@article {785, title = {Collaborative meta-analysis of prospective studies of plasma fibrinogen and cardiovascular disease.}, journal = {Eur J Cardiovasc Prev Rehabil}, volume = {11}, year = {2004}, month = {2004 Feb}, pages = {9-17}, abstract = {

BACKGROUND: Many long-term studies have reported on associations of plasma fibrinogen concentration with cardiovascular disease, but few have been large enough to provide reliable estimates in different circumstances. Moreover, most published prospective studies have related disease risk only to baseline values of plasma fibrinogen (which can lead to substantial underestimation of any risk relationships) and have corrected only for baseline values of possible confounding factors (which can lead to residual biases).

OBJECTIVES: By appropriate combination of data from individual participants from all relevant prospective studies in a systematic {\textquoteright}meta-analysis{\textquoteright}, with correction for regression dilution, the Fibrinogen Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age- and sex-specific associations of plasma fibrinogen with coronary heart disease (and, where data are sufficient, with other vascular diseases). It will also help to determine to what extent such associations are independent of possible confounding factors.

METHODS: A central database has been established containing data on plasma fibrinogen, sex and other potential confounding factors, age at baseline fibrinogen measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of fibrinogen and potential confounding factors is being sought to allow study-specific correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available prospective studies of plasma fibrinogen will yield information on more than 10000 incident cardiovascular deaths and events among the approximately 200000 total participants who have been monitored, on average, for about 10 years.

}, keywords = {Biomarkers, Cardiovascular Diseases, Cooperative Behavior, Data Interpretation, Statistical, Fibrinogen, Humans, Meta-Analysis as Topic, Prospective Studies}, issn = {1741-8267}, doi = {10.1097/01.hjr.0000114968.39211.01} } @article {826, title = {Cardiovascular risk factors for retinal vein occlusion and arteriolar emboli: the Atherosclerosis Risk in Communities \& Cardiovascular Health studies.}, journal = {Ophthalmology}, volume = {112}, year = {2005}, month = {2005 Apr}, pages = {540-7}, abstract = {

OBJECTIVE: To examine the associations of retinal vein occlusion and arteriolar emboli with cardiovascular disease.

DESIGN: Population-based cross-sectional study.

PARTICIPANTS: Pooled from the Atherosclerosis Risk in Communities Study (n = 12,642; mean age, 60 years) and the Cardiovascular Health Study (n = 2824; mean age, 79 years).

METHODS: Retinal vein occlusion and arteriolar emboli were identified from a single nonmydriatic retinal photograph using a standardized protocol. Photographs were also graded for arteriovenous nicking and focal arteriolar narrowing. All participants had a comprehensive systemic evaluation, including standardized carotid ultrasonography.

MAIN OUTCOME MEASURES: Retinal vein occlusion and arteriolar emboli.

RESULTS: Prevalences of retinal vein occlusion and arteriolar emboli were 0.3\% (n = 39 cases) and 0.2\% (n = 34 cases), respectively. After adjusting for age, retinal vein occlusion was associated with hypertension (odds ratio [OR], 2.96; 95\% confidence interval [CI], 1.43-6.14), systolic blood pressure (BP) (OR, 4.12; 95\% CI, 1.40-12.16; highest quartile vs. lowest), diastolic BP (OR, 2.64; 95\% CI, 1.07-6.46; highest quartile vs. lowest), carotid artery plaque (OR, 5.62; 95\% CI, 2.60-12.16), body mass index (OR, 3.88; 95\% CI, 1.23-12.18; highest quartile vs. lowest), plasma fibrinogen (OR, 3.29; 95\% CI, 1.08-10.02; highest quartile vs. lowest), arteriovenous nicking (OR, 4.09; 95\% CI, 2.00-8.36), and focal arteriolar narrowing (OR, 5.17; 95\% CI, 2.59-10.29). After adjusting for age, retinal arteriolar emboli were associated with hypertension (OR, 3.14; 95\% CI, 1.44-6.84), systolic BP (OR, 3.46; 95\% CI, 1.13-10.65; highest quartile vs. lowest), prevalent coronary heart disease (OR, 2.33; 95\% CI, 1.01-5.42), carotid artery plaque (OR, 4.62; 95\% CI, 1.85-11.57), plasma lipoprotein (a) (OR, 3.69; 95\% CI, 1.20-11.41; highest quartile vs. lowest), plasma fibrinogen (OR, 3.09; 95\% CI, 0.98-9.76; highest quartile vs. lowest), and current cigarette smoking (OR, 3.08; 95\% CI, 1.47-6.47). Approximately a quarter of participants with retinal vein occlusion and arteriolar emboli had evidence of carotid artery plaque as defined from ultrasound.

CONCLUSIONS: Retinal vein occlusion and retinal arteriolar emboli are associated with carotid artery disease, hypertension, and other cardiovascular risk factors.

}, keywords = {Aged, Aged, 80 and over, Arterioles, Blood Pressure, Cardiovascular Diseases, Carotid Stenosis, Coronary Artery Disease, Cross-Sectional Studies, Embolism, Female, Fibrinogen, Humans, Hypertension, Lipoprotein(a), Male, Meta-Analysis as Topic, Middle Aged, Retinal Artery, Retinal Vein Occlusion, Risk Factors}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2004.10.039}, author = {Wong, Tien Yin and Larsen, Emily K Marino and Klein, Ronald and Mitchell, Paul and Couper, David J and Klein, Barbara E K and Hubbard, Larry D and Siscovick, David S and Sharrett, A Richey} } @article {931, title = {Regression dilution methods for meta-analysis: assessing long-term variability in plasma fibrinogen among 27,247 adults in 15 prospective studies.}, journal = {Int J Epidemiol}, volume = {35}, year = {2006}, month = {2006 Dec}, pages = {1570-8}, abstract = {

BACKGROUND: Within-person variability in measured values of a risk factor can bias its association with disease. The extent of this regression dilution bias for plasma fibrinogen was investigated using repeat measurement data collected at varying time intervals on 27 247 adults in 15 prospective studies.

METHODS: Regression dilution ratios (RDRs) were estimated from a linear regression of repeat measurements on baseline values in each study and for each time interval, and pooled allowing for within- and between-study heterogeneity. RDRs were estimated both without and with adjustment for confounders, and factors were investigated that might influence the RDRs.

RESULTS: The unadjusted overall RDR was 0.51 (95\% CI: 0.47, 0.55), which decreased to 0.46 (95\% CI: 0.42, 0.49) after adjustment for age, sex and measured values of other established vascular risk factors. The RDR did not vary materially by assay method, age, sex or smoking status, but decreased at higher levels of baseline fibrinogen.

CONCLUSION: It is appropriate to use an RDR of 0.5 to correct approximately for regression dilution bias in plasma fibrinogen values; however, this correction factor may produce somewhat conservative hazard ratios in adjusted analyses, at higher fibrinogen concentrations and in follow-up beyond a decade. More generally, the methods described in this report have widespread applicability to quantifying regression dilution bias in repeatability data from multiple prospective studies.

}, keywords = {Adult, Age Factors, Bias, Cardiovascular Diseases, Female, Fibrinogen, Humans, Male, Meta-Analysis as Topic, Prospective Studies, Regression Analysis, Risk Factors, Sex Factors, Smoking, Time Factors}, issn = {0300-5771}, doi = {10.1093/ije/dyl233}, author = {Wood, Angela M and White, Ian and Thompson, Simon G and Lewington, Sarah and Danesh, John} } @article {1152, title = {Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts.}, journal = {Circ Cardiovasc Genet}, volume = {2}, year = {2009}, month = {2009 Feb}, pages = {73-80}, abstract = {

BACKGROUND: The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.

CONCLUSIONS: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.

}, keywords = {Adult, Aged, Aging, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Diseases, Humans, Male, Meta-Analysis as Topic, Middle Aged, Phenotype, Research Design, Risk Factors}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.108.829747}, author = {Psaty, Bruce M and O{\textquoteright}Donnell, Christopher J and Gudnason, Vilmundur and Lunetta, Kathryn L and Folsom, Aaron R and Rotter, Jerome I and Uitterlinden, Andr{\'e} G and Harris, Tamara B and Witteman, Jacqueline C M and Boerwinkle, Eric} } @article {1087, title = {Common variants at ten loci influence QT interval duration in the QTGEN Study.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Apr}, pages = {399-406}, abstract = {

QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5\% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, Aged, Arrhythmias, Cardiac, Chromosome Mapping, Death, Sudden, Cardiac, Electroencephalography, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, European Continental Ancestry Group, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, KCNQ1 Potassium Channel, Meta-Analysis as Topic, Muscle Proteins, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Potassium Channels, Voltage-Gated, Risk Factors, Sodium Channels}, issn = {1546-1718}, doi = {10.1038/ng.364}, author = {Newton-Cheh, Christopher and Eijgelsheim, Mark and Rice, Kenneth M and de Bakker, Paul I W and Yin, Xiaoyan and Estrada, Karol and Bis, Joshua C and Marciante, Kristin and Rivadeneira, Fernando and Noseworthy, Peter A and Sotoodehnia, Nona and Smith, Nicholas L and Rotter, Jerome I and Kors, Jan A and Witteman, Jacqueline C M and Hofman, Albert and Heckbert, Susan R and O{\textquoteright}Donnell, Christopher J and Uitterlinden, Andr{\'e} G and Psaty, Bruce M and Lumley, Thomas and Larson, Martin G and Stricker, Bruno H Ch} } @article {1078, title = {Correcting for multivariate measurement error by regression calibration in meta-analyses of epidemiological studies.}, journal = {Stat Med}, volume = {28}, year = {2009}, month = {2009 Mar 30}, pages = {1067-92}, abstract = {

Within-person variability in measured values of multiple risk factors can bias their associations with disease. The multivariate regression calibration (RC) approach can correct for such measurement error and has been applied to studies in which true values or independent repeat measurements of the risk factors are observed on a subsample. We extend the multivariate RC techniques to a meta-analysis framework where multiple studies provide independent repeat measurements and information on disease outcome. We consider the cases where some or all studies have repeat measurements, and compare study-specific, averaged and empirical Bayes estimates of RC parameters. Additionally, we allow for binary covariates (e.g. smoking status) and for uncertainty and time trends in the measurement error corrections. Our methods are illustrated using a subset of individual participant data from prospective long-term studies in the Fibrinogen Studies Collaboration to assess the relationship between usual levels of plasma fibrinogen and the risk of coronary heart disease, allowing for measurement error in plasma fibrinogen and several confounders.

}, keywords = {Bias, Cardiovascular Diseases, Epidemiologic Studies, Fibrinogen, Meta-Analysis as Topic, Models, Statistical, Multivariate Analysis, Regression Analysis}, issn = {0277-6715}, doi = {10.1002/sim.3530} } @article {1098, title = {Genome-wide association study of blood pressure and hypertension.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {677-87}, abstract = {

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 {\texttimes} 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 {\texttimes} 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.

