Hofman, Albert %A Kaplan, Robert C %A Kardia, Sharon L R %A Kiel, Douglas P %A Oostra, Ben A %A Orwoll, Eric S %A Parimi, Neeta %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Seshadri, Sudha %A Singleton, Andrew %A Tiemeier, Henning %A Uitterlinden, André G %A Zhao, Wei %A Bandinelli, Stefania %A Bennett, David A %A Ferrucci, Luigi %A Gudnason, Vilmundur %A Harris, Tamara B %A Karasik, David %A Launer, Lenore J %A Perls, Thomas T %A Slagboom, P Eline %A Tranah, Gregory J %A Weir, David R %A Newman, Anne B %A van Duijn, Cornelia M %A Murabito, Joanne M %K Aged %K Aged, 80 and over %K Apolipoproteins E %K Cell Adhesion Molecules %K Cohort Studies %K Female %K Forkhead Box Protein O3 %K Forkhead Transcription Factors %K Genome-Wide Association Study %K Humans %K Longevity %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Kainic Acid %X

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 110-8 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract %R 10.1093/gerona/glu166 %0 Journal Article %J Genome Biol %D 2016 %T DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. %A Ligthart, Symen %A Marzi, Carola %A Aslibekyan, Stella %A Mendelson, Michael M %A Conneely, Karen N %A Tanaka, Toshiko %A Colicino, Elena %A Waite, Lindsay L %A Joehanes, Roby %A Guan, Weihua %A Brody, Jennifer A %A Elks, Cathy %A Marioni, Riccardo %A Jhun, Min A %A Agha, Golareh %A Bressler, Jan %A Ward-Caviness, Cavin K %A Chen, Brian H %A Huan, Tianxiao %A Bakulski, Kelly %A Salfati, Elias L %A Fiorito, Giovanni %A Wahl, Simone %A Schramm, Katharina %A Sha, Jin %A Hernandez, Dena G %A Just, Allan C %A Smith, Jennifer A %A Sotoodehnia, Nona %A Pilling, Luke C %A Pankow, James S %A Tsao, Phil S %A Liu, Chunyu %A Zhao, Wei %A Guarrera, Simonetta %A Michopoulos, Vasiliki J %A Smith, Alicia K %A Peters, Marjolein J %A Melzer, David %A Vokonas, Pantel %A Fornage, Myriam %A Prokisch, Holger %A Bis, Joshua C %A Chu, Audrey Y %A Herder, Christian %A Grallert, Harald %A Yao, Chen %A Shah, Sonia %A McRae, Allan F %A Lin, Honghuang %A Horvath, Steve %A Fallin, Daniele %A Hofman, Albert %A Wareham, Nicholas J %A Wiggins, Kerri L %A Feinberg, Andrew P %A Starr, John M %A Visscher, Peter M %A Murabito, Joanne M %A Kardia, Sharon L R %A Absher, Devin M %A Binder, Elisabeth B %A Singleton, Andrew B %A Bandinelli, Stefania %A Peters, Annette %A Waldenberger, Melanie %A Matullo, Giuseppe %A Schwartz, Joel D %A Demerath, Ellen W %A Uitterlinden, André G %A van Meurs, Joyce B J %A Franco, Oscar H %A Chen, Yii-Der Ida %A Levy, Daniel %A Turner, Stephen T %A Deary, Ian J %A Ressler, Kerry J %A Dupuis, Josée %A Ferrucci, Luigi %A Ong, Ken K %A Assimes, Themistocles L %A Boerwinkle, Eric %A Koenig, Wolfgang %A Arnett, Donna K %A Baccarelli, Andrea A %A Benjamin, Emelia J %A Dehghan, Abbas %X

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

%B Genome Biol %V 17 %P 255 %8 2016 Dec 12 %G eng %N 1 %R 10.1186/s13059-016-1119-5 %0 Journal Article %J PLoS One %D 2016 %T Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. %A Dehghan, Abbas %A Bis, Joshua C %A White, Charles C %A Smith, Albert Vernon %A Morrison, Alanna C %A Cupples, L Adrienne %A Trompet, Stella %A Chasman, Daniel I %A Lumley, Thomas %A Völker, Uwe %A Buckley, Brendan M %A Ding, Jingzhong %A Jensen, Majken K %A Folsom, Aaron R %A Kritchevsky, Stephen B %A Girman, Cynthia J %A Ford, Ian %A Dörr, Marcus %A Salomaa, Veikko %A Uitterlinden, André G %A Eiriksdottir, Gudny %A Vasan, Ramachandran S %A Franceschini, Nora %A Carty, Cara L %A Virtamo, Jarmo %A Demissie, Serkalem %A Amouyel, Philippe %A Arveiler, Dominique %A Heckbert, Susan R %A Ferrieres, Jean %A Ducimetiere, Pierre %A Smith, Nicholas L %A Wang, Ying A %A Siscovick, David S %A Rice, Kenneth M %A Wiklund, Per-Gunnar %A Taylor, Kent D %A Evans, Alun %A Kee, Frank %A Rotter, Jerome I %A Karvanen, Juha %A Kuulasmaa, Kari %A Heiss, Gerardo %A Kraft, Peter %A Launer, Lenore J %A Hofman, Albert %A Markus, Marcello R P %A Rose, Lynda M %A Silander, Kaisa %A Wagner, Peter %A Benjamin, Emelia J %A Lohman, Kurt %A Stott, David J %A Rivadeneira, Fernando %A Harris, Tamara B %A Levy, Daniel %A Liu, Yongmei %A Rimm, Eric B %A Jukema, J Wouter %A Völzke, Henry %A Ridker, Paul M %A Blankenberg, Stefan %A Franco, Oscar H %A Gudnason, Vilmundur %A Psaty, Bruce M %A Boerwinkle, Eric %A O'Donnell, Christopher J %K Aged %K Cohort Studies %K Cooperative Behavior %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

%B PLoS One %V 11 %P e0144997 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract %R 10.1371/journal.pone.0144997 %0 Journal Article %J PLoS Genet %D 2016 %T Whole Exome Sequencing in Atrial Fibrillation. %A Lubitz, Steven A %A Brody, Jennifer A %A Bihlmeyer, Nathan A %A Roselli, Carolina %A Weng, Lu-Chen %A Christophersen, Ingrid E %A Alonso, Alvaro %A Boerwinkle, Eric %A Gibbs, Richard A %A Bis, Joshua C %A Cupples, L Adrienne %A Mohler, Peter J %A Nickerson, Deborah A %A Muzny, Donna %A Perez, Marco V %A Psaty, Bruce M %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Lunetta, Kathryn L %A Benjamin, Emelia J %A Heckbert, Susan R %A Arking, Dan E %A Ellinor, Patrick T %A Lin, Honghuang %X

Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

%B PLoS Genet %V 12 %P e1006284 %8 2016 Sep %G eng %N 9 %R 10.1371/journal.pgen.1006284 %0 Journal Article %J Clin J Am Soc Nephrol %D 2017 %T eGFR and Albuminuria in Relation to Risk of Incident Atrial Fibrillation: A Meta-Analysis of the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. %A Bansal, Nisha %A Zelnick, Leila R %A Alonso, Alvaro %A Benjamin, Emelia J %A de Boer, Ian H %A Deo, Rajat %A Katz, Ronit %A Kestenbaum, Bryan %A Mathew, Jehu %A Robinson-Cohen, Cassianne %A Sarnak, Mark J %A Shlipak, Michael G %A Sotoodehnia, Nona %A Young, Bessie %A Heckbert, Susan R %X

BACKGROUND AND OBJECTIVES: The incidence of atrial fibrillation is high in ESRD, but limited data are available on the incidence of atrial fibrillation across a broad range of kidney function. Thus, we examined the association of eGFR and urine albumin-to-creatinine ratio with risk of incident atrial fibrillation.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We meta-analyzed three prospective cohorts: the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Cox regression models were performed examining the association of eGFR and urine albumin-to-creatinine ratio with incident atrial fibrillation adjusting for demographics and comorbidity. In additional analyses, we adjusted for measures of subclinical cardiovascular disease (by electrocardiogram and cardiac imaging) and interim heart failure and myocardial infarction events.