}, keywords = {Blood Pressure, Cell Line, Chromosome Mapping, Chromosomes, Human, Diastole, Gene Expression Regulation, Genetic Association Studies, Genome-Wide Association Study, Humans, Hypertension, Liver, Lymphocytes, Meta-Analysis as Topic, Odds Ratio, Phenotype, Prevalence, Risk Assessment, Systole}, issn = {1546-1718}, doi = {10.1038/ng.384}, author = {Levy, Daniel and Ehret, Georg B and Rice, Kenneth and Verwoert, Germaine C and Launer, Lenore J and Dehghan, Abbas and Glazer, Nicole L and Morrison, Alanna C and Johnson, Andrew D and Aspelund, Thor and Aulchenko, Yurii and Lumley, Thomas and K{\"o}ttgen, Anna and Vasan, Ramachandran S and Rivadeneira, Fernando and Eiriksdottir, Gudny and Guo, Xiuqing and Arking, Dan E and Mitchell, Gary F and Mattace-Raso, Francesco U S and Smith, Albert V and Taylor, Kent and Scharpf, Robert B and Hwang, Shih-Jen and Sijbrands, Eric J G and Bis, Joshua and Harris, Tamara B and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Hofman, Albert and Rotter, Jerome I and Coresh, Josef and Benjamin, Emelia J and Uitterlinden, Andr{\'e} G and Heiss, Gerardo and Fox, Caroline S and Witteman, Jacqueline C M and Boerwinkle, Eric and Wang, Thomas J and Gudnason, Vilmundur and Larson, Martin G and Chakravarti, Aravinda and Psaty, Bruce M and van Duijn, Cornelia M} } @article {1099, title = {Multiple loci associated with indices of renal function and chronic kidney disease.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {712-7}, abstract = {

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 {\texttimes} 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.

}, keywords = {Chromosome Mapping, Cohort Studies, Genetic Variation, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Meta-Analysis as Topic, Mucoproteins, Netherlands, Polymorphism, Single Nucleotide, Prevalence, Uromodulin}, issn = {1546-1718}, doi = {10.1038/ng.377}, author = {K{\"o}ttgen, Anna and Glazer, Nicole L and Dehghan, Abbas and Hwang, Shih-Jen and Katz, Ronit and Li, Man and Yang, Qiong and Gudnason, Vilmundur and Launer, Lenore J and Harris, Tamara B and Smith, Albert V and Arking, Dan E and Astor, Brad C and Boerwinkle, Eric and Ehret, Georg B and Ruczinski, Ingo and Scharpf, Robert B and Chen, Yii-Der Ida and de Boer, Ian H and Haritunians, Talin and Lumley, Thomas and Sarnak, Mark and Siscovick, David and Benjamin, Emelia J and Levy, Daniel and Upadhyay, Ashish and Aulchenko, Yurii S and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Chasman, Daniel I and Par{\'e}, Guillaume and Ridker, Paul M and Kao, W H Linda and Witteman, Jacqueline C and Coresh, Josef and Shlipak, Michael G and Fox, Caroline S} } @article {1079, title = {Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.}, journal = {Stat Med}, volume = {28}, year = {2009}, month = {2009 Apr 15}, pages = {1218-37}, abstract = {

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

}, keywords = {Cohort Studies, Computer Simulation, Coronary Disease, Data Interpretation, Statistical, Female, Fibrinogen, Humans, Male, Meta-Analysis as Topic, Models, Statistical}, issn = {0277-6715}, doi = {10.1002/sim.3540}, author = {Jackson, Dan and White, Ian and Kostis, J B and Wilson, A C and Folsom, A R and Wu, K and Chambless, L and Benderly, M and Goldbourt, U and Willeit, J and Kiechl, S and Yarnell, J W G and Sweetnam, P M and Elwood, P C and Cushman, M and Psaty, B M and Tracy, R P and Tybjaerg-Hansen, A and Haverkate, F and de Maat, M P M and Thompson, S G and Fowkes, F G R and Lee, A J and Smith, F B and Salomaa, V and Harald, K and Rasi, V and Vahtera, E and Jousilahti, P and D{\textquoteright}Agostino, R and Kannel, W B and Wilson, P W F and Tofler, G and Levy, D and Marchioli, R and Valagussa, F and Rosengren, A and Wilhelmsen, L and Lappas, G and Eriksson, H and Cremer, P and Nagel, D and Curb, J D and Rodriguez, B and Yano, K and Salonen, J T and Nyyss{\"o}nen, K and Tuomainen, T-P and Hedblad, B and Engstrom, G and Berglund, G and Loewel, H and Koenig, W and Hense, H W and Meade, T W and Cooper, J A and De Stavola, B and Knottenbelt, C and Miller, G J and Cooper, J A and Bauer, K A and Rosenberg, R D and Sato, S and Kitamura, A and Naito, Y and Iso, H and Salomaa, V and Harald, K and Rasi, V and Vahtera, E and Jousilahti, P and Palosuo, T and Ducimetiere, P and Amouyel, P and Arveiler, D and Evans, A E and Ferrieres, J and Juhan-Vague, I and Bingham, A and Schulte, H and Assmann, G and Cantin, B and Lamarche, B and Despr{\'e}s, J-P and Dagenais, G R and Tunstall-Pedoe, H and Lowe, G D O and Woodward, M and Ben-Shlomo, Y and Davey Smith, G and Palmieri, V and Yeh, J L and Meade, T W and Rudnicka, A and Brennan, P and Knottenbelt, C and Cooper, J A and Ridker, P and Rodeghiero, F and Tosetto, A and Shepherd, J and Lowe, G D O and Ford, I and Robertson, M and Brunner, E and Shipley, M and Feskens, E J M and Di Angelantonio, E and Kaptoge, S and Lewington, S and Lowe, G D O and Sarwar, N and Thompson, S G and Walker, M and Watson, S and White, I R and Wood, A M and Danesh, J} } @article {1114, title = {Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Aug}, pages = {879-81}, abstract = {

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)).

}, keywords = {Atrial Fibrillation, Chromosomes, Human, Pair 16, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeodomain Proteins, Humans, Meta-Analysis as Topic, Mutation, Polymorphism, Single Nucleotide, Reproducibility of Results}, issn = {1546-1718}, doi = {10.1038/ng.416}, author = {Benjamin, Emelia J and Rice, Kenneth M and Arking, Dan E and Pfeufer, Arne and van Noord, Charlotte and Smith, Albert V and Schnabel, Renate B and Bis, Joshua C and Boerwinkle, Eric and Sinner, Moritz F and Dehghan, Abbas and Lubitz, Steven A and D{\textquoteright}Agostino, Ralph B and Lumley, Thomas and Ehret, Georg B and Heeringa, Jan and Aspelund, Thor and Newton-Cheh, Christopher and Larson, Martin G and Marciante, Kristin D and Soliman, Elsayed Z and Rivadeneira, Fernando and Wang, Thomas J and Eiriksdottir, Gudny and Levy, Daniel and Psaty, Bruce M and Li, Man and Chamberlain, Alanna M and Hofman, Albert and Vasan, Ramachandran S and Harris, Tamara B and Rotter, Jerome I and Kao, W H Linda and Agarwal, Sunil K and Stricker, Bruno H Ch and Wang, Ke and Launer, Lenore J and Smith, Nicholas L and Chakravarti, Aravinda and Uitterlinden, Andr{\'e} G and Wolf, Philip A and Sotoodehnia, Nona and K{\"o}ttgen, Anna and van Duijn, Cornelia M and Meitinger, Thomas and Mueller, Martina and Perz, Siegfried and Steinbeck, Gerhard and Wichmann, H-Erich and Lunetta, Kathryn L and Heckbert, Susan R and Gudnason, Vilmundur and Alonso, Alvaro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T and Witteman, Jacqueline C M} } @article {1171, title = {Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables.}, journal = {Stat Med}, volume = {29}, year = {2010}, month = {2010 May 30}, pages = {1298-311}, abstract = {

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.

}, keywords = {Bayes Theorem, Biostatistics, C-Reactive Protein, Fibrinogen, Genetic Markers, Humans, Meta-Analysis as Topic, Models, Statistical, Phenotype, Polymorphism, Single Nucleotide}, issn = {1097-0258}, doi = {10.1002/sim.3843}, author = {Burgess, Stephen and Thompson, Simon G and Burgess, S and Thompson, S G and Andrews, G and Samani, N J and Hall, A and Whincup, P and Morris, R and Lawlor, D A and Davey Smith, G and Timpson, N and Ebrahim, S and Ben-Shlomo, Y and Davey Smith, G and Timpson, N and Brown, M and Ricketts, S and Sandhu, M and Reiner, A and Psaty, B and Lange, L and Cushman, M and Hung, J and Thompson, P and Beilby, J and Warrington, N and Palmer, L J and Nordestgaard, B G and Tybjaerg-Hansen, A and Zacho, J and Wu, C and Lowe, G and Tzoulaki, I and Kumari, M and Sandhu, M and Yamamoto, J F and Chiodini, B and Franzosi, M and Hankey, G J and Jamrozik, K and Palmer, L and Rimm, E and Pai, J and Psaty, B and Heckbert, S and Bis, J and Anand, S and Engert, J and Collins, R and Clarke, R and Melander, O and Berglund, G and Ladenvall, P and Johansson, L and Jansson, J-H and Hallmans, G and Hingorani, A and Humphries, S and Rimm, E and Manson, J and Pai, J and Watkins, H and Clarke, R and Hopewell, J and Saleheen, D and Frossard, R and Danesh, J and Sattar, N and Robertson, M and Shepherd, J and Schaefer, E and Hofman, A and Witteman, J C M and Kardys, I and Ben-Shlomo, Y and Davey Smith, G and Timpson, N and de Faire, U and Bennet, A and Sattar, N and Ford, I and Packard, C and Kumari, M and Manson, J and Lawlor, Debbie A and Davey Smith, George and Anand, S and Collins, R and Casas, J P and Danesh, J and Davey Smith, G and Franzosi, M and Hingorani, A and Lawlor, D A and Manson, J and Nordestgaard, B G and Samani, N J and Sandhu, M and Smeeth, L and Wensley, F and Anand, S and Bowden, J and Burgess, S and Casas, J P and Di Angelantonio, E and Engert, J and Gao, P and Shah, T and Smeeth, L and Thompson, S G and Verzilli, C and Walker, M and Whittaker, J and Hingorani, A and Danesh, J} } @article {1170, title = {Common variants in KCNN3 are associated with lone atrial fibrillation.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Mar}, pages = {240-4}, abstract = {

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.

}, keywords = {Adolescent, Adult, Aged, Atrial Fibrillation, Case-Control Studies, Cohort Studies, Female, Genome-Wide Association Study, Humans, Introns, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Small-Conductance Calcium-Activated Potassium Channels, Young Adult}, issn = {1546-1718}, doi = {10.1038/ng.537}, author = {Ellinor, Patrick T and Lunetta, Kathryn L and Glazer, Nicole L and Pfeufer, Arne and Alonso, Alvaro and Chung, Mina K and Sinner, Moritz F and de Bakker, Paul I W and Mueller, Martina and Lubitz, Steven A and Fox, Ervin and Darbar, Dawood and Smith, Nicholas L and Smith, Jonathan D and Schnabel, Renate B and Soliman, Elsayed Z and Rice, Kenneth M and Van Wagoner, David R and Beckmann, Britt-M and van Noord, Charlotte and Wang, Ke and Ehret, Georg B and Rotter, Jerome I and Hazen, Stanley L and Steinbeck, Gerhard and Smith, Albert V and Launer, Lenore J and Harris, Tamara B and Makino, Seiko and Nelis, Mari and Milan, David J and Perz, Siegfried and Esko, T{\~o}nu and K{\"o}ttgen, Anna and Moebus, Susanne and Newton-Cheh, Christopher and Li, Man and M{\"o}hlenkamp, Stefan and Wang, Thomas J and Kao, W H Linda and Vasan, Ramachandran S and N{\"o}then, Markus M and MacRae, Calum A and Stricker, Bruno H Ch and Hofman, Albert and Uitterlinden, Andr{\'e} G and Levy, Daniel and Boerwinkle, Eric and Metspalu, Andres and Topol, Eric J and Chakravarti, Aravinda and Gudnason, Vilmundur and Psaty, Bruce M and Roden, Dan M and Meitinger, Thomas and Wichmann, H-Erich and Witteman, Jacqueline C M and Barnard, John and Arking, Dan E and Benjamin, Emelia J and Heckbert, Susan R and K{\"a}{\"a}b, Stefan} } @article {1243, title = {Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.}, journal = {PLoS Genet}, volume = {6}, year = {2010}, month = {2010 Oct 28}, pages = {e1001184}, abstract = {

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0{\texttimes}10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0\%-3.2\% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61{\texttimes}10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25{\texttimes}10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15{\texttimes}10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32{\texttimes}10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Cohort Studies, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Microcirculation, Middle Aged, Polymorphism, Single Nucleotide, Retinal Vessels, Young Adult}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001184}, author = {Ikram, M Kamran and Sim, Xueling and Xueling, Sim and Jensen, Richard A and Cotch, Mary Frances and Hewitt, Alex W and Ikram, M Arfan and Wang, Jie Jin and Klein, Ronald and Klein, Barbara E K and Breteler, Monique M B and Cheung, Ning and Liew, Gerald and Mitchell, Paul and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Hofman, Albert and de Jong, Paulus T V M and van Duijn, Cornelia M and Kao, Linda and Cheng, Ching-Yu and Smith, Albert Vernon and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Jonasson, Fridbert and Eiriksdottir, Gudny and Aspelund, Thor and Harris, Tamara B and Launer, Lenore J and Taylor, Kent D and Li, Xiaohui and Iyengar, Sudha K and Xi, Quansheng and Sivakumaran, Theru A and Mackey, David A and Macgregor, Stuart and Martin, Nicholas G and Young, Terri L and Bis, Josh C and Wiggins, Kerri L and Heckbert, Susan R and Hammond, Christopher J and Andrew, Toby and Fahy, Samantha and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Islam, F M Amirul and Rotter, Jerome I and McAuley, Annie K and Boerwinkle, Eric and Tai, E Shyong and Gudnason, Vilmundur and Siscovick, David S and Vingerling, Johannes R and Wong, Tien Y} } @article {1174, title = {Genome-wide association identifies multiple ulcerative colitis susceptibility loci.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Apr}, pages = {332-7}, abstract = {

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn{\textquoteright}s disease loci showed that roughly half of the known Crohn{\textquoteright}s disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

}, keywords = {Colitis, Ulcerative, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Membrane Proteins, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Receptors, IgG}, issn = {1546-1718}, doi = {10.1038/ng.549}, author = {McGovern, Dermot P B and Gardet, Agn{\`e}s and T{\"o}rkvist, Leif and Goyette, Philippe and Essers, Jonah and Taylor, Kent D and Neale, Benjamin M and Ong, Rick T H and Lagac{\'e}, Caroline and Li, Chun and Green, Todd and Stevens, Christine R and Beauchamp, Claudine and Fleshner, Phillip R and Carlson, Marie and D{\textquoteright}Amato, Mauro and Halfvarson, Jonas and Hibberd, Martin L and L{\"o}rdal, Mikael and Padyukov, Leonid and Andriulli, Angelo and Colombo, Elisabetta and Latiano, Anna and Palmieri, Orazio and Bernard, Edmond-Jean and Deslandres, Colette and Hommes, Daan W and de Jong, Dirk J and Stokkers, Pieter C and Weersma, Rinse K and Sharma, Yashoda and Silverberg, Mark S and Cho, Judy H and Wu, Jing and Roeder, Kathryn and Brant, Steven R and Schumm, L Phillip and Duerr, Richard H and Dubinsky, Marla C and Glazer, Nicole L and Haritunians, Talin and Ippoliti, Andy and Melmed, Gil Y and Siscovick, David S and Vasiliauskas, Eric A and Targan, Stephan R and Annese, Vito and Wijmenga, Cisca and Pettersson, Sven and Rotter, Jerome I and Xavier, Ramnik J and Daly, Mark J and Rioux, John D and Seielstad, Mark} } @article {1159, title = {Genome-wide association study of PR interval.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Feb}, pages = {153-9}, abstract = {

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.

}, keywords = {Aged, Atrial Fibrillation, Cohort Studies, Electrocardiography, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Meta-Analysis as Topic}, issn = {1546-1718}, doi = {10.1038/ng.517}, author = {Pfeufer, Arne and van Noord, Charlotte and Marciante, Kristin D and Arking, Dan E and Larson, Martin G and Smith, Albert Vernon and Tarasov, Kirill V and M{\"u}ller, Martina and Sotoodehnia, Nona and Sinner, Moritz F and Verwoert, Germaine C and Li, Man and Kao, W H Linda and K{\"o}ttgen, Anna and Coresh, Josef and Bis, Joshua C and Psaty, Bruce M and Rice, Kenneth and Rotter, Jerome I and Rivadeneira, Fernando and Hofman, Albert and Kors, Jan A and Stricker, Bruno H C and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Beckmann, Britt M and Sauter, Wiebke and Gieger, Christian and Lubitz, Steven A and Newton-Cheh, Christopher and Wang, Thomas J and Magnani, Jared W and Schnabel, Renate B and Chung, Mina K and Barnard, John and Smith, Jonathan D and Van Wagoner, David R and Vasan, Ramachandran S and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Launer, Lenore J and Najjar, Samer S and Lakatta, Edward and Schlessinger, David and Uda, Manuela and Abecasis, Goncalo R and M{\"u}ller-Myhsok, Bertram and Ehret, Georg B and Boerwinkle, Eric and Chakravarti, Aravinda and Soliman, Elsayed Z and Lunetta, Kathryn L and Perz, Siegfried and Wichmann, H-Erich and Meitinger, Thomas and Levy, Daniel and Gudnason, Vilmundur and Ellinor, Patrick T and Sanna, Serena and K{\"a}{\"a}b, Stefan and Witteman, Jacqueline C M and Alonso, Alvaro and Benjamin, Emelia J and Heckbert, Susan R} } @article {1150, title = {Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Jan}, pages = {45-52}, abstract = {

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

}, keywords = {Databases, Genetic, Female, Forced Expiratory Volume, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Lung, Lung Diseases, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Spirometry, Vital Capacity}, issn = {1546-1718}, doi = {10.1038/ng.500}, author = {Hancock, Dana B and Eijgelsheim, Mark and Wilk, Jemma B and Gharib, Sina A and Loehr, Laura R and Marciante, Kristin D and Franceschini, Nora and van Durme, Yannick M T A and Chen, Ting-Hsu and Barr, R Graham and Schabath, Matthew B and Couper, David J and Brusselle, Guy G and Psaty, Bruce M and van Duijn, Cornelia M and Rotter, Jerome I and Uitterlinden, Andr{\'e} G and Hofman, Albert and Punjabi, Naresh M and Rivadeneira, Fernando and Morrison, Alanna C and Enright, Paul L and North, Kari E and Heckbert, Susan R and Lumley, Thomas and Stricker, Bruno H C and O{\textquoteright}Connor, George T and London, Stephanie J} } @article {1236, title = {Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Nov}, pages = {949-60}, abstract = {

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 {\texttimes} 10$^{-}$$^{9}$ to P = 1.8 {\texttimes} 10$^{-}$$^{4}$$^{0}$) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 {\texttimes} 10$^{-}${\textthreesuperior} to P = 1.2 {\texttimes} 10$^{-}${\textonesuperior}{\textthreesuperior}). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