RESULTS: In the meta-analyzed study population of 16,769 participants without prevalent atrial fibrillation, across categories of decreasing eGFR (eGFR>90 [reference], 60-89, 45-59, 30-44, and <30 ml/min per 1.73 m(2)), there was a stepwise increase in the adjusted risk of incident atrial fibrillation: hazard ratios (95% confidence intervals) were 1.00, 1.09 (0.97 to 1.24), 1.17 (1.00 to 1.38), 1.59 (1.28 to 1.98), and 2.03 (1.40 to 2.96), respectively. There was a stepwise increase in the adjusted risk of incident atrial fibrillation across categories of increasing urine albumin-to-creatinine ratio (urine albumin-to-creatinine ratio <15 [reference], 15-29, 30-299, and ≥300 mg/g): hazard ratios (95% confidence intervals) were 1.00, 1.04 (0.83 to 1.30), 1.47 (1.20 to 1.79), and 1.76 (1.18 to 2.62), respectively. The associations were consistent after adjustment for subclinical cardiovascular disease measures and interim heart failure and myocardial infarction events.

CONCLUSIONS: In this meta-analysis of three cohorts, reduced eGFR and elevated urine albumin-to-creatinine ratio were significantly associated with greater risk of incident atrial fibrillation, highlighting the need for further studies to understand mechanisms linking kidney disease with atrial fibrillation.

%B Clin J Am Soc Nephrol %V 12 %P 1386-1398 %8 2017 Sep 07 %G eng %N 9 %R 10.2215/CJN.01860217 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T Fifteen Genetic Loci Associated With the Electrocardiographic P Wave. %A Christophersen, Ingrid E %A Magnani, Jared W %A Yin, Xiaoyan %A Barnard, John %A Weng, Lu-Chen %A Arking, Dan E %A Niemeijer, Maartje N %A Lubitz, Steven A %A Avery, Christy L %A Duan, Qing %A Felix, Stephan B %A Bis, Joshua C %A Kerr, Kathleen F %A Isaacs, Aaron %A Müller-Nurasyid, Martina %A Müller, Christian %A North, Kari E %A Reiner, Alex P %A Tinker, Lesley F %A Kors, Jan A %A Teumer, Alexander %A Petersmann, Astrid %A Sinner, Moritz F %A Bůzková, Petra %A Smith, Jonathan D %A Van Wagoner, David R %A Völker, Uwe %A Waldenberger, Melanie %A Peters, Annette %A Meitinger, Thomas %A Limacher, Marian C %A Wilhelmsen, Kirk C %A Psaty, Bruce M %A Hofman, Albert %A Uitterlinden, Andre %A Krijthe, Bouwe P %A Zhang, Zhu-Ming %A Schnabel, Renate B %A Kääb, Stefan %A van Duijn, Cornelia %A Rotter, Jerome I %A Sotoodehnia, Nona %A Dörr, Marcus %A Li, Yun %A Chung, Mina K %A Soliman, Elsayed Z %A Alonso, Alvaro %A Whitsel, Eric A %A Stricker, Bruno H %A Benjamin, Emelia J %A Heckbert, Susan R %A Ellinor, Patrick T %K Arrhythmias, Cardiac %K Caveolin 1 %K Caveolin 2 %K Electrocardiography %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Heart Atria %K Humans %K NAV1.5 Voltage-Gated Sodium Channel %K NAV1.8 Voltage-Gated Sodium Channel %K T-Box Domain Proteins %X

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.

METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.

CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

%B Circ Cardiovasc Genet %V 10 %8 2017 Aug %G eng %N 4 %R 10.1161/CIRCGENETICS.116.001667 %0 Journal Article %J Sci Rep %D 2017 %T Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. %A Weng, Lu-Chen %A Lunetta, Kathryn L %A Müller-Nurasyid, Martina %A Smith, Albert Vernon %A Thériault, Sébastien %A Weeke, Peter E %A Barnard, John %A Bis, Joshua C %A Lyytikäinen, Leo-Pekka %A Kleber, Marcus E %A Martinsson, Andreas %A Lin, Henry J %A Rienstra, Michiel %A Trompet, Stella %A Krijthe, Bouwe P %A Dörr, Marcus %A Klarin, Derek %A Chasman, Daniel I %A Sinner, Moritz F %A Waldenberger, Melanie %A Launer, Lenore J %A Harris, Tamara B %A Soliman, Elsayed Z %A Alonso, Alvaro %A Paré, Guillaume %A Teixeira, Pedro L %A Denny, Joshua C %A Shoemaker, M Benjamin %A Van Wagoner, David R %A Smith, Jonathan D %A Psaty, Bruce M %A Sotoodehnia, Nona %A Taylor, Kent D %A Kähönen, Mika %A Nikus, Kjell %A Delgado, Graciela E %A Melander, Olle %A Engström, Gunnar %A Yao, Jie %A Guo, Xiuqing %A Christophersen, Ingrid E %A Ellinor, Patrick T %A Geelhoed, Bastiaan %A Verweij, Niek %A Macfarlane, Peter %A Ford, Ian %A Heeringa, Jan %A Franco, Oscar H %A Uitterlinden, André G %A Völker, Uwe %A Teumer, Alexander %A Rose, Lynda M %A Kääb, Stefan %A Gudnason, Vilmundur %A Arking, Dan E %A Conen, David %A Roden, Dan M %A Chung, Mina K %A Heckbert, Susan R %A Benjamin, Emelia J %A Lehtimäki, Terho %A März, Winfried %A Smith, J Gustav %A Rotter, Jerome I %A van der Harst, Pim %A Jukema, J Wouter %A Stricker, Bruno H %A Felix, Stephan B %A Albert, Christine M %A Lubitz, Steven A %X

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

%B Sci Rep %V 7 %P 11303 %8 2017 Sep 12 %G eng %N 1 %R 10.1038/s41598-017-09396-7 %0 Journal Article %J Nat Genet %D 2017 %T Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. %A Christophersen, Ingrid E %A Rienstra, Michiel %A Roselli, Carolina %A Yin, Xiaoyan %A Geelhoed, Bastiaan %A Barnard, John %A Lin, Honghuang %A Arking, Dan E %A Smith, Albert V %A Albert, Christine M %A Chaffin, Mark %A Tucker, Nathan R %A Li, Molong %A Klarin, Derek %A Bihlmeyer, Nathan A %A Low, Siew-Kee %A Weeke, Peter E %A Müller-Nurasyid, Martina %A Smith, J Gustav %A Brody, Jennifer A %A Niemeijer, Maartje N %A Dörr, Marcus %A Trompet, Stella %A Huffman, Jennifer %A Gustafsson, Stefan %A Schurmann, Claudia %A Kleber, Marcus E %A Lyytikäinen, Leo-Pekka %A Seppälä, Ilkka %A Malik, Rainer %A Horimoto, Andrea R V R %A Perez, Marco %A Sinisalo, Juha %A Aeschbacher, Stefanie %A Thériault, Sébastien %A Yao, Jie %A Radmanesh, Farid %A Weiss, Stefan %A Teumer, Alexander %A Choi, Seung Hoan %A Weng, Lu-Chen %A Clauss, Sebastian %A Deo, Rajat %A Rader, Daniel J %A Shah, Svati H %A Sun, Albert %A Hopewell, Jemma C %A Debette, Stephanie %A Chauhan, Ganesh %A Yang, Qiong %A Worrall, Bradford B %A Paré, Guillaume %A Kamatani, Yoichiro %A Hagemeijer, Yanick P %A Verweij, Niek %A Siland, Joylene E %A Kubo, Michiaki %A Smith, Jonathan D %A Van Wagoner, David R %A Bis, Joshua C %A Perz, Siegfried %A Psaty, Bruce M %A Ridker, Paul M %A Magnani, Jared W %A Harris, Tamara B %A Launer, Lenore J %A Shoemaker, M Benjamin %A Padmanabhan, Sandosh %A Haessler, Jeffrey %A Bartz, Traci M %A Waldenberger, Melanie %A Lichtner, Peter %A Arendt, Marina %A Krieger, Jose E %A Kähönen, Mika %A Risch, Lorenz %A Mansur, Alfredo J %A Peters, Annette %A Smith, Blair H %A Lind, Lars %A Scott, Stuart A %A Lu, Yingchang %A Bottinger, Erwin B %A Hernesniemi, Jussi %A Lindgren, Cecilia M %A Wong, Jorge A %A Huang, Jie %A Eskola, Markku %A Morris, Andrew P %A Ford, Ian %A Reiner, Alex P %A Delgado, Graciela %A Chen, Lin Y %A Chen, Yii-Der Ida %A Sandhu, Roopinder K %A Li, Man %A Boerwinkle, Eric %A Eisele, Lewin %A Lannfelt, Lars %A Rost, Natalia %A Anderson, Christopher D %A Taylor, Kent D %A Campbell, Archie %A Magnusson, Patrik K %A Porteous, David %A Hocking, Lynne J %A Vlachopoulou, Efthymia %A Pedersen, Nancy L %A Nikus, Kjell %A Orho-Melander, Marju %A Hamsten, Anders %A Heeringa, Jan %A Denny, Joshua C %A Kriebel, Jennifer %A Darbar, Dawood %A Newton-Cheh, Christopher %A Shaffer, Christian %A Macfarlane, Peter W %A Heilmann-Heimbach, Stefanie %A Almgren, Peter %A Huang, Paul L %A Sotoodehnia, Nona %A Soliman, Elsayed Z %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Völker, Uwe %A Jöckel, Karl-Heinz %A Sinner, Moritz F %A Lin, Henry J %A Guo, Xiuqing %A Dichgans, Martin %A Ingelsson, Erik %A Kooperberg, Charles %A Melander, Olle %A Loos, Ruth J F %A Laurikka, Jari %A Conen, David %A Rosand, Jonathan %A van der Harst, Pim %A Lokki, Marja-Liisa %A Kathiresan, Sekar %A Pereira, Alexandre %A Jukema, J Wouter %A Hayward, Caroline %A Rotter, Jerome I %A März, Winfried %A Lehtimäki, Terho %A Stricker, Bruno H %A Chung, Mina K %A Felix, Stephan B %A Gudnason, Vilmundur %A Alonso, Alvaro %A Roden, Dan M %A Kääb, Stefan %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Tanaka, Toshihiro %A Lunetta, Kathryn L %A Lubitz, Steven A %A Ellinor, Patrick T %X

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

%B Nat Genet %V 49 %P 946-952 %8 2017 Jun %G eng %N 6 %R 10.1038/ng.3843 %0 Journal Article %J J Clin Invest %D 2017 %T Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. %A Wild, Philipp S %A Felix, Janine F %A Schillert, Arne %A Teumer, Alexander %A Chen, Ming-Huei %A Leening, Maarten J G %A Völker, Uwe %A Großmann, Vera %A Brody, Jennifer A %A Irvin, Marguerite R %A Shah, Sanjiv J %A Pramana, Setia %A Lieb, Wolfgang %A Schmidt, Reinhold %A Stanton, Alice V %A Malzahn, Dörthe %A Smith, Albert Vernon %A Sundström, Johan %A Minelli, Cosetta %A Ruggiero, Daniela %A Lyytikäinen, Leo-Pekka %A Tiller, Daniel %A Smith, J Gustav %A Monnereau, Claire %A Di Tullio, Marco R %A Musani, Solomon K %A Morrison, Alanna C %A Pers, Tune H %A Morley, Michael %A Kleber, Marcus E %A Aragam, Jayashri %A Benjamin, Emelia J %A Bis, Joshua C %A Bisping, Egbert %A Broeckel, Ulrich %A Cheng, Susan %A Deckers, Jaap W %A del Greco M, Fabiola %A Edelmann, Frank %A Fornage, Myriam %A Franke, Lude %A Friedrich, Nele %A Harris, Tamara B %A Hofer, Edith %A Hofman, Albert %A Huang, Jie %A Hughes, Alun D %A Kähönen, Mika %A Investigators, Knhi %A Kruppa, Jochen %A Lackner, Karl J %A Lannfelt, Lars %A Laskowski, Rafael %A Launer, Lenore J %A Leosdottir, Margrét %A Lin, Honghuang %A Lindgren, Cecilia M %A Loley, Christina %A MacRae, Calum A %A Mascalzoni, Deborah %A Mayet, Jamil %A Medenwald, Daniel %A Morris, Andrew P %A Müller, Christian %A Müller-Nurasyid, Martina %A Nappo, Stefania %A Nilsson, Peter M %A Nuding, Sebastian %A Nutile, Teresa %A Peters, Annette %A Pfeufer, Arne %A Pietzner, Diana %A Pramstaller, Peter P %A Raitakari, Olli T %A Rice, Kenneth M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Ruohonen, Saku T %A Sacco, Ralph L %A Samdarshi, Tandaw E %A Schmidt, Helena %A Sharp, Andrew S P %A Shields, Denis C %A Sorice, Rossella %A Sotoodehnia, Nona %A Stricker, Bruno H %A Surendran, Praveen %A Thom, Simon %A Töglhofer, Anna M %A Uitterlinden, André G %A Wachter, Rolf %A Völzke, Henry %A Ziegler, Andreas %A Münzel, Thomas %A März, Winfried %A Cappola, Thomas P %A Hirschhorn, Joel N %A Mitchell, Gary F %A Smith, Nicholas L %A Fox, Ervin R %A Dueker, Nicole D %A Jaddoe, Vincent W V %A Melander, Olle %A Russ, Martin %A Lehtimäki, Terho %A Ciullo, Marina %A Hicks, Andrew A %A Lind, Lars %A Gudnason, Vilmundur %A Pieske, Burkert %A Barron, Anthony J %A Zweiker, Robert %A Schunkert, Heribert %A Ingelsson, Erik %A Liu, Kiang %A Arnett, Donna K %A Psaty, Bruce M %A Blankenberg, Stefan %A Larson, Martin G %A Felix, Stephan B %A Franco, Oscar H %A Zeller, Tanja %A Vasan, Ramachandran S %A Dörr, Marcus %X

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.

METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.

RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.

CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

FUNDING: For detailed information per study, see Acknowledgments.

%B J Clin Invest %V 127 %P 1798-1812 %8 2017 May 01 %G eng %N 5 %R 10.1172/JCI84840 %0 Journal Article %J Eur J Heart Fail %D 2017 %T Predictors and outcomes of heart failure with mid-range ejection fraction. %A Bhambhani, Vijeta %A Kizer, Jorge R %A Lima, João A C %A van der Harst, Pim %A Bahrami, Hossein %A Nayor, Matthew %A de Filippi, Christopher R %A Enserro, Danielle %A Blaha, Michael J %A Cushman, Mary %A Wang, Thomas J %A Gansevoort, Ron T %A Fox, Caroline S %A Gaggin, Hanna K %A Kop, Willem J %A Liu, Kiang %A Vasan, Ramachandran S %A Psaty, Bruce M %A Lee, Douglas S %A Brouwers, Frank P %A Hillege, Hans L %A Bartz, Traci M %A Benjamin, Emelia J %A Chan, Cheeling %A Allison, Matthew %A Gardin, Julius M %A Januzzi, James L %A Levy, Daniel %A Herrington, David M %A van Gilst, Wiek H %A Bertoni, Alain G %A Larson, Martin G %A de Boer, Rudolf A %A Gottdiener, John S %A Shah, Sanjiv J %A Ho, Jennifer E %X

AIMS: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.

METHODS AND RESULTS: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78).

CONCLUSIONS: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.

%B Eur J Heart Fail %8 2017 Dec 11 %G eng %R 10.1002/ejhf.1091 %0 Journal Article %J JAMA Cardiol %D 2018 %T Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction. %A de Boer, Rudolf A %A Nayor, Matthew %A deFilippi, Christopher R %A Enserro, Danielle %A Bhambhani, Vijeta %A Kizer, Jorge R %A Blaha, Michael J %A Brouwers, Frank P %A Cushman, Mary %A Lima, João A C %A Bahrami, Hossein %A van der Harst, Pim %A Wang, Thomas J %A Gansevoort, Ron T %A Fox, Caroline S %A Gaggin, Hanna K %A Kop, Willem J %A Liu, Kiang %A Vasan, Ramachandran S %A Psaty, Bruce M %A Lee, Douglas S %A Hillege, Hans L %A Bartz, Traci M %A Benjamin, Emelia J %A Chan, Cheeling %A Allison, Matthew %A Gardin, Julius M %A Januzzi, James L %A Shah, Sanjiv J %A Levy, Daniel %A Herrington, David M %A Larson, Martin G %A van Gilst, Wiek H %A Gottdiener, John S %A Bertoni, Alain G %A Ho, Jennifer E %X

Importance: Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood.

Objective: To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population.

Design, Setting, and Participants: This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017.

Exposures: The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6.

Main Outcomes and Measures: Development of incident HFpEF and incident HFrEF.

Results: Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF.

Conclusions and Relevance: Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.

%B JAMA Cardiol %8 2018 Jan 10 %G eng %R 10.1001/jamacardio.2017.4987 %0 Journal Article %J Clin Cardiol %D 2018 %T Atrial fibrillation in an African-American cohort: The Jackson Heart Study. %A Austin, Thomas R %A Wiggins, Kerri L %A Blackshear, Chad %A Yang, Yi %A Benjamin, Emelia J %A Curtis, Lesley H %A Sotoodehnia, Nona %A Correa, Adolfo %A Heckbert, Susan R %X

BACKGROUND: Atrial fibrillation (AF) is an important public health problem across race/ethnic groups. Data from US cohort studies initiated in the 1980s suggest a higher prevalence of AF risk factors among African-Americans (AAs) than whites, but lower AF incidence. The Jackson Heart Study (JHS) is a community-based study of 5306 AAs recruited starting in 2000.