}, keywords = {Adipose Tissue, Age Factors, Chromosome Mapping, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Sex Characteristics, Waist-Hip Ratio}, issn = {1546-1718}, doi = {10.1038/ng.685}, author = {Heid, Iris M and Jackson, Anne U and Randall, Joshua C and Winkler, Thomas W and Qi, Lu and Steinthorsdottir, Valgerdur and Thorleifsson, Gudmar and Zillikens, M Carola and Speliotes, Elizabeth K and M{\"a}gi, Reedik and Workalemahu, Tsegaselassie and White, Charles C and Bouatia-Naji, Nabila and Harris, Tamara B and Berndt, Sonja I and Ingelsson, Erik and Willer, Cristen J and Weedon, Michael N and Luan, Jian{\textquoteright}an and Vedantam, Sailaja and Esko, T{\~o}nu and Kilpel{\"a}inen, Tuomas O and Kutalik, Zolt{\'a}n and Li, Shengxu and Monda, Keri L and Dixon, Anna L and Holmes, Christopher C and Kaplan, Lee M and Liang, Liming and Min, Josine L and Moffatt, Miriam F and Molony, Cliona and Nicholson, George and Schadt, Eric E and Zondervan, Krina T and Feitosa, Mary F and Ferreira, Teresa and Lango Allen, Hana and Weyant, Robert J and Wheeler, Eleanor and Wood, Andrew R and Estrada, Karol and Goddard, Michael E and Lettre, Guillaume and Mangino, Massimo and Nyholt, Dale R and Purcell, Shaun and Smith, Albert Vernon and Visscher, Peter M and Yang, Jian and McCarroll, Steven A and Nemesh, James and Voight, Benjamin F and Absher, Devin and Amin, Najaf and Aspelund, Thor and Coin, Lachlan and Glazer, Nicole L and Hayward, Caroline and Heard-Costa, Nancy L and Hottenga, Jouke-Jan and Johansson, Asa and Johnson, Toby and Kaakinen, Marika and Kapur, Karen and Ketkar, Shamika and Knowles, Joshua W and Kraft, Peter and Kraja, Aldi T and Lamina, Claudia and Leitzmann, Michael F and McKnight, Barbara and Morris, Andrew P and Ong, Ken K and Perry, John R B and Peters, Marjolein J and Polasek, Ozren and Prokopenko, Inga and Rayner, Nigel W and Ripatti, Samuli and Rivadeneira, Fernando and Robertson, Neil R and Sanna, Serena and Sovio, Ulla and Surakka, Ida and Teumer, Alexander and van Wingerden, Sophie and Vitart, Veronique and Zhao, Jing Hua and Cavalcanti-Proen{\c c}a, Christine and Chines, Peter S and Fisher, Eva and Kulzer, Jennifer R and Lecoeur, C{\'e}cile and Narisu, Narisu and Sandholt, Camilla and Scott, Laura J and Silander, Kaisa and Stark, Klaus and Tammesoo, Mari-Liis and Teslovich, Tanya M and Timpson, Nicholas John and Watanabe, Richard M and Welch, Ryan and Chasman, Daniel I and Cooper, Matthew N and Jansson, John-Olov and Kettunen, Johannes and Lawrence, Robert W and Pellikka, Niina and Perola, Markus and Vandenput, Liesbeth and Alavere, Helene and Almgren, Peter and Atwood, Larry D and Bennett, Amanda J and Biffar, Reiner and Bonnycastle, Lori L and Bornstein, Stefan R and Buchanan, Thomas A and Campbell, Harry and Day, Ian N M and Dei, Mariano and D{\"o}rr, Marcus and Elliott, Paul and Erdos, Michael R and Eriksson, Johan G and Freimer, Nelson B and Fu, Mao and Gaget, Stefan and Geus, Eco J C and Gjesing, Anette P and Grallert, Harald and Gr{\"a}ssler, J{\"u}rgen and Groves, Christopher J and Guiducci, Candace and Hartikainen, Anna-Liisa and Hassanali, Neelam and Havulinna, Aki S and Herzig, Karl-Heinz and Hicks, Andrew A and Hui, Jennie and Igl, Wilmar and Jousilahti, Pekka and Jula, Antti and Kajantie, Eero and Kinnunen, Leena and Kolcic, Ivana and Koskinen, Seppo and Kovacs, Peter and Kroemer, Heyo K and Krzelj, Vjekoslav and Kuusisto, Johanna and Kvaloy, Kirsti and Laitinen, Jaana and Lantieri, Olivier and Lathrop, G Mark and Lokki, Marja-Liisa and Luben, Robert N and Ludwig, Barbara and McArdle, Wendy L and McCarthy, Anne and Morken, Mario A and Nelis, Mari and Neville, Matt J and Par{\'e}, Guillaume and Parker, Alex N and Peden, John F and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Platou, Carl G P and Pouta, Anneli and Ridderstr{\r a}le, Martin and Samani, Nilesh J and Saramies, Jouko and Sinisalo, Juha and Smit, Jan H and Strawbridge, Rona J and Stringham, Heather M and Swift, Amy J and Teder-Laving, Maris and Thomson, Brian and Usala, Gianluca and van Meurs, Joyce B J and van Ommen, Gert-Jan and Vatin, Vincent and Volpato, Claudia B and Wallaschofski, Henri and Walters, G Bragi and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Witte, Daniel R and Zgaga, Lina and Zitting, Paavo and Beilby, John P and James, Alan L and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Nieminen, Markku S and Ohlsson, Claes and Palmer, Lyle J and Raitakari, Olli and Ridker, Paul M and Stumvoll, Michael and T{\"o}njes, Anke and Viikari, Jorma and Balkau, Beverley and Ben-Shlomo, Yoav and Bergman, Richard N and Boeing, Heiner and Smith, George Davey and Ebrahim, Shah and Froguel, Philippe and Hansen, Torben and Hengstenberg, Christian and Hveem, Kristian and Isomaa, Bo and J{\o}rgensen, Torben and Karpe, Fredrik and Khaw, Kay-Tee and Laakso, Markku and Lawlor, Debbie A and Marre, Michel and Meitinger, Thomas and Metspalu, Andres and Midthjell, Kristian and Pedersen, Oluf and Salomaa, Veikko and Schwarz, Peter E H and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Valle, Timo T and Wareham, Nicholas J and Arnold, Alice M and Beckmann, Jacques S and Bergmann, Sven and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Collins, Francis S and Eiriksdottir, Gudny and Gudnason, Vilmundur and Gyllensten, Ulf and Hamsten, Anders and Hattersley, Andrew T and Hofman, Albert and Hu, Frank B and Illig, Thomas and Iribarren, Carlos and Jarvelin, Marjo-Riitta and Kao, W H Linda and Kaprio, Jaakko and Launer, Lenore J and Munroe, Patricia B and Oostra, Ben and Penninx, Brenda W and Pramstaller, Peter P and Psaty, Bruce M and Quertermous, Thomas and Rissanen, Aila and Rudan, Igor and Shuldiner, Alan R and Soranzo, Nicole and Spector, Timothy D and Syv{\"a}nen, Ann-Christine and Uda, Manuela and Uitterlinden, Andre and V{\"o}lzke, Henry and Vollenweider, Peter and Wilson, James F and Witteman, Jacqueline C and Wright, Alan F and Abecasis, Goncalo R and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Frayling, Timothy M and Groop, Leif C and Haritunians, Talin and Hunter, David J and Kaplan, Robert C and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Peltonen, Leena and Schlessinger, David and Strachan, David P and Hirschhorn, Joel N and Assimes, Themistocles L and Wichmann, H-Erich and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Stefansson, Kari and Cupples, L Adrienne and Loos, Ruth J F and Barroso, In{\^e}s and McCarthy, Mark I and Fox, Caroline S and Mohlke, Karen L and Lindgren, Cecilia M} } @article {1160, title = {New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Feb}, pages = {105-16}, abstract = {

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

}, keywords = {Adolescent, Adult, Alleles, Blood Glucose, Child, Databases, Genetic, Diabetes Mellitus, Type 2, DNA Copy Number Variations, Fasting, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Reproducibility of Results}, issn = {1546-1718}, doi = {10.1038/ng.520}, author = {Dupuis, Jos{\'e}e and Langenberg, Claudia and Prokopenko, Inga and Saxena, Richa and Soranzo, Nicole and Jackson, Anne U and Wheeler, Eleanor and Glazer, Nicole L and Bouatia-Naji, Nabila and Gloyn, Anna L and Lindgren, Cecilia M and M{\"a}gi, Reedik and Morris, Andrew P and Randall, Joshua and Johnson, Toby and Elliott, Paul and Rybin, Denis and Thorleifsson, Gudmar and Steinthorsdottir, Valgerdur and Henneman, Peter and Grallert, Harald and Dehghan, Abbas and Hottenga, Jouke Jan and Franklin, Christopher S and Navarro, Pau and Song, Kijoung and Goel, Anuj and Perry, John R B and Egan, Josephine M and Lajunen, Taina and Grarup, Niels and Spars{\o}, Thomas and Doney, Alex and Voight, Benjamin F and Stringham, Heather M and Li, Man and Kanoni, Stavroula and Shrader, Peter and Cavalcanti-Proen{\c c}a, Christine and Kumari, Meena and Qi, Lu and Timpson, Nicholas J and Gieger, Christian and Zabena, Carina and Rocheleau, Ghislain and Ingelsson, Erik and An, Ping and O{\textquoteright}Connell, Jeffrey and Luan, Jian{\textquoteright}an and Elliott, Amanda and McCarroll, Steven A and Payne, Felicity and Roccasecca, Rosa Maria and Pattou, Fran{\c c}ois and Sethupathy, Praveen and Ardlie, Kristin and Ariyurek, Yavuz and Balkau, Beverley and Barter, Philip and Beilby, John P and Ben-Shlomo, Yoav and Benediktsson, Rafn and Bennett, Amanda J and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bonnefond, Am{\'e}lie and Bonnycastle, Lori L and Borch-Johnsen, Knut and B{\"o}ttcher, Yvonne and Brunner, Eric and Bumpstead, Suzannah J and Charpentier, Guillaume and Chen, Yii-Der Ida and Chines, Peter and Clarke, Robert and Coin, Lachlan J M and Cooper, Matthew N and Cornelis, Marilyn and Crawford, Gabe and Crisponi, Laura and Day, Ian N M and de Geus, Eco J C and Delplanque, Jerome and Dina, Christian and Erdos, Michael R and Fedson, Annette C and Fischer-Rosinsky, Antje and Forouhi, Nita G and Fox, Caroline S and Frants, Rune and Franzosi, Maria Grazia and Galan, Pilar and Goodarzi, Mark O and Graessler, J{\"u}rgen and Groves, Christopher J and Grundy, Scott and Gwilliam, Rhian and Gyllensten, Ulf and Hadjadj, Samy and Hallmans, G{\"o}ran and Hammond, Naomi and Han, Xijing and Hartikainen, Anna-Liisa and Hassanali, Neelam and Hayward, Caroline and Heath, Simon C and Hercberg, Serge and Herder, Christian and Hicks, Andrew A and Hillman, David R and Hingorani, Aroon D and Hofman, Albert and Hui, Jennie and Hung, Joe and Isomaa, Bo and Johnson, Paul R V and J{\o}rgensen, Torben and Jula, Antti and Kaakinen, Marika and Kaprio, Jaakko and Kesaniemi, Y Antero and Kivimaki, Mika and Knight, Beatrice and Koskinen, Seppo and Kovacs, Peter and Kyvik, Kirsten Ohm and Lathrop, G Mark and Lawlor, Debbie A and Le Bacquer, Olivier and Lecoeur, C{\'e}cile and Li, Yun and Lyssenko, Valeriya and Mahley, Robert and Mangino, Massimo and Manning, Alisa K and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and McAteer, Jarred B and McCulloch, Laura J and McPherson, Ruth and Meisinger, Christa and Melzer, David and Meyre, David and Mitchell, Braxton D and Morken, Mario A and Mukherjee, Sutapa and Naitza, Silvia and Narisu, Narisu and Neville, Matthew J and Oostra, Ben A and Orr{\`u}, Marco and Pakyz, Ruth and Palmer, Colin N A and Paolisso, Giuseppe and Pattaro, Cristian and Pearson, Daniel and Peden, John F and Pedersen, Nancy L and Perola, Markus and Pfeiffer, Andreas F H and Pichler, Irene and Polasek, Ozren and Posthuma, Danielle and Potter, Simon C and Pouta, Anneli and Province, Michael A and Psaty, Bruce M and Rathmann, Wolfgang and Rayner, Nigel W and Rice, Kenneth and Ripatti, Samuli and Rivadeneira, Fernando and Roden, Michael and Rolandsson, Olov and Sandbaek, Annelli and Sandhu, Manjinder and Sanna, Serena and Sayer, Avan Aihie and Scheet, Paul and Scott, Laura J and Seedorf, Udo and Sharp, Stephen J and Shields, Beverley and Sigurethsson, Gunnar and Sijbrands, Eric J G and Silveira, Angela and Simpson, Laila and Singleton, Andrew and Smith, Nicholas L and Sovio, Ulla and Swift, Amy and Syddall, Holly and Syv{\"a}nen, Ann-Christine and Tanaka, Toshiko and Thorand, Barbara and Tichet, Jean and T{\"o}njes, Anke and Tuomi, Tiinamaija and Uitterlinden, Andr{\'e} G and van Dijk, Ko Willems and van Hoek, Mandy and Varma, Dhiraj and Visvikis-Siest, Sophie and Vitart, Veronique and Vogelzangs, Nicole and Waeber, G{\'e}rard and Wagner, Peter J and Walley, Andrew and Walters, G Bragi and Ward, Kim L and Watkins, Hugh and Weedon, Michael N and Wild, Sarah H and Willemsen, Gonneke and Witteman, Jaqueline C M and Yarnell, John W G and Zeggini, Eleftheria and Zelenika, Diana and Zethelius, Bj{\"o}rn and Zhai, Guangju and Zhao, Jing Hua and Zillikens, M Carola and Borecki, Ingrid B and Loos, Ruth J F and Meneton, Pierre and Magnusson, Patrik K E and Nathan, David M and Williams, Gordon H and Hattersley, Andrew T and Silander, Kaisa and Salomaa, Veikko and Smith, George Davey and Bornstein, Stefan R and Schwarz, Peter and Spranger, Joachim and Karpe, Fredrik and Shuldiner, Alan R and Cooper, Cyrus and Dedoussis, George V and Serrano-R{\'\i}os, Manuel and Morris, Andrew D and Lind, Lars and Palmer, Lyle J and Hu, Frank B and Franks, Paul W and Ebrahim, Shah and Marmot, Michael and Kao, W H Linda and Pankow, James S and Sampson, Michael J and Kuusisto, Johanna and Laakso, Markku and Hansen, Torben and Pedersen, Oluf and Pramstaller, Peter Paul and Wichmann, H Erich and Illig, Thomas and Rudan, Igor and Wright, Alan F and Stumvoll, Michael and Campbell, Harry and Wilson, James F and Bergman, Richard N and Buchanan, Thomas A and Collins, Francis S and Mohlke, Karen L and Tuomilehto, Jaakko and Valle, Timo T and Altshuler, David and Rotter, Jerome I and Siscovick, David S and Penninx, Brenda W J H and Boomsma, Dorret I and Deloukas, Panos and Spector, Timothy D and Frayling, Timothy M and Ferrucci, Luigi and Kong, Augustine and Thorsteinsdottir, Unnur and Stefansson, Kari and van Duijn, Cornelia M and Aulchenko, Yurii S and Cao, Antonio and Scuteri, Angelo and Schlessinger, David and Uda, Manuela and Ruokonen, Aimo and Jarvelin, Marjo-Riitta and Waterworth, Dawn M and Vollenweider, Peter and Peltonen, Leena and Mooser, Vincent and Abecasis, Goncalo R and Wareham, Nicholas J and Sladek, Robert and Froguel, Philippe and Watanabe, Richard M and Meigs, James B and Groop, Leif and Boehnke, Michael and McCarthy, Mark I and Florez, Jose C and Barroso, In{\^e}s} } @article {1274, title = {A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium.}, journal = {Diabetes}, volume = {60}, year = {2011}, month = {2011 Apr}, pages = {1329-39}, abstract = {