HYPOTHESIS: Demographic, anthropometric, cardiovascular, and/or electrocardiographic factors are associated with AF incidence in JHS.

METHODS: Using baseline participant characteristics and incident AF identified through hospital surveillance, study electrocardiogram, and Medicare claims, we estimated age- and sex-specific AF incidence rates, compared them with rates in AA participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS), and examined associations of cardiovascular risk factors with AF.

RESULTS: A total of 66 participants had prevalent AF at baseline. Over an average follow-up of 8.5 years, 242 cases of incident AF were identified. Age- and sex-specific AF incidence rates in JHS were similar to those among AAs in MESA and appeared slightly lower than those among AAs in CHS. In an age- and sex-adjusted model, associations with incident AF were observed for modifiable risk factors: high body weight (HR = 1.23 per 15 kg, 95%CI 1.13-1.35), systolic blood pressure (HR = 1.29 per 20 mmHg, 95%CI 1.13-1.47), and current smoking (HR = 1.80, 95%CI 1.27-2.55). Risk estimates associated with these risk factors were only slightly attenuated after multivariable adjustments.

CONCLUSIONS: These findings underscore the potential additional benefits of interventions for weight management, control of hypertension, and smoking cessation for the prevention of AF among AAs.

%B Clin Cardiol %8 2018 Jul 02 %G eng %R 10.1002/clc.23020 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. %A Lin, Honghuang %A van Setten, Jessica %A Smith, Albert V %A Bihlmeyer, Nathan A %A Warren, Helen R %A Brody, Jennifer A %A Radmanesh, Farid %A Hall, Leanne %A Grarup, Niels %A Müller-Nurasyid, Martina %A Boutin, Thibaud %A Verweij, Niek %A Lin, Henry J %A Li-Gao, Ruifang %A van den Berg, Marten E %A Marten, Jonathan %A Weiss, Stefan %A Prins, Bram P %A Haessler, Jeffrey %A Lyytikäinen, Leo-Pekka %A Mei, Hao %A Harris, Tamara B %A Launer, Lenore J %A Li, Man %A Alonso, Alvaro %A Soliman, Elsayed Z %A Connell, John M %A Huang, Paul L %A Weng, Lu-Chen %A Jameson, Heather S %A Hucker, William %A Hanley, Alan %A Tucker, Nathan R %A Chen, Yii-Der Ida %A Bis, Joshua C %A Rice, Kenneth M %A Sitlani, Colleen M %A Kors, Jan A %A Xie, Zhijun %A Wen, Chengping %A Magnani, Jared W %A Nelson, Christopher P %A Kanters, Jørgen K %A Sinner, Moritz F %A Strauch, Konstantin %A Peters, Annette %A Waldenberger, Melanie %A Meitinger, Thomas %A Bork-Jensen, Jette %A Pedersen, Oluf %A Linneberg, Allan %A Rudan, Igor %A de Boer, Rudolf A %A van der Meer, Peter %A Yao, Jie %A Guo, Xiuqing %A Taylor, Kent D %A Sotoodehnia, Nona %A Rotter, Jerome I %A Mook-Kanamori, Dennis O %A Trompet, Stella %A Rivadeneira, Fernando %A Uitterlinden, Andre %A Eijgelsheim, Mark %A Padmanabhan, Sandosh %A Smith, Blair H %A Völzke, Henry %A Felix, Stephan B %A Homuth, Georg %A Völker, Uwe %A Mangino, Massimo %A Spector, Timothy D %A Bots, Michiel L %A Perez, Marco %A Kähönen, Mika %A Raitakari, Olli T %A Gudnason, Vilmundur %A Arking, Dan E %A Munroe, Patricia B %A Psaty, Bruce M %A van Duijn, Cornelia M %A Benjamin, Emelia J %A Rosand, Jonathan %A Samani, Nilesh J %A Hansen, Torben %A Kääb, Stefan %A Polasek, Ozren %A van der Harst, Pim %A Heckbert, Susan R %A Jukema, J Wouter %A Stricker, Bruno H %A Hayward, Caroline %A Dörr, Marcus %A Jamshidi, Yalda %A Asselbergs, Folkert W %A Kooperberg, Charles %A Lehtimäki, Terho %A Wilson, James G %A Ellinor, Patrick T %A Lubitz, Steven A %A Isaacs, Aaron %X

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.

METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.

RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.

CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

%B Circ Genom Precis Med %V 11 %P e002037 %8 2018 May %G eng %N 5 %R 10.1161/CIRCGEN.117.002037 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T Common Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction. %A Macri, Vincenzo %A Brody, Jennifer A %A Arking, Dan E %A Hucker, William J %A Yin, Xiaoyan %A Lin, Honghuang %A Mills, Robert W %A Sinner, Moritz F %A Lubitz, Steven A %A Liu, Ching-Ti %A Morrison, Alanna C %A Alonso, Alvaro %A Li, Ning %A Fedorov, Vadim V %A Janssen, Paul M %A Bis, Joshua C %A Heckbert, Susan R %A Dolmatova, Elena V %A Lumley, Thomas %A Sitlani, Colleen M %A Cupples, L Adrienne %A Pulit, Sara L %A Newton-Cheh, Christopher %A Barnard, John %A Smith, Jonathan D %A Van Wagoner, David R %A Chung, Mina K %A Vlahakes, Gus J %A O'Donnell, Christopher J %A Rotter, Jerome I %A Margulies, Kenneth B %A Morley, Michael P %A Cappola, Thomas P %A Benjamin, Emelia J %A Muzny, Donna %A Gibbs, Richard A %A Jackson, Rebecca D %A Magnani, Jared W %A Herndon, Caroline N %A Rich, Stephen S %A Psaty, Bruce M %A Milan, David J %A Boerwinkle, Eric %A Mohler, Peter J %A Sotoodehnia, Nona %A Ellinor, Patrick T %X

BACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized.

METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.

RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (  =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52×10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2×10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium (  ≥0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, =0.03, and I962V+V1073A, 22.4±0.8%, =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, =0.03).

CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction.

%B Circ Genom Precis Med %V 11 %P e001663 %8 2018 May %G eng %N 5 %R 10.1161/CIRCGEN.116.001663 %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, Rene %A Zhu, Gu %A Mace, Aurelien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michèle M %A Chen, Yii-der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J SAGE Open Med %D 2018 %T Hospital and clinical care costs associated with atrial fibrillation for Medicare beneficiaries in the Cardiovascular Health Study and the Framingham Heart Study. %A Delaney, Joseph Ac %A Yin, Xiaoyan %A Fontes, João Daniel %A Wallace, Erin R %A Skinner, Asheley %A Wang, Na %A Hammill, Bradley G %A Benjamin, Emelia J %A Curtis, Lesley H %A Heckbert, Susan R %X

Background: Atrial fibrillation is increasingly prevalent as the US population ages and is associated with significant morbidity and mortality. Care for patients with atrial fibrillation can be costly, US health care costs are comparatively high, and there are few cost estimates available that incorporate detailed measurement of comorbidities and their effects on costs.

Methods and Results: In the Cardiovascular Health Study and the Framingham Heart Study, participants aged 65 years or older with newly diagnosed atrial fibrillation were matched on age and follow-up time to referents free of atrial fibrillation. The total clinical and hospital medical costs paid by Medicare Parts A and B (drug costs from Medicare Part D costs were not included) in the year prior to diagnosis (or matching) were compared with costs in the following year. Estimates were adjusted for other medical conditions and adjusted to 2009 dollars. In the Cardiovascular Health Study, 513 participants were diagnosed with new-onset atrial fibrillation and survived 30 days post-atrial fibrillation diagnosis, and 513 referents (as a control cohort) were identified, with a mean age of 77 years. In the Framingham Heart Study, we identified 336 participants diagnosed with atrial fibrillation, who survived 30 days post-atrial fibrillation diagnosis and matched these participants to 336 referents. We compared these new-onset atrial fibrillation participants with referents, using a difference in difference design to account for both time trends and differences between the two groups. The adjusted incremental cost for participants with atrial fibrillation, compared with referents, was US$18,060 (95% confidence interval: US$14,965-US$21,155) in the Cardiovascular Health Study and US$20,012 (95% confidence interval: US$15,057-US$24,966) in the Framingham Heart Study. The pooled estimate was US$18,601 (95% confidence interval: US$15,981-US$21,234).

Conclusion: Atrial fibrillation was associated with increased costs in the year after diagnosis in two community-based cohorts, even after careful accounting for age, time period, and systematically measured comorbidities.

%B SAGE Open Med %V 6 %P 2050312118759444 %8 2018 %G eng %R 10.1177/2050312118759444 %0 Journal Article %J Nat Genet %D 2018 %T Multi-ethnic genome-wide association study for atrial fibrillation. %A Roselli, Carolina %A Chaffin, Mark D %A Weng, Lu-Chen %A Aeschbacher, Stefanie %A Ahlberg, Gustav %A Albert, Christine M %A Almgren, Peter %A Alonso, Alvaro %A Anderson, Christopher D %A Aragam, Krishna G %A Arking, Dan E %A Barnard, John %A Bartz, Traci M %A Benjamin, Emelia J %A Bihlmeyer, Nathan A %A Bis, Joshua C %A Bloom, Heather L %A Boerwinkle, Eric %A Bottinger, Erwin B %A Brody, Jennifer A %A Calkins, Hugh %A Campbell, Archie %A Cappola, Thomas P %A Carlquist, John %A Chasman, Daniel I %A Chen, Lin Y %A Chen, Yii-Der Ida %A Choi, Eue-Keun %A Choi, Seung Hoan %A Christophersen, Ingrid E %A Chung, Mina K %A Cole, John W %A Conen, David %A Cook, James %A Crijns, Harry J %A Cutler, Michael J %A Damrauer, Scott M %A Daniels, Brian R %A Darbar, Dawood %A Delgado, Graciela %A Denny, Joshua C %A Dichgans, Martin %A Dörr, Marcus %A Dudink, Elton A %A Dudley, Samuel C %A Esa, Nada %A Esko, Tõnu %A Eskola, Markku %A Fatkin, Diane %A Felix, Stephan B %A Ford, Ian %A Franco, Oscar H %A Geelhoed, Bastiaan %A Grewal, Raji P %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gupta, Namrata %A Gustafsson, Stefan %A Gutmann, Rebecca %A Hamsten, Anders %A Harris, Tamara B %A Hayward, Caroline %A Heckbert, Susan R %A Hernesniemi, Jussi %A Hocking, Lynne J %A Hofman, Albert %A Horimoto, Andrea R V R %A Huang, Jie %A Huang, Paul L %A Huffman, Jennifer %A Ingelsson, Erik %A Ipek, Esra Gucuk %A Ito, Kaoru %A Jimenez-Conde, Jordi %A Johnson, Renee %A Jukema, J Wouter %A Kääb, Stefan %A Kähönen, Mika %A Kamatani, Yoichiro %A Kane, John P %A Kastrati, Adnan %A Kathiresan, Sekar %A Katschnig-Winter, Petra %A Kavousi, Maryam %A Kessler, Thorsten %A Kietselaer, Bas L %A Kirchhof, Paulus %A Kleber, Marcus E %A Knight, Stacey %A Krieger, Jose E %A Kubo, Michiaki %A Launer, Lenore J %A Laurikka, Jari %A Lehtimäki, Terho %A Leineweber, Kirsten %A Lemaitre, Rozenn N %A Li, Man %A Lim, Hong Euy %A Lin, Henry J %A Lin, Honghuang %A Lind, Lars %A Lindgren, Cecilia M %A Lokki, Marja-Liisa %A London, Barry %A Loos, Ruth J F %A Low, Siew-Kee %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Macfarlane, Peter W %A Magnusson, Patrik K %A Mahajan, Anubha %A Malik, Rainer %A Mansur, Alfredo J %A Marcus, Gregory M %A Margolin, Lauren %A Margulies, Kenneth B %A März, Winfried %A McManus, David D %A Melander, Olle %A Mohanty, Sanghamitra %A Montgomery, Jay A %A Morley, Michael P %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Natale, Andrea %A Nazarian, Saman %A Neumann, Benjamin %A Newton-Cheh, Christopher %A Niemeijer, Maartje N %A Nikus, Kjell %A Nilsson, Peter %A Noordam, Raymond %A Oellers, Heidi %A Olesen, Morten S %A Orho-Melander, Marju %A Padmanabhan, Sandosh %A Pak, Hui-Nam %A Paré, Guillaume %A Pedersen, Nancy L %A Pera, Joanna %A Pereira, Alexandre %A Porteous, David %A Psaty, Bruce M %A Pulit, Sara L %A Pullinger, Clive R %A Rader, Daniel J %A Refsgaard, Lena %A Ribasés, Marta %A Ridker, Paul M %A Rienstra, Michiel %A Risch, Lorenz %A Roden, Dan M %A Rosand, Jonathan %A Rosenberg, Michael A %A Rost, Natalia %A Rotter, Jerome I %A Saba, Samir %A Sandhu, Roopinder K %A Schnabel, Renate B %A Schramm, Katharina %A Schunkert, Heribert %A Schurman, Claudia %A Scott, Stuart A %A Seppälä, Ilkka %A Shaffer, Christian %A Shah, Svati %A Shalaby, Alaa A %A Shim, Jaemin %A Shoemaker, M Benjamin %A Siland, Joylene E %A Sinisalo, Juha %A Sinner, Moritz F %A Slowik, Agnieszka %A Smith, Albert V %A Smith, Blair H %A Smith, J Gustav %A Smith, Jonathan D %A Smith, Nicholas L %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Stricker, Bruno H %A Sun, Albert %A Sun, Han %A Svendsen, Jesper H %A Tanaka, Toshihiro %A Tanriverdi, Kahraman %A Taylor, Kent D %A Teder-Laving, Maris %A Teumer, Alexander %A Thériault, Sébastien %A Trompet, Stella %A Tucker, Nathan R %A Tveit, Arnljot %A Uitterlinden, André G %A van der Harst, Pim %A Van Gelder, Isabelle C %A Van Wagoner, David R %A Verweij, Niek %A Vlachopoulou, Efthymia %A Völker, Uwe %A Wang, Biqi %A Weeke, Peter E %A Weijs, Bob %A Weiss, Raul %A Weiss, Stefan %A Wells, Quinn S %A Wiggins, Kerri L %A Wong, Jorge A %A Woo, Daniel %A Worrall, Bradford B %A Yang, Pil-Sung %A Yao, Jie %A Yoneda, Zachary T %A Zeller, Tanja %A Zeng, Lingyao %A Lubitz, Steven A %A Lunetta, Kathryn L %A Ellinor, Patrick T %X

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. 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.

%B Nat Genet %V 50 %P 1225-1233 %8 2018 Sep %G eng %N 9 %R 10.1038/s41588-018-0133-9 %0 Journal Article %J Nat Commun %D 2018 %T PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. %A van Setten, Jessica %A Brody, Jennifer A %A Jamshidi, Yalda %A Swenson, Brenton R %A Butler, Anne M %A Campbell, Harry %A Del Greco, Fabiola M %A Evans, Daniel S %A Gibson, Quince %A Gudbjartsson, Daniel F %A Kerr, Kathleen F %A Krijthe, Bouwe P %A Lyytikäinen, Leo-Pekka %A Müller, Christian %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Ritchie, Marylyn D %A Robino, Antonietta %A Smith, Albert V %A Steri, Maristella %A Tanaka, Toshiko %A Teumer, Alexander %A Trompet, Stella %A Ulivi, Sheila %A Verweij, Niek %A Yin, Xiaoyan %A Arnar, David O %A Asselbergs, Folkert W %A Bader, Joel S %A Barnard, John %A Bis, Josh %A Blankenberg, Stefan %A Boerwinkle, Eric %A Bradford, Yuki %A Buckley, Brendan M %A Chung, Mina K %A Crawford, Dana %A den Hoed, Marcel %A Denny, Josh C %A Dominiczak, Anna F %A Ehret, Georg B %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Felix, Stephan B %A Franco, Oscar H %A Franke, Lude %A Harris, Tamara B %A Holm, Hilma %A Ilaria, Gandin %A Iorio, Annamaria %A Kähönen, Mika %A Kolcic, Ivana %A Kors, Jan A %A Lakatta, Edward G %A Launer, Lenore J %A Lin, Honghuang %A Lin, Henry J %A Loos, Ruth J F %A Lubitz, Steven A %A Macfarlane, Peter W %A Magnani, Jared W %A Leach, Irene Mateo %A Meitinger, Thomas %A Mitchell, Braxton D %A Münzel, Thomas %A Papanicolaou, George J %A Peters, Annette %A Pfeufer, Arne %A Pramstaller, Peter P %A Raitakari, Olli T %A Rotter, Jerome I %A Rudan, Igor %A Samani, Nilesh J %A Schlessinger, David %A Silva Aldana, Claudia T %A Sinner, Moritz F %A Smith, Jonathan D %A Snieder, Harold %A Soliman, Elsayed Z %A Spector, Timothy D %A Stott, David J %A Strauch, Konstantin %A Tarasov, Kirill V %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Jan Westra, Harm %A Wild, Philipp S %A Zeller, Tanja %A Alonso, Alvaro %A Avery, Christy L %A Bandinelli, Stefania %A Benjamin, Emelia J %A Cucca, Francesco %A Dörr, Marcus %A Ferrucci, Luigi %A Gasparini, Paolo %A Gudnason, Vilmundur %A Hayward, Caroline %A Heckbert, Susan R %A Hicks, Andrew A %A Jukema, J Wouter %A Kääb, Stefan %A Lehtimäki, Terho %A Liu, Yongmei %A Munroe, Patricia B %A Parsa, Afshin %A Polasek, Ozren %A Psaty, Bruce M %A Roden, Dan M %A Schnabel, Renate B %A Sinagra, Gianfranco %A Stefansson, Kari %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Wilson, James F %A Gharib, Sina A %A de Bakker, Paul I W %A Isaacs, Aaron %A Arking, Dan E %A Sotoodehnia, Nona %X