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of \~{}2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from \~{}9\% of the variance in triglycerides, 5.8\% of high-density lipoprotein cholesterol, 3.6\% of fasting glucose, and 1.4\% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

}, keywords = {Adult, Aged, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Meta-Analysis as Topic, Metabolic Syndrome, Middle Aged, Phenotype, Polymorphism, Single Nucleotide}, issn = {1939-327X}, doi = {10.2337/db10-1011}, author = {Kraja, Aldi T and Vaidya, Dhananjay and Pankow, James S and Goodarzi, Mark O and Assimes, Themistocles L and Kullo, Iftikhar J and Sovio, Ulla and Mathias, Rasika A and Sun, Yan V and Franceschini, Nora and Absher, Devin and Li, Guo and Zhang, Qunyuan and Feitosa, Mary F and Glazer, Nicole L and Haritunians, Talin and Hartikainen, Anna-Liisa and Knowles, Joshua W and North, Kari E and Iribarren, Carlos and Kral, Brian and Yanek, Lisa and O{\textquoteright}Reilly, Paul F and McCarthy, Mark I and Jaquish, Cashell and Couper, David J and Chakravarti, Aravinda and Psaty, Bruce M and Becker, Lewis C and Province, Michael A and Boerwinkle, Eric and Quertermous, Thomas and Palotie, Leena and Jarvelin, Marjo-Riitta and Becker, Diane M and Kardia, Sharon L R and Rotter, Jerome I and Chen, Yii-Der Ida and Borecki, Ingrid B} } @article {1301, title = {Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Jun 26}, pages = {753-60}, abstract = {

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between \~{}2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 {\texttimes} 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 {\texttimes} 10(-11)) and one near SPRY2 (P = 3 {\texttimes} 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

}, keywords = {Adiponectin, Adiposity, Alleles, Body Fat Distribution, Body Mass Index, Body Weight, Female, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Meta-Analysis as Topic, Metabolome, Obesity, Polymorphism, Single Nucleotide, Subcutaneous Fat}, issn = {1546-1718}, doi = {10.1038/ng.866}, author = {Kilpel{\"a}inen, Tuomas O and Zillikens, M Carola and Stan{\v c}{\'a}kov{\'a}, Alena and Finucane, Francis M and Ried, Janina S and Langenberg, Claudia and Zhang, Weihua and Beckmann, Jacques S and Luan, Jian{\textquoteright}an and Vandenput, Liesbeth and Styrkarsdottir, Unnur and Zhou, Yanhua and Smith, Albert Vernon and Zhao, Jing-Hua and Amin, Najaf and Vedantam, Sailaja and Shin, So-Youn and Haritunians, Talin and Fu, Mao and Feitosa, Mary F and Kumari, Meena and Halldorsson, Bjarni V and Tikkanen, Emmi and Mangino, Massimo and Hayward, Caroline and Song, Ci and Arnold, Alice M and Aulchenko, Yurii S and Oostra, Ben A and Campbell, Harry and Cupples, L Adrienne and Davis, Kathryn E and D{\"o}ring, Angela and Eiriksdottir, Gudny and Estrada, Karol and Fern{\'a}ndez-Real, Jos{\'e} Manuel and Garcia, Melissa and Gieger, Christian and Glazer, Nicole L and Guiducci, Candace and Hofman, Albert and Humphries, Steve E and Isomaa, Bo and Jacobs, Leonie C and Jula, Antti and Karasik, David and Karlsson, Magnus K and Khaw, Kay-Tee and Kim, Lauren J and Kivimaki, Mika and Klopp, Norman and Kuhnel, Brigitte and Kuusisto, Johanna and Liu, Yongmei and Ljunggren, Osten and Lorentzon, Mattias and Luben, Robert N and McKnight, Barbara and Mellstr{\"o}m, Dan and Mitchell, Braxton D and Mooser, Vincent and Moreno, Jos{\'e} Maria and M{\"a}nnist{\"o}, Satu and O{\textquoteright}Connell, Jeffery R and Pascoe, Laura and Peltonen, Leena and Peral, Bel{\'e}n and Perola, Markus and Psaty, Bruce M and Salomaa, Veikko and Savage, David B and Semple, Robert K and Skaric-Juric, Tatjana and Sigurdsson, Gunnar and Song, Kijoung S and Spector, Timothy D and Syv{\"a}nen, Ann-Christine and Talmud, Philippa J and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Vidal-Puig, Antonio and Wild, Sarah H and Wright, Alan F and Clegg, Deborah J and Schadt, Eric and Wilson, James F and Rudan, Igor and Ripatti, Samuli and Borecki, Ingrid B and Shuldiner, Alan R and Ingelsson, Erik and Jansson, John-Olov and Kaplan, Robert C and Gudnason, Vilmundur and Harris, Tamara B and Groop, Leif and Kiel, Douglas P and Rivadeneira, Fernando and Walker, Mark and Barroso, In{\^e}s and Vollenweider, Peter and Waeber, G{\'e}rard and Chambers, John C and Kooner, Jaspal S and Soranzo, Nicole and Hirschhorn, Joel N and Stefansson, Kari and Wichmann, H-Erich and Ohlsson, Claes and O{\textquoteright}Rahilly, Stephen and Wareham, Nicholas J and Speliotes, Elizabeth K and Fox, Caroline S and Laakso, Markku and Loos, Ruth J F} } @article {1258, title = {Meta-analysis of gene-environment interaction: joint estimation of SNP and SNP {\texttimes} environment regression coefficients.}, journal = {Genet Epidemiol}, volume = {35}, year = {2011}, month = {2011 Jan}, pages = {11-8}, abstract = {

INTRODUCTION: Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP {\texttimes} E) regression coefficients for use in gene-environment interaction studies.

METHODS: In testing SNP {\texttimes} E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP {\texttimes} E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP {\texttimes} E terms, and a test of homogeneity across samples.

RESULTS: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.

}, keywords = {Adult, Aged, Body Mass Index, Confidence Intervals, Diabetes Mellitus, Type 2, Environment, Fasting, Female, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Insulin, Least-Squares Analysis, Male, Mathematical Computing, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, PPAR gamma}, issn = {1098-2272}, doi = {10.1002/gepi.20546}, author = {Manning, Alisa K and LaValley, Michael and Liu, Ching-Ti and Rice, Kenneth and An, Ping and Liu, Yongmei and Miljkovic, Iva and Rasmussen-Torvik, Laura and Harris, Tamara B and Province, Michael A and Borecki, Ingrid B and Florez, Jose C and Meigs, James B and Cupples, L Adrienne and Dupuis, Jos{\'e}e} } @article {1556, title = {Assessment of gene-by-sex interaction effect on bone mineral density.}, journal = {J Bone Miner Res}, volume = {27}, year = {2012}, month = {2012 Oct}, pages = {2051-64}, abstract = {

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 {\texttimes} 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 {\texttimes} 10(-5) ; female effect = -0.007 and p = 3.3 {\texttimes} 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 {\texttimes} 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08\% of the variation in these traits per implicated SNP. {\textcopyright} 2012 American Society for Bone and Mineral Research.

}, keywords = {Bone Density, Cohort Studies, Female, Genes, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reproducibility of Results, Sex Characteristics}, issn = {1523-4681}, doi = {10.1002/jbmr.1679}, author = {Liu, Ching-Ti and Estrada, Karol and Yerges-Armstrong, Laura M and Amin, Najaf and Evangelou, Evangelos and Li, Guo and Minster, Ryan L and Carless, Melanie A and Kammerer, Candace M and Oei, Ling and Zhou, Yanhua and Alonso, Nerea and Dailiana, Zoe and Eriksson, Joel and Garc{\'\i}a-Giralt, Natalia and Giroux, Sylvie and Husted, Lise Bjerre and Khusainova, Rita I and Koromila, Theodora and Kung, Annie Waichee and Lewis, Joshua R and Masi, Laura and Mencej-Bedrac, Simona and Nogues, Xavier and Patel, Millan S and Prezelj, Janez and Richards, J Brent and Sham, Pak Chung and Spector, Timothy and Vandenput, Liesbeth and Xiao, Su-Mei and Zheng, Hou-Feng and Zhu, Kun and Balcells, Susana and Brandi, Maria Luisa and Frost, Morten and Goltzman, David and Gonz{\'a}lez-Mac{\'\i}as, Jes{\'u}s and Karlsson, Magnus and Khusnutdinova, Elza K and Kollia, Panagoula and Langdahl, Bente Lomholt and Ljunggren, Osten and Lorentzon, Mattias and Marc, Janja and Mellstr{\"o}m, Dan and Ohlsson, Claes and Olmos, Jos{\'e} M and Ralston, Stuart H and Riancho, Jos{\'e} A and Rousseau, Fran{\c c}ois and Urreizti, Roser and Van Hul, Wim and Zarrabeitia, Mar{\'\i}a T and Castano-Betancourt, Martha and Demissie, Serkalem and Grundberg, Elin and Herrera, Lizbeth and Kwan, Tony and Medina-G{\'o}mez, Carolina and Pastinen, Tomi and Sigurdsson, Gunnar and Thorleifsson, Gudmar and Vanmeurs, Joyce Bj and Blangero, John and Hofman, Albert and Liu, Yongmei and Mitchell, Braxton D and O{\textquoteright}Connell, Jeffrey R and Oostra, Ben A and Rotter, Jerome I and Stefansson, Kari and Streeten, Elizabeth A and Styrkarsdottir, Unnur and Thorsteinsdottir, Unnur and Tylavsky, Frances A and Uitterlinden, Andre and Cauley, Jane A and Harris, Tamara B and Ioannidis, John Pa and Psaty, Bruce M and Robbins, John A and Zillikens, M Carola and Vanduijn, Cornelia M and Prince, Richard L and Karasik, David and Rivadeneira, Fernando and Kiel, Douglas P and Cupples, L Adrienne and Hsu, Yi-Hsiang} } @article {1554, title = {Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.}, journal = {JAMA}, volume = {308}, year = {2012}, month = {2012 Nov 14}, pages = {1898-905}, abstract = {

CONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.

OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.

MAIN OUTCOME MEASURE: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.

RESULTS: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95\% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95\% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95\% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.

CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

}, keywords = {25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Aged, Chronic Disease, Cohort Studies, Female, Genetic Variation, Genotype, Hip Fractures, Humans, Low Density Lipoprotein Receptor-Related Protein-2, Male, Meta-Analysis as Topic, Myocardial Infarction, Neoplasms, Polymorphism, Single Nucleotide, Receptors, Calcitriol, Receptors, Cell Surface, Risk, Steroid Hydroxylases, Vitamin D, Vitamin D3 24-Hydroxylase}, issn = {1538-3598}, doi = {10.1001/jama.2012.17304}, author = {Levin, Gregory P and Robinson-Cohen, Cassianne and de Boer, Ian H and Houston, Denise K and Lohman, Kurt and Liu, Yongmei and Kritchevsky, Stephen B and Cauley, Jane A and Tanaka, Toshiko and Ferrucci, Luigi and Bandinelli, Stefania and Patel, Kushang V and Hagstr{\"o}m, Emil and Micha{\"e}lsson, Karl and Melhus, H{\r a}kan and Wang, Thomas and Wolf, Myles and Psaty, Bruce M and Siscovick, David and Kestenbaum, Bryan} } @article {6089, title = {Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.}, journal = {Blood}, volume = {120}, year = {2012}, month = {2012 Dec 06}, pages = {4873-81}, abstract = {

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 {\texttimes} 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 {\texttimes} 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 {\texttimes} 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 {\texttimes} 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

}, keywords = {Adaptor Proteins, Signal Transducing, ARNTL Transcription Factors, ATPases Associated with Diverse Cellular Activities, Cell Line, Cell Line, Tumor, Cohort Studies, Coronary Artery Disease, Diabetes Mellitus, Type 2, Gene Expression Profiling, Gene Expression Regulation, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, LIM Domain Proteins, Meta-Analysis as Topic, Monocytes, Mucin-3, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, PPAR gamma, Proteasome Endopeptidase Complex, RNA Interference, Transcription Factors}, issn = {1528-0020}, doi = {10.1182/blood-2012-06-436188}, author = {Huang, Jie and Sabater-Lleal, Maria and Asselbergs, Folkert W and Tregouet, David and Shin, So-Youn and Ding, Jingzhong and Baumert, Jens and Oudot-Mellakh, Tiphaine and Folkersen, Lasse and Johnson, Andrew D and Smith, Nicholas L and Williams, Scott M and Ikram, Mohammad A and Kleber, Marcus E and Becker, Diane M and Truong, Vinh and Mychaleckyj, Josyf C and Tang, Weihong and Yang, Qiong and Sennblad, Bengt and Moore, Jason H and Williams, Frances M K and Dehghan, Abbas and Silbernagel, G{\"u}nther and Schrijvers, Elisabeth M C and Smith, Shelly and Karakas, Mahir and Tofler, Geoffrey H and Silveira, Angela and Navis, Gerjan J and Lohman, Kurt and Chen, Ming-Huei and Peters, Annette and Goel, Anuj and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Lundmark, Per and Psaty, Bruce M and Strawbridge, Rona J and Boehm, Bernhard O and Carter, Angela M and Meisinger, Christa and Peden, John F and Bis, Joshua C and McKnight, Barbara and Ohrvik, John and Taylor, Kent and Franzosi, Maria Grazia and Seedorf, Udo and Collins, Rory and Franco-Cereceda, Anders and Syv{\"a}nen, Ann-Christine and Goodall, Alison H and Yanek, Lisa R and Cushman, Mary and M{\"u}ller-Nurasyid, Martina and Folsom, Aaron R and Basu, Saonli and Matijevic, Nena and van Gilst, Wiek H and Kooner, Jaspal S and Hofman, Albert and Danesh, John and Clarke, Robert and Meigs, James B and Kathiresan, Sekar and Reilly, Muredach P and Klopp, Norman and Harris, Tamara B and Winkelmann, Bernhard R and Grant, Peter J and Hillege, Hans L and Watkins, Hugh and Spector, Timothy D and Becker, Lewis C and Tracy, Russell P and M{\"a}rz, Winfried and Uitterlinden, Andr{\'e} G and Eriksson, Per and Cambien, Francois and Morange, Pierre-Emmanuel and Koenig, Wolfgang and Soranzo, Nicole and van der Harst, Pim and Liu, Yongmei and O{\textquoteright}Donnell, Christopher J and Hamsten, Anders} } @article {6084, title = {Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Dec}, pages = {639-46}, abstract = {

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 {\texttimes} 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 {\texttimes} 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.

}, keywords = {Adult, African Americans, Cohort Studies, Electrocardiography, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.112.963991}, author = {Butler, Anne M and Yin, Xiaoyan and Evans, Daniel S and Nalls, Michael A and Smith, Erin N and Tanaka, Toshiko and Li, Guo and Buxbaum, Sarah G and Whitsel, Eric A and Alonso, Alvaro and Arking, Dan E and Benjamin, Emelia J and Berenson, Gerald S and Bis, Josh C and Chen, Wei and Deo, Rajat and Ellinor, Patrick T and Heckbert, Susan R and Heiss, Gerardo and Hsueh, Wen-Chi and Keating, Brendan J and Kerr, Kathleen F and Li, Yun and Limacher, Marian C and Liu, Yongmei and Lubitz, Steven A and Marciante, Kristin D and Mehra, Reena and Meng, Yan A and Newman, Anne B and Newton-Cheh, Christopher and North, Kari E and Palmer, Cameron D and Psaty, Bruce M and Quibrera, P Miguel and Redline, Susan and Reiner, Alex P and Rotter, Jerome I and Schnabel, Renate B and Schork, Nicholas J and Singleton, Andrew B and Smith, J Gustav and Soliman, Elsayed Z and Srinivasan, Sathanur R and Zhang, Zhu-Ming and Zonderman, Alan B and Ferrucci, Luigi and Murray, Sarah S and Evans, Michele K and Sotoodehnia, Nona and Magnani, Jared W and Avery, Christy L} } @article {6063, title = {Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Mar}, pages = {401-8}, abstract = {

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.

OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.

METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P<=2.5{\texttimes}10(-8)).

RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98{\texttimes}10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.

CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

}, keywords = {Adult, African Americans, Aged, Arrhythmias, Cardiac, Connexin 43, Electrocardiography, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Heart Rate, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Rest, United States}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2012.11.014}, author = {Deo, R and Nalls, M A and Avery, C L and Smith, J G and Evans, D S and Keller, M F and Butler, A M and Buxbaum, S G and Li, G and Miguel Quibrera, P and Smith, E N and Tanaka, T and Akylbekova, E L and Alonso, A and Arking, D E and Benjamin, E J and Berenson, G S and Bis, J C and Chen, L Y and Chen, W and Cummings, S R and Ellinor, P T and Evans, M K and Ferrucci, L and Fox, E R and Heckbert, S R and Heiss, G and Hsueh, W C and Kerr, K F and Limacher, M C and Liu, Y and Lubitz, S A and Magnani, J W and Mehra, R and Marcus, G M and Murray, S S and Newman, A B and Njajou, O and North, K E and Paltoo, D N and Psaty, B M and Redline, S S and Reiner, A P and Robinson, J G and Rotter, J I and Samdarshi, T E and Schnabel, R B and Schork, N J and Singleton, A B and Siscovick, D and Soliman, E Z and Sotoodehnia, N and Srinivasan, S R and Taylor, H A and Trevisan, M and Zhang, Z and Zonderman, A B and Newton-Cheh, C and Whitsel, E A} } @article {6029, title = {A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.}, journal = {Genet Epidemiol}, volume = {37}, year = {2013}, month = {2013 Jul}, pages = {512-521}, abstract = {

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P <= 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 {\texttimes} 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 {\texttimes} 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

}, keywords = {Aged, Aging, Case-Control Studies, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, Venous Thromboembolism}, issn = {1098-2272}, doi = {10.1002/gepi.21731}, author = {Tang, Weihong and Teichert, Martina and Chasman, Daniel I and Heit, John A and Morange, Pierre-Emmanuel and Li, Guo and Pankratz, Nathan and Leebeek, Frank W and Par{\'e}, Guillaume and de Andrade, Mariza and Tzourio, Christophe and Psaty, Bruce M and Basu, Saonli and Ruiter, Rikje and Rose, Lynda and Armasu, Sebastian M and Lumley, Thomas and Heckbert, Susan R and Uitterlinden, Andr{\'e} G and Lathrop, Mark and Rice, Kenneth M and Cushman, Mary and Hofman, Albert and Lambert, Jean-Charles and Glazer, Nicole L and Pankow, James S and Witteman, Jacqueline C and Amouyel, Philippe and Bis, Joshua C and Bovill, Edwin G and Kong, Xiaoxiao and Tracy, Russell P and Boerwinkle, Eric and Rotter, Jerome I and Tr{\'e}gou{\"e}t, David-Alexandre and Loth, Daan W and Stricker, Bruno H Ch and Ridker, Paul M and Folsom, Aaron R and Smith, Nicholas L} } @article {6152, title = {Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 May}, pages = {501-12}, abstract = {

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

}, keywords = {Anthropometry, Body Height, Body Mass Index, Case-Control Studies, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Waist-Hip Ratio}, issn = {1546-1718}, doi = {10.1038/ng.2606}, author = {Berndt, Sonja I and Gustafsson, Stefan and M{\"a}gi, Reedik and Ganna, Andrea and Wheeler, Eleanor and Feitosa, Mary F and Justice, Anne E and Monda, Keri L and Croteau-Chonka, Damien C and Day, Felix R and Esko, T{\~o}nu and Fall, Tove and Ferreira, Teresa and Gentilini, Davide and Jackson, Anne U and Luan, Jian{\textquoteright}an and Randall, Joshua C and Vedantam, Sailaja and Willer, Cristen J and Winkler, Thomas W and Wood, Andrew R and Workalemahu, Tsegaselassie and Hu, Yi-Juan and Lee, Sang Hong and Liang, Liming and Lin, Dan-Yu and Min, Josine L and Neale, Benjamin M and Thorleifsson, Gudmar and Yang, Jian and Albrecht, Eva and Amin, Najaf and Bragg-Gresham, Jennifer L and Cadby, Gemma and den Heijer, Martin and Eklund, Niina and Fischer, Krista and Goel, Anuj and Hottenga, Jouke-Jan and Huffman, Jennifer E and Jarick, Ivonne and Johansson, Asa and Johnson, Toby and Kanoni, Stavroula and Kleber, Marcus E and K{\"o}nig, Inke R and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Lamina, Claudia and Lecoeur, C{\'e}cile and Li, Guo and Mangino, Massimo and McArdle, Wendy L and Medina-G{\'o}mez, Carolina and M{\"u}ller-Nurasyid, Martina and Ngwa, Julius S and Nolte, Ilja M and Paternoster, Lavinia and Pechlivanis, Sonali and Perola, Markus and Peters, Marjolein J and Preuss, Michael and Rose, Lynda M and Shi, Jianxin and Shungin, Dmitry and Smith, Albert Vernon and Strawbridge, Rona J and Surakka, Ida and Teumer, Alexander and Trip, Mieke D and Tyrer, Jonathan and van Vliet-Ostaptchouk, Jana V and Vandenput, Liesbeth and Waite, Lindsay L and Zhao, Jing Hua and Absher, Devin and Asselbergs, Folkert W and Atalay, Mustafa and Attwood, Antony P and Balmforth, Anthony J and Basart, Hanneke and Beilby, John and Bonnycastle, Lori L and Brambilla, Paolo and Bruinenberg, Marcel and Campbell, Harry and Chasman, Daniel I and Chines, Peter S and Collins, Francis S and Connell, John M and Cookson, William O and de Faire, Ulf and de Vegt, Femmie and Dei, Mariano and Dimitriou, Maria and Edkins, Sarah and Estrada, Karol and Evans, David M and Farrall, Martin and Ferrario, Marco M and Ferrieres, Jean and Franke, Lude and Frau, Francesca and Gejman, Pablo V and Grallert, Harald and Gr{\"o}nberg, Henrik and Gudnason, Vilmundur and Hall, Alistair S and Hall, Per and Hartikainen, Anna-Liisa and Hayward, Caroline and Heard-Costa, Nancy L and Heath, Andrew C and Hebebrand, Johannes and Homuth, Georg and Hu, Frank B and Hunt, Sarah E and Hypp{\"o}nen, Elina and Iribarren, Carlos and Jacobs, Kevin B and Jansson, John-Olov and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Kee, Frank and Khaw, Kay-Tee and Kivimaki, Mika and Koenig, Wolfgang and Kraja, Aldi T and Kumari, Meena and Kuulasmaa, Kari and Kuusisto, Johanna and Laitinen, Jaana H and Lakka, Timo A and Langenberg, Claudia and Launer, Lenore J and Lind, Lars and Lindstr{\"o}m, Jaana and Liu, Jianjun and Liuzzi, Antonio and Lokki, Marja-Liisa and Lorentzon, Mattias and Madden, Pamela A and Magnusson, Patrik K and Manunta, Paolo and Marek, Diana and M{\"a}rz, Winfried and Mateo Leach, Irene and McKnight, Barbara and Medland, Sarah E and Mihailov, Evelin and Milani, Lili and Montgomery, Grant W and Mooser, Vincent and M{\"u}hleisen, Thomas W and Munroe, Patricia B and Musk, Arthur W and Narisu, Narisu and Navis, Gerjan and Nicholson, George and Nohr, Ellen A and Ong, Ken K and Oostra, Ben A and Palmer, Colin N A and Palotie, Aarno and Peden, John F and Pedersen, Nancy and Peters, Annette and Polasek, Ozren and Pouta, Anneli and Pramstaller, Peter P and Prokopenko, Inga and P{\"u}tter, Carolin and Radhakrishnan, Aparna and Raitakari, Olli and Rendon, Augusto and Rivadeneira, Fernando and Rudan, Igor and Saaristo, Timo E and Sambrook, Jennifer G and Sanders, Alan R and Sanna, Serena and Saramies, Jouko and Schipf, Sabine and Schreiber, Stefan and Schunkert, Heribert and Shin, So-Youn and Signorini, Stefano and Sinisalo, Juha and Skrobek, Boris and Soranzo, Nicole and Stan{\v c}{\'a}kov{\'a}, Alena and Stark, Klaus and Stephens, Jonathan C and Stirrups, Kathleen and Stolk, Ronald P and Stumvoll, Michael and Swift, Amy J and Theodoraki, Eirini V and Thorand, Barbara and Tr{\'e}gou{\"e}t, David-Alexandre and Tremoli, Elena and van der Klauw, Melanie M and van Meurs, Joyce B J and Vermeulen, Sita H and Viikari, Jorma and Virtamo, Jarmo and Vitart, Veronique and Waeber, G{\'e}rard and Wang, Zhaoming and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Winkelmann, Bernhard R and Witteman, Jacqueline C M and Wolffenbuttel, Bruce H R and Wong, Andrew and Wright, Alan F and Zillikens, M Carola and Amouyel, Philippe and Boehm, Bernhard O and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Chanock, Stephen J and Cupples, L Adrienne and Cusi, Daniele and Dedoussis, George V and Erdmann, Jeanette and Eriksson, Johan G and Franks, Paul W and Froguel, Philippe and Gieger, Christian and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Hengstenberg, Christian and Hicks, Andrew A and Hingorani, Aroon and Hinney, Anke and Hofman, Albert and Hovingh, Kees G and Hveem, Kristian and Illig, Thomas and Jarvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Keinanen-Kiukaanniemi, Sirkka M and Kiemeney, Lambertus A and Kuh, Diana and Laakso, Markku and Lehtim{\"a}ki, Terho and Levinson, Douglas F and Martin, Nicholas G and Metspalu, Andres and Morris, Andrew D and Nieminen, Markku S and Nj{\o}lstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J and Ouwehand, Willem H and Palmer, Lyle J and Penninx, Brenda and Power, Chris and Province, Michael A and Psaty, Bruce M and Qi, Lu and Rauramaa, Rainer and Ridker, Paul M and Ripatti, Samuli and Salomaa, Veikko and Samani, Nilesh J and Snieder, Harold and S{\o}rensen, Thorkild I A and Spector, Timothy D and Stefansson, Kari and T{\"o}njes, Anke and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and van der Harst, Pim and Vollenweider, Peter and Wallaschofski, Henri and Wareham, Nicholas J and Watkins, Hugh and Wichmann, H-Erich and Wilson, James F and Abecasis, Goncalo R and Assimes, Themistocles L and Barroso, In{\^e}s and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Frayling, Timothy and Groop, Leif C and Haritunian, Talin and Heid, Iris M and Hunter, David and Kaplan, Robert C and Karpe, Fredrik and Moffatt, Miriam F and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Pawitan, Yudi and Schadt, Eric E and Schlessinger, David and Steinthorsdottir, Valgerdur and Strachan, David P and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Visscher, Peter M and Di Blasio, Anna Maria and Hirschhorn, Joel N and Lindgren, Cecilia M and Morris, Andrew P and Meyre, David and Scherag, Andre and McCarthy, Mark I and Speliotes, Elizabeth K and North, Kari E and Loos, Ruth J F and Ingelsson, Erik} } @article {6549, title = {Common carotid intima-media thickness measurements do not improve cardiovascular risk prediction in individuals with elevated blood pressure: the USE-IMT collaboration.}, journal = {Hypertension}, volume = {63}, year = {2014}, month = {2014 Jun}, pages = {1173-81}, abstract = {

Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure >=140 mm Hg and a diastolic blood pressure >= 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4\%; 95\% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10\% to 20\%), the NRI was 5.6\% (95\% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.

}, keywords = {Adult, Aged, Antihypertensive Agents, Blood Pressure, Cardiovascular Diseases, Carotid Artery, Common, Carotid Intima-Media Thickness, Cohort Studies, Female, Humans, Hypertension, Male, Meta-Analysis as Topic, Middle Aged, Risk Assessment, Risk Factors}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.113.02683}, author = {Bots, Michiel L and Groenewegen, Karlijn A and Anderson, Todd J and Britton, Annie R and Dekker, Jacqueline M and Engstr{\"o}m, Gunnar and Evans, Greg W and de Graaf, Jacqueline and Grobbee, Diederick E and Hedblad, Bo and Hofman, Albert and Holewijn, Suzanne and Ikeda, Ai and Kavousi, Maryam and Kitagawa, Kazuo and Kitamura, Akihiko and Ikram, M Arfan and Lonn, Eva M and Lorenz, Matthias W and Mathiesen, Ellisiv B and Nijpels, Giel and Okazaki, Shuhei and O{\textquoteright}Leary, Daniel H and Polak, Joseph F and Price, Jacqueline F and Robertson, Christine and Rembold, Christopher M and Rosvall, Maria and Rundek, Tatjana and Salonen, Jukka T and Sitzer, Matthias and Stehouwer, Coen D A and Franco, Oscar H and Peters, Sanne A E and den Ruijter, Hester M} } @article {6582, title = {Genome-wide association analysis identifies six new loci associated with forced vital capacity.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Jul}, pages = {669-77}, abstract = {

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 {\texttimes} 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

}, keywords = {Cohort Studies, Databases, Genetic, Follow-Up Studies, Forced Expiratory Volume, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Lung Diseases, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Respiratory Function Tests, Spirometry, Vital Capacity}, issn = {1546-1718}, doi = {10.1038/ng.3011}, author = {Loth, Daan W and Soler Artigas, Maria and Gharib, Sina A and Wain, Louise V and Franceschini, Nora and Koch, Beate and Pottinger, Tess D and Smith, Albert Vernon and Duan, Qing and Oldmeadow, Chris and Lee, Mi Kyeong and Strachan, David P and James, Alan L and Huffman, Jennifer E and Vitart, Veronique and Ramasamy, Adaikalavan and Wareham, Nicholas J and Kaprio, Jaakko and Wang, Xin-Qun and Trochet, Holly and K{\"a}h{\"o}nen, Mika and Flexeder, Claudia and Albrecht, Eva and Lopez, Lorna M and de Jong, Kim and Thyagarajan, Bharat and Alves, Alexessander Couto and Enroth, Stefan and Omenaas, Ernst and Joshi, Peter K and Fall, Tove and Vi{\~n}uela, Ana and Launer, Lenore J and Loehr, Laura R and Fornage, Myriam and Li, Guo and Wilk, Jemma B and Tang, Wenbo and Manichaikul, Ani and Lahousse, Lies and Harris, Tamara B and North, Kari E and Rudnicka, Alicja R and Hui, Jennie and Gu, Xiangjun and Lumley, Thomas and Wright, Alan F and Hastie, Nicholas D and Campbell, Susan and Kumar, Rajesh and Pin, Isabelle and Scott, Robert A and Pietil{\"a}inen, Kirsi H and Surakka, Ida and Liu, Yongmei and Holliday, Elizabeth G and Schulz, Holger and Heinrich, Joachim and Davies, Gail and Vonk, Judith M and Wojczynski, Mary and Pouta, Anneli and Johansson, Asa and Wild, Sarah H and Ingelsson, Erik and Rivadeneira, Fernando and V{\"o}lzke, Henry and Hysi, Pirro G and Eiriksdottir, Gudny and Morrison, Alanna C and Rotter, Jerome I and Gao, Wei and Postma, Dirkje S and White, Wendy B and Rich, Stephen S and Hofman, Albert and Aspelund, Thor and Couper, David and Smith, Lewis J and Psaty, Bruce M and Lohman, Kurt and Burchard, Esteban G and Uitterlinden, Andr{\'e} G and Garcia, Melissa and Joubert, Bonnie R and McArdle, Wendy L and Musk, A Bill and Hansel, Nadia and Heckbert, Susan R and Zgaga, Lina and van Meurs, Joyce B J and Navarro, Pau and Rudan, Igor and Oh, Yeon-Mok and Redline, Susan and Jarvis, Deborah L and Zhao, Jing Hua and Rantanen, Taina and O{\textquoteright}Connor, George T and Ripatti, Samuli and Scott, Rodney J and Karrasch, Stefan and Grallert, Harald and Gaddis, Nathan C and Starr, John M and Wijmenga, Cisca and Minster, Ryan L and Lederer, David J and Pekkanen, Juha and Gyllensten, Ulf and Campbell, Harry and Morris, Andrew P and Gl{\"a}ser, Sven and Hammond, Christopher J and Burkart, Kristin M and Beilby, John and Kritchevsky, Stephen B and Gudnason, Vilmundur and Hancock, Dana B and Williams, O Dale and Polasek, Ozren and Zemunik, Tatijana and Kolcic, Ivana and Petrini, Marcy F and Wjst, Matthias and Kim, Woo Jin and Porteous, David J and Scotland, Generation and Smith, Blair H and Viljanen, Anne and Heli{\"o}vaara, Markku and Attia, John R and Sayers, Ian and Hampel, Regina and Gieger, Christian and Deary, Ian J and Boezen, H Marike and Newman, Anne and Jarvelin, Marjo-Riitta and Wilson, James F and Lind, Lars and Stricker, Bruno H and Teumer, Alexander and Spector, Timothy D and Mel{\'e}n, Erik and Peters, Marjolein J and Lange, Leslie A and Barr, R Graham and Bracke, Ken R and Verhamme, Fien M and Sung, Joohon and Hiemstra, Pieter S and Cassano, Patricia A and Sood, Akshay and Hayward, Caroline and Dupuis, Jos{\'e}e and Hall, Ian P and Brusselle, Guy G and Tobin, Martin D and London, Stephanie J} } @article {6558, title = {Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans.}, journal = {Hum Genet}, volume = {133}, year = {2014}, month = {2014 Aug}, pages = {985-95}, abstract = {

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{\textquoteright}s Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 {\texttimes} 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 {\texttimes} 10(-6); CRP, p = 4.2 {\texttimes} 10(-71); APOE, p = 1.6 {\texttimes} 10(-6)). The fourth significant locus, CD36 (p = 1.6 {\texttimes} 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 {\texttimes} 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 {\texttimes} 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 {\texttimes} 10(-6); CD36, p = 1.4 {\texttimes} 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.