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

%B Nat Commun %V 9 %P 2904 %8 2018 Jul 25 %G eng %N 1 %R 10.1038/s41467-018-04766-9 %0 Journal Article %J JAMA Cardiol %D 2019 %T Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study. %A Ellervik, Christina %A Roselli, Carolina %A Christophersen, Ingrid E %A Alonso, Alvaro %A Pietzner, Maik %A Sitlani, Collen M %A Trompet, Stella %A Arking, Dan E %A Geelhoed, Bastiaan %A Guo, Xiuqing %A Kleber, Marcus E %A Lin, Henry J %A Lin, Honghuang %A Macfarlane, Peter %A Selvin, Elizabeth %A Shaffer, Christian %A Smith, Albert V %A Verweij, Niek %A Weiss, Stefan %A Cappola, Anne R %A Dörr, Marcus %A Gudnason, Vilmundur %A Heckbert, Susan %A Mooijaart, Simon %A März, Winfried %A Psaty, Bruce M %A Ridker, Paul M %A Roden, Dan %A Stott, David J %A Völzke, Henry %A Benjamin, Emelia J %A Delgado, Graciela %A Ellinor, Patrick %A Homuth, Georg %A Köttgen, Anna %A Jukema, Johan W %A Lubitz, Steven A %A Mora, Samia %A Rienstra, Michiel %A Rotter, Jerome I %A Shoemaker, M Benjamin %A Sotoodehnia, Nona %A Taylor, Kent D %A van der Harst, Pim %A Albert, Christine M %A Chasman, Daniel I %X

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.

Objective: To evaluate the potential direct involvement of thyroid traits on AF.

Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.

Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.

Main Outcomes and Measures: Prevalent and incident AF.

Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).

Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

%B JAMA Cardiol %8 2019 Jan 23 %G eng %R 10.1001/jamacardio.2018.4635 %0 Journal Article %J Circ Genom Precis Med %D 2019 %T Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation. %A Dörr, Marcus %A Hamburg, Naomi M %A Müller, Christian %A Smith, Nicholas L %A Gustafsson, Stefan %A Lehtimäki, Terho %A Teumer, Alexander %A Zeller, Tanja %A Li, Xiaohui %A Lind, Lars %A Raitakari, Olli T %A Völker, Uwe %A Blankenberg, Stefan %A McKnight, Barbara %A Morris, Andrew P %A Kähönen, Mika %A Lemaitre, Rozenn N %A Wild, Philipp S %A Nauck, Matthias %A Völzke, Henry %A Münzel, Thomas %A Mitchell, Gary F %A Psaty, Bruce M %A Lindgren, Cecilia M %A Larson, Martin G %A Felix, Stephan B %A Ingelsson, Erik %A Lyytikäinen, Leo-Pekka %A Herrington, David %A Benjamin, Emelia J %A Schnabel, Renate B %B Circ Genom Precis Med %V 12 %P e002409 %8 2019 Feb %G eng %N 2 %R 10.1161/CIRCGEN.118.002409 %0 Journal Article %J Nat Commun %D 2020 %T Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. %A Ntalla, Ioanna %A Weng, Lu-Chen %A Cartwright, James H %A Hall, Amelia Weber %A Sveinbjornsson, Gardar %A Tucker, Nathan R %A Choi, Seung Hoan %A Chaffin, Mark D %A Roselli, Carolina %A Barnes, Michael R %A Mifsud, Borbala %A Warren, Helen R %A Hayward, Caroline %A Marten, Jonathan %A Cranley, James J %A Concas, Maria Pina %A Gasparini, Paolo %A Boutin, Thibaud %A Kolcic, Ivana %A Polasek, Ozren %A Rudan, Igor %A Araujo, Nathalia M %A Lima-Costa, Maria Fernanda %A Ribeiro, Antonio Luiz P %A Souza, Renan P %A Tarazona-Santos, Eduardo %A Giedraitis, Vilmantas %A Ingelsson, Erik %A Mahajan, Anubha %A Morris, Andrew P %A del Greco M, Fabiola %A Foco, Luisa %A Gögele, Martin %A Hicks, Andrew A %A Cook, James P %A Lind, Lars %A Lindgren, Cecilia M %A Sundström, Johan %A Nelson, Christopher P %A Riaz, Muhammad B %A Samani, Nilesh J %A Sinagra, Gianfranco %A Ulivi, Sheila %A Kähönen, Mika %A Mishra, Pashupati P %A Mononen, Nina %A Nikus, Kjell %A Caulfield, Mark J %A Dominiczak, Anna %A Padmanabhan, Sandosh %A Montasser, May E %A O'Connell, Jeff R %A Ryan, Kathleen %A Shuldiner, Alan R %A Aeschbacher, Stefanie %A Conen, David %A Risch, Lorenz %A Thériault, Sébastien %A Hutri-Kähönen, Nina %A Lehtimäki, Terho %A Lyytikäinen, Leo-Pekka %A Raitakari, Olli T %A Barnes, Catriona L K %A Campbell, Harry %A Joshi, Peter K %A Wilson, James F %A Isaacs, Aaron %A Kors, Jan A %A van Duijn, Cornelia M %A Huang, Paul L %A Gudnason, Vilmundur %A Harris, Tamara B %A Launer, Lenore J %A Smith, Albert V %A Bottinger, Erwin P %A Loos, Ruth J F %A Nadkarni, Girish N %A Preuss, Michael H %A Correa, Adolfo %A Mei, Hao %A Wilson, James %A Meitinger, Thomas %A Müller-Nurasyid, Martina %A Peters, Annette %A Waldenberger, Melanie %A Mangino, Massimo %A Spector, Timothy D %A Rienstra, Michiel %A van de Vegte, Yordi J %A van der Harst, Pim %A Verweij, Niek %A Kääb, Stefan %A Schramm, Katharina %A Sinner, Moritz F %A Strauch, Konstantin %A Cutler, Michael J %A Fatkin, Diane %A London, Barry %A Olesen, Morten %A Roden, Dan M %A Benjamin Shoemaker, M %A Gustav Smith, J %A Biggs, Mary L %A Bis, Joshua C %A Brody, Jennifer A %A Psaty, Bruce M %A Rice, Kenneth %A Sotoodehnia, Nona %A De Grandi, Alessandro %A Fuchsberger, Christian %A Pattaro, Cristian %A Pramstaller, Peter P %A Ford, Ian %A Wouter Jukema, J %A Macfarlane, Peter W %A Trompet, Stella %A Dörr, Marcus %A Felix, Stephan B %A Völker, Uwe %A Weiss, Stefan %A Havulinna, Aki S %A Jula, Antti %A Sääksjärvi, Katri %A Salomaa, Veikko %A Guo, Xiuqing %A Heckbert, Susan R %A Lin, Henry J %A Rotter, Jerome I %A Taylor, Kent D %A Yao, Jie %A de Mutsert, Renée %A Maan, Arie C %A Mook-Kanamori, Dennis O %A Noordam, Raymond %A Cucca, Francesco %A Ding, Jun %A Lakatta, Edward G %A Qian, Yong %A Tarasov, Kirill V %A Levy, Daniel %A Lin, Honghuang %A Newton-Cheh, Christopher H %A Lunetta, Kathryn L %A Murray, Alison D %A Porteous, David J %A Smith, Blair H %A Stricker, Bruno H %A Uitterlinden, Andre %A van den Berg, Marten E %A Haessler, Jeffrey %A Jackson, Rebecca D %A Kooperberg, Charles %A Peters, Ulrike %A Reiner, Alexander P %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Boerwinkle, Eric %A Ehret, Georg B %A Soliman, Elsayed Z %A Avery, Christy L %A Gogarten, Stephanie M %A Kerr, Kathleen F %A Laurie, Cathy C %A Seyerle, Amanda A %A Stilp, Adrienne %A Assa, Solmaz %A Abdullah Said, M %A Yldau van der Ende, M %A Lambiase, Pier D %A Orini, Michele %A Ramirez, Julia %A Van Duijvenboden, Stefan %A Arnar, David O %A Gudbjartsson, Daniel F %A Holm, Hilma %A Sulem, Patrick %A Thorleifsson, Gudmar %A Thorolfsdottir, Rosa B %A Thorsteinsdottir, Unnur %A Benjamin, Emelia J %A Tinker, Andrew %A Stefansson, Kari %A Ellinor, Patrick T %A Jamshidi, Yalda %A Lubitz, Steven A %A Munroe, Patricia B %X

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

%B Nat Commun %V 11 %P 2542 %8 2020 May 21 %G eng %N 1 %R 10.1038/s41467-020-15706-x %0 Journal Article %J J Am Coll Cardiol %D 2020 %T Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure. %A Suthahar, Navin %A Lau, Emily S %A Blaha, Michael J %A Paniagua, Samantha M %A Larson, Martin G %A Psaty, Bruce M %A Benjamin, Emelia J %A Allison, Matthew A %A Bartz, Traci M %A Januzzi, James L %A Levy, Daniel %A Meems, Laura M G %A Bakker, Stephan J L %A Lima, João A C %A Cushman, Mary %A Lee, Douglas S %A Wang, Thomas J %A deFilippi, Christopher R %A Herrington, David M %A Nayor, Matthew %A Vasan, Ramachandran S %A Gardin, Julius M %A Kizer, Jorge R %A Bertoni, Alain G %A Allen, Norrina B %A Gansevoort, Ron T %A Shah, Sanjiv J %A Gottdiener, John S %A Ho, Jennifer E %A de Boer, Rudolf A %X

BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear.

OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF.

METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio.

RESULTS: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001).

CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.

%B J Am Coll Cardiol %V 76 %P 1455-1465 %8 2020 Sep 22 %G eng %N 12 %R 10.1016/j.jacc.2020.07.044 %0 Journal Article %J Circulation %D 2021 %T Epigenetic Age and the Risk of Incident Atrial Fibrillation. %A Roberts, Jason D %A Vittinghoff, Eric %A Lu, Ake T %A Alonso, Alvaro %A Wang, Biqi %A Sitlani, Colleen M %A Mohammadi-Shemirani, Pedrum %A Fornage, Myriam %A Kornej, Jelena %A Brody, Jennifer A %A Arking, Dan E %A Lin, Honghuang %A Heckbert, Susan R %A Prokic, Ivana %A Ghanbari, Mohsen %A Skanes, Allan C %A Bartz, Traci M %A Perez, Marco V %A Taylor, Kent D %A Lubitz, Steven A %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Pankow, James S %A Paré, Guillaume %A Sotoodehnia, Nona %A Benjamin, Emelia J %A Horvath, Steve %A Marcus, Gregory M %K Aged %K Aging %K Atrial Fibrillation %K DNA Methylation %K Epigenesis, Genetic %K Epigenomics %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Models, Cardiovascular %K Models, Genetic %X

BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.

METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.

RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.

CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

%B Circulation %V 144 %P 1899-1911 %8 2021 12 14 %G eng %N 24 %R 10.1161/CIRCULATIONAHA.121.056456 %0 Journal Article %J Nature %D 2021 %T Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. %A Taliun, Daniel %A Harris, Daniel N %A Kessler, Michael D %A Carlson, Jedidiah %A Szpiech, Zachary A %A Torres, Raul %A Taliun, Sarah A Gagliano %A Corvelo, André %A Gogarten, Stephanie M %A Kang, Hyun Min %A Pitsillides, Achilleas N %A LeFaive, Jonathon %A Lee, Seung-Been %A Tian, Xiaowen %A Browning, Brian L %A Das, Sayantan %A Emde, Anne-Katrin %A Clarke, Wayne E %A Loesch, Douglas P %A Shetty, Amol C %A Blackwell, Thomas W %A Smith, Albert V %A Wong, Quenna %A Liu, Xiaoming %A Conomos, Matthew P %A Bobo, Dean M %A Aguet, Francois %A Albert, Christine %A Alonso, Alvaro %A Ardlie, Kristin G %A Arking, Dan E %A Aslibekyan, Stella %A Auer, Paul L %A Barnard, John %A Barr, R Graham %A Barwick, Lucas %A Becker, Lewis C %A Beer, Rebecca L %A Benjamin, Emelia J %A Bielak, Lawrence F %A Blangero, John %A Boehnke, Michael %A Bowden, Donald W %A Brody, Jennifer A %A Burchard, Esteban G %A Cade, Brian E %A Casella, James F %A Chalazan, Brandon %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Cho, Michael H %A Choi, Seung Hoan %A Chung, Mina K %A Clish, Clary B %A Correa, Adolfo %A Curran, Joanne E %A Custer, Brian %A Darbar, Dawood %A Daya, Michelle %A de Andrade, Mariza %A DeMeo, Dawn L %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Eng, Celeste %A Fatkin, Diane %A Fingerlin, Tasha %A Forer, Lukas %A Fornage, Myriam %A Franceschini, Nora %A Fuchsberger, Christian %A Fullerton, Stephanie M %A Germer, Soren %A Gladwin, Mark T %A Gottlieb, Daniel J %A Guo, Xiuqing %A Hall, Michael E %A He, Jiang %A Heard-Costa, Nancy L %A Heckbert, Susan R %A Irvin, Marguerite R %A Johnsen, Jill M %A Johnson, Andrew D %A Kaplan, Robert %A Kardia, Sharon L R %A Kelly, Tanika %A Kelly, Shannon %A Kenny, Eimear E %A Kiel, Douglas P %A Klemmer, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Köttgen, Anna %A Lange, Leslie A %A Lasky-Su, Jessica %A Levy, Daniel %A Lin, Xihong %A Lin, Keng-Han %A Liu, Chunyu %A Loos, Ruth J F %A Garman, Lori %A Gerszten, Robert %A Lubitz, Steven A %A Lunetta, Kathryn L %A Mak, Angel C Y %A Manichaikul, Ani %A Manning, Alisa K %A Mathias, Rasika A %A McManus, David D %A McGarvey, Stephen T %A Meigs, James B %A Meyers, Deborah A %A Mikulla, Julie L %A Minear, Mollie A %A Mitchell, Braxton D %A Mohanty, Sanghamitra %A Montasser, May E %A Montgomery, Courtney %A Morrison, Alanna C %A Murabito, Joanne M %A Natale, Andrea %A Natarajan, Pradeep %A Nelson, Sarah C %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pankratz, Nathan %A Peloso, Gina M %A Peyser, Patricia A %A Pleiness, Jacob %A Post, Wendy S %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Roden, Dan %A Rotter, Jerome I %A Ruczinski, Ingo %A Sarnowski, Chloe %A Schoenherr, Sebastian %A Schwartz, David A %A Seo, Jeong-Sun %A Seshadri, Sudha %A Sheehan, Vivien A %A Sheu, Wayne H %A Shoemaker, M Benjamin %A Smith, Nicholas L %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stilp, Adrienne M %A Tang, Weihong %A Taylor, Kent D %A Telen, Marilyn %A Thornton, Timothy A %A Tracy, Russell P %A Van Den Berg, David J %A Vasan, Ramachandran S %A Viaud-Martinez, Karine A %A Vrieze, Scott %A Weeks, Daniel E %A Weir, Bruce S %A Weiss, Scott T %A Weng, Lu-Chen %A Willer, Cristen J %A Zhang, Yingze %A Zhao, Xutong %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Boerwinkle, Eric %A Gabriel, Stacey %A Gibbs, Richard %A Rice, Kenneth M %A Rich, Stephen S %A Silverman, Edwin K %A Qasba, Pankaj %A Gan, Weiniu %A Papanicolaou, George J %A Nickerson, Deborah A %A Browning, Sharon R %A Zody, Michael C %A Zöllner, Sebastian %A Wilson, James G %A Cupples, L Adrienne %A Laurie, Cathy C %A Jaquish, Cashell E %A Hernandez, Ryan D %A O'Connor, Timothy D %A Abecasis, Goncalo R %X