}, keywords = {Adult, African Americans, Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, CD36 Antigens, Female, Genetic Loci, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1432-1203}, doi = {10.1007/s00439-014-1439-z}, author = {Ellis, Jaclyn and Lange, Ethan M and Li, Jin and Dupuis, Jos{\'e}e and Baumert, Jens and Walston, Jeremy D and Keating, Brendan J and Durda, Peter and Fox, Ervin R and Palmer, Cameron D and Meng, Yan A and Young, Taylor and Farlow, Deborah N and Schnabel, Renate B and Marzi, Carola S and Larkin, Emma and Martin, Lisa W and Bis, Joshua C and Auer, Paul and Ramachandran, Vasan S and Gabriel, Stacey B and Willis, Monte S and Pankow, James S and Papanicolaou, George J and Rotter, Jerome I and Ballantyne, Christie M and Gross, Myron D and Lettre, Guillaume and Wilson, James G and Peters, Ulrike and Koenig, Wolfgang and Tracy, Russell P and Redline, Susan and Reiner, Alex P and Benjamin, Emelia J and Lange, Leslie A} } @article {6296, title = {A robust method for genome-wide association meta-analysis with the application to circulating insulin-like growth factor I concentrations.}, journal = {Genet Epidemiol}, volume = {38}, year = {2014}, month = {2014 Feb}, pages = {162-71}, abstract = {

Genome-wide association studies (GWAS) offer an excellent opportunity to identify the genetic variants underlying complex human diseases. Successful utilization of this approach requires a large sample size to identify single nucleotide polymorphisms (SNPs) with subtle effects. Meta-analysis is a cost-efficient means to achieve large sample size by combining data from multiple independent GWAS; however, results from studies performed on different populations can be variable due to various reasons, including varied linkage equilibrium structures as well as gene-gene and gene-environment interactions. Nevertheless, one should expect effects of the SNP are more similar between similar populations than those between populations with quite different genetic and environmental backgrounds. Prior information on populations of GWAS is often not considered in current meta-analysis methods, rendering such analyses less optimal for the detecting association. This article describes a test that improves meta-analysis to incorporate variable heterogeneity among populations. The proposed method is remarkably simple in computation and hence can be performed in a rapid fashion in the setting of GWAS. Simulation results demonstrate the validity and higher power of the proposed method over conventional methods in the presence of heterogeneity. As a demonstration, we applied the test to real GWAS data to identify SNPs associated with circulating insulin-like growth factor I concentrations.

}, keywords = {Computer Simulation, Genetic Linkage, Genome, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor I, Meta-Analysis as Topic, Models, Genetic, Polymorphism, Single Nucleotide, Sample Size}, issn = {1098-2272}, doi = {10.1002/gepi.21766}, author = {Wang, Tao and Zhou, Baiyu and Guo, Tingwei and Bidlingmaier, Martin and Wallaschofski, Henri and Teumer, Alexander and Vasan, Ramachandran S and Kaplan, Robert C} } @article {6602, title = {Generalized estimating equations for genome-wide association studies using longitudinal phenotype data.}, journal = {Stat Med}, volume = {34}, year = {2015}, month = {2015 Jan 15}, pages = {118-30}, abstract = {

Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.

}, keywords = {Aged, Aging, Cardiovascular Diseases, Cohort Studies, Computer Simulation, Cross-Sectional Studies, Epidemiologic Research Design, Gene-Environment Interaction, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Longitudinal Studies, Meta-Analysis as Topic, Models, Genetic, Pharmacogenetics, Risk Assessment, United States}, issn = {1097-0258}, doi = {10.1002/sim.6323}, author = {Sitlani, Colleen M and Rice, Kenneth M and Lumley, Thomas and McKnight, Barbara and Cupples, L Adrienne and Avery, Christy L and Noordam, Raymond and Stricker, Bruno H C and Whitsel, Eric A and Psaty, Bruce M} } @article {6688, title = {Genetic overlap between diagnostic subtypes of ischemic stroke.}, journal = {Stroke}, volume = {46}, year = {2015}, month = {2015 Mar}, pages = {615-9}, abstract = {

BACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.

METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.

RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9{\texttimes}10(-4)) and profile scores (rg=0.72; 95\% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1{\texttimes}10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.

CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

}, keywords = {Alleles, Atherosclerosis, Cerebral Small Vessel Diseases, Cohort Studies, Data Interpretation, Statistical, Embolism, Genome-Wide Association Study, Genotype, Humans, Ischemia, Linear Models, Meta-Analysis as Topic, Phenotype, Polymorphism, Single Nucleotide, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.114.007930}, author = {Holliday, Elizabeth G and Traylor, Matthew and Malik, Rainer and Bevan, Steve and Falcone, Guido and Hopewell, Jemma C and Cheng, Yu-Ching and Cotlarciuc, Ioana and Bis, Joshua C and Boerwinkle, Eric and Boncoraglio, Giorgio B and Clarke, Robert and Cole, John W and Fornage, Myriam and Furie, Karen L and Ikram, M Arfan and Jannes, Jim and Kittner, Steven J and Lincz, Lisa F and Maguire, Jane M and Meschia, James F and Mosley, Thomas H and Nalls, Mike A and Oldmeadow, Christopher and Parati, Eugenio A and Psaty, Bruce M and Rothwell, Peter M and Seshadri, Sudha and Scott, Rodney J and Sharma, Pankaj and Sudlow, Cathie and Wiggins, Kerri L and Worrall, Bradford B and Rosand, Jonathan and Mitchell, Braxton D and Dichgans, Martin and Markus, Hugh S and Levi, Christopher and Attia, John and Wray, Naomi R} } @article {6683, title = {Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.}, journal = {Circ Cardiovasc Genet}, volume = {8}, year = {2015}, month = {2015 Apr}, pages = {398-409}, abstract = {

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7{\texttimes}10(-19)) and identified novel loci on chr10q24 (P=1.6{\texttimes}10(-9)) and chr2p21 (P=4.4{\texttimes}10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0{\texttimes}10(-8)) and chr2p16 (P=1.5{\texttimes}10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

}, keywords = {Aged, Aged, 80 and over, Chromosomes, Human, Continental Population Groups, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Models, Genetic, Stroke, White Matter}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.114.000858}, author = {Verhaaren, Benjamin F J and Debette, Stephanie and Bis, Joshua C and Smith, Jennifer A and Ikram, M Kamran and Adams, Hieab H and Beecham, Ashley H and Rajan, Kumar B and Lopez, Lorna M and Barral, Sandra and van Buchem, Mark A and van der Grond, Jeroen and Smith, Albert V and Hegenscheid, Katrin and Aggarwal, Neelum T and de Andrade, Mariza and Atkinson, Elizabeth J and Beekman, Marian and Beiser, Alexa S and Blanton, Susan H and Boerwinkle, Eric and Brickman, Adam M and Bryan, R Nick and Chauhan, Ganesh and Chen, Christopher P L H and Chouraki, Vincent and de Craen, Anton J M and Crivello, Fabrice and Deary, Ian J and Deelen, Joris and De Jager, Philip L and Dufouil, Carole and Elkind, Mitchell S V and Evans, Denis A and Freudenberger, Paul and Gottesman, Rebecca F and Gu{\dh}nason, Vilmundur and Habes, Mohamad and Heckbert, Susan R and Heiss, Gerardo and Hilal, Saima and Hofer, Edith and Hofman, Albert and Ibrahim-Verbaas, Carla A and Knopman, David S and Lewis, Cora E and Liao, Jiemin and Liewald, David C M and Luciano, Michelle and van der Lugt, Aad and Martinez, Oliver O and Mayeux, Richard and Mazoyer, Bernard and Nalls, Mike and Nauck, Matthias and Niessen, Wiro J and Oostra, Ben A and Psaty, Bruce M and Rice, Kenneth M and Rotter, Jerome I and von Sarnowski, Bettina and Schmidt, Helena and Schreiner, Pamela J and Schuur, Maaike and Sidney, Stephen S and Sigurdsson, Sigurdur and Slagboom, P Eline and Stott, David J M and van Swieten, John C and Teumer, Alexander and T{\"o}glhofer, Anna Maria and Traylor, Matthew and Trompet, Stella and Turner, Stephen T and Tzourio, Christophe and Uh, Hae-Won and Uitterlinden, Andr{\'e} G and Vernooij, Meike W and Wang, Jing J and Wong, Tien Y and Wardlaw, Joanna M and Windham, B Gwen and Wittfeld, Katharina and Wolf, Christiane and Wright, Clinton B and Yang, Qiong and Zhao, Wei and Zijdenbos, Alex and Jukema, J Wouter and Sacco, Ralph L and Kardia, Sharon L R and Amouyel, Philippe and Mosley, Thomas H and Longstreth, W T and DeCarli, Charles C and van Duijn, Cornelia M and Schmidt, Reinhold and Launer, Lenore J and Grabe, Hans J and Seshadri, Sudha S and Ikram, M Arfan and Fornage, Myriam} } @article {7928, title = {Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 10 12}, pages = {4228}, abstract = {

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among <=19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 {\texttimes} 10) and SLC2A9 (p = 4.5 {\texttimes} 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 {\texttimes} 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

}, keywords = {Exome, Genetic Predisposition to Disease, Glucose Transport Proteins, Facilitative, Humans, Kidney Function Tests, Meta-Analysis as Topic, Organic Anion Transporters, Organic Cation Transport Proteins, Protein Structure, Secondary, Uric Acid}, issn = {2041-1723}, doi = {10.1038/s41467-018-06620-4}, author = {Tin, Adrienne and Li, Yong and Brody, Jennifer A and Nutile, Teresa and Chu, Audrey Y and Huffman, Jennifer E and Yang, Qiong and Chen, Ming-Huei and Robinson-Cohen, Cassianne and Mace, Aurelien and Liu, Jun and Demirkan, Ayse and Sorice, Rossella and Sedaghat, Sanaz and Swen, Melody and Yu, Bing and Ghasemi, Sahar and Teumer, Alexanda and Vollenweider, Peter and Ciullo, Marina and Li, Meng and Uitterlinden, Andr{\'e} G and Kraaij, Robert and Amin, Najaf and van Rooij, Jeroen and Kutalik, Zolt{\'a}n and Dehghan, Abbas and McKnight, Barbara and van Duijn, Cornelia M and Morrison, Alanna and Psaty, Bruce M and Boerwinkle, Eric and Fox, Caroline S and Woodward, Owen M and K{\"o}ttgen, Anna} }