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

%B Nature %V 590 %P 290-299 %8 2021 02 %G eng %N 7845 %R 10.1038/s41586-021-03205-y %0 Journal Article %J Nat Commun %D 2022 %T Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes. %A Halford, Jennifer L %A Morrill, Valerie N %A Choi, Seung Hoan %A Jurgens, Sean J %A Melloni, Giorgio %A Marston, Nicholas A %A Weng, Lu-Chen %A Nauffal, Victor %A Hall, Amelia W %A Gunn, Sophia %A Austin-Tse, Christina A %A Pirruccello, James P %A Khurshid, Shaan %A Rehm, Heidi L %A Benjamin, Emelia J %A Boerwinkle, Eric %A Brody, Jennifer A %A Correa, Adolfo %A Fornwalt, Brandon K %A Gupta, Namrata %A Haggerty, Christopher M %A Harris, Stephanie %A Heckbert, Susan R %A Hong, Charles C %A Kooperberg, Charles %A Lin, Henry J %A Loos, Ruth J F %A Mitchell, Braxton D %A Morrison, Alanna C %A Post, Wendy %A Psaty, Bruce M %A Redline, Susan %A Rice, Kenneth M %A Rich, Stephen S %A Rotter, Jerome I %A Schnatz, Peter F %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Wong, Eugene K %A Sabatine, Marc S %A Ruff, Christian T %A Lunetta, Kathryn L %A Ellinor, Patrick T %A Lubitz, Steven A %K Disease Susceptibility %K Endophenotypes %K Humans %K Long QT Syndrome %K Virulence %X

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

%B Nat Commun %V 13 %P 5106 %8 2022 08 30 %G eng %N 1 %R 10.1038/s41467-022-32009-5 %0 Journal Article %J Circulation %D 2022 %T Monogenic and Polygenic Contributions to QTc Prolongation in the Population. %A Nauffal, Victor %A Morrill, Valerie N %A Jurgens, Sean J %A Choi, Seung Hoan %A Hall, Amelia W %A Weng, Lu-Chen %A Halford, Jennifer L %A Austin-Tse, Christina %A Haggerty, Christopher M %A Harris, Stephanie L %A Wong, Eugene K %A Alonso, Alvaro %A Arking, Dan E %A Benjamin, Emelia J %A Boerwinkle, Eric %A Min, Yuan-I %A Correa, Adolfo %A Fornwalt, Brandon K %A Heckbert, Susan R %A Kooperberg, Charles %A Lin, Henry J %A Loos, Ruth J F %A Rice, Kenneth M %A Gupta, Namrata %A Blackwell, Thomas W %A Mitchell, Braxton D %A Morrison, Alanna C %A Psaty, Bruce M %A Post, Wendy S %A Redline, Susan %A Rehm, Heidi L %A Rich, Stephen S %A Rotter, Jerome I %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Lunetta, Kathryn L %A Ellinor, Patrick T %A Lubitz, Steven A %X

Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/ = 1.4 ms, 95% CI 1.3 -1.5; p-value=1.1×10). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

%B Circulation %8 2022 Apr 07 %G eng %R 10.1161/CIRCULATIONAHA.121.057261 %0 Journal Article %J J Am Coll Cardiol %D 2023 %T Effect of 2022 ACC/AHA/HFSA Criteria on Stages of Heart Failure in a Pooled Community Cohort. %A Mohebi, Reza %A Wang, Dongyu %A Lau, Emily S %A Parekh, Juhi K %A Allen, Norrina %A Psaty, Bruce M %A Benjamin, Emelia J %A Levy, Daniel %A Wang, Thomas J %A Shah, Sanjiv J %A Gottdiener, John S %A Januzzi, James L %A Ho, Jennifer E %K American Heart Association %K Atherosclerosis %K Cardiology %K Female %K Heart Failure %K Humans %K Longitudinal Studies %K Prognosis %K United States %X

BACKGROUND: The 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) clinical practice guideline proposed an updated definition for heart failure (HF) stages.

OBJECTIVES: This study aimed to compare prevalence and prognosis of HF stages according to classification/definition originally described in 2013 and 2022 ACC/AHA/HFSA definitions.

METHODS: Study participants from 3 longitudinal cohorts (the MESA [Multi-Ethnic Study of Atherosclerosis], CHS [Cardiovascular Health Study], and the FHS [Framingham Heart Study]), were categorized into 4 HF stages according to the 2013 and 2022 criteria. Cox proportional hazards regression was used to assess predictors of progression to symptomatic HF and adverse clinical outcomes associated with each HF stage.

RESULTS: Among 11,618 study participants, according to the 2022 staging, 1,943 (16.7%) were healthy, 4,348 (37.4%) were in stage A (at risk), 5,019 (43.2%) were in stage B (pre-HF), and 308 (2.7%) were in stage C/D (symptomatic HF). Compared to the classification/definition originally described in 2013, the 2022 ACC/AHA/HFSA approach resulted in a higher proportion of individuals with stage B HF (increase from 15.9% to 43.2%); this shift disproportionately involved women as well as Hispanic and Black individuals. Despite the 2022 criteria designating a greater proportion of individuals as stage B, the relative risk of progression to symptomatic HF remained similar (HR: 10.61; 95% CI: 9.00-12.51; P < 0.001).

CONCLUSIONS: New standards for HF staging resulted in a substantial shift of community-based individuals from stage A to stage B. Those with stage B HF in the new system were at high risk for progression to symptomatic HF.

%B J Am Coll Cardiol %V 81 %P 2231-2242 %8 2023 Jun 13 %G eng %N 23 %R 10.1016/j.jacc.2023.04.007 %0 Journal Article %J J Card Fail %D 2023 %T Multiple Prior Live Births are Associated with Cardiac Remodeling and Heart Failure Risk in Women. %A Sarma, Amy A %A Paniagua, Samantha M %A Lau, Emily S %A Wang, Dongyu %A Liu, Elizabeth E %A Larson, Martin G %A Hamburg, Naomi M %A Mitchell, Gary F %A Kizer, Jorge %A Psaty, Bruce M %A Allen, Norrina B %A Lely, A Titia %A Gansevoort, Ronald T %A Rosenberg, Emily %A Mukamal, Kenneth %A Benjamin, Emelia J %A Vasan, Ramachandran S %A Cheng, Susan %A Levy, Daniel %A de Boer, Rudolf A %A Gottdiener, John S %A Shah, Sanjiv J %A Ho, Jennifer E %X

INTRODUCTION: Greater parity has been associated with cardiovascular disease risk, though effects on cardiac remodeling and heart failure risk remain unclear.

METHODS: We examined the association of number of live births and echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of n=12,635 participants of FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major CVD, MI, and stroke.

RESULTS: Among n=3931 FHS participants (mean age 48 ± 13 years), higher number of live births was associated with worse LV fractional shortening (multivariable β -1.11 (0.31), p= 0.0005 in ≥ 5 live births vs nulliparous women) and worse cardiac mechanics including global circumferential strain and longitudinal and radial dyssynchrony (p< 0.01 for all comparing ≥ 5 live births vs nulliparity). When examining HF subtypes, women with ≥5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95% CI 1.19-3.12, p=0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95% CI 0.37-0.91, p=0.02).

CONCLUSIONS: Greater number of live births are associated with worse cardiac structure and function. While there was no association with overall HF, a higher number of live births was associated with greater risk for incident HFrEF.

%B J Card Fail %8 2023 Jan 10 %G eng %R 10.1016/j.cardfail.2022.12.014 %0 Journal Article %J bioRxiv %D 2023 %T Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium. %A Jiang, Min-Zhi %A Gaynor, Sheila M %A Li, Xihao %A Van Buren, Eric %A Stilp, Adrienne %A Buth, Erin %A Wang, Fei Fei %A Manansala, Regina %A Gogarten, Stephanie M %A Li, Zilin %A Polfus, Linda M %A Salimi, Shabnam %A Bis, Joshua C %A Pankratz, Nathan %A Yanek, Lisa R %A Durda, Peter %A Tracy, Russell P %A Rich, Stephen S %A Rotter, Jerome I %A Mitchell, Braxton D %A Lewis, Joshua P %A Psaty, Bruce M %A Pratte, Katherine A %A Silverman, Edwin K %A Kaplan, Robert C %A Avery, Christy %A North, Kari %A Mathias, Rasika A %A Faraday, Nauder %A Lin, Honghuang %A Wang, Biqi %A Carson, April P %A Norwood, Arnita F %A Gibbs, Richard A %A Kooperberg, Charles %A Lundin, Jessica %A Peters, Ulrike %A Dupuis, Josée %A Hou, Lifang %A Fornage, Myriam %A Benjamin, Emelia J %A Reiner, Alexander P %A Bowler, Russell P %A Lin, Xihong %A Auer, Paul L %A Raffield, Laura M %X

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

%B bioRxiv %8 2023 Sep 12 %G eng %R 10.1101/2023.09.10.555215