Publications
403 results found
Chasman DI, Fuchsberger C, Pattaro C, et al., 2012, Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function, HUMAN MOLECULAR GENETICS, Vol: 21, Pages: 5329-5343, ISSN: 0964-6906
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- Citations: 56
Huang J, Sabater-Lleal M, Asselbergs FW, et al., 2012, Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation, BLOOD, Vol: 120, Pages: 4873-4881, ISSN: 0006-4971
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- Citations: 72
Franceschini N, van Rooij FJA, Prins BP, et al., 2012, Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 744-753, ISSN: 0002-9297
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- Citations: 58
Kaptoge S, Di Angelantonio E, Pennells L, et al., 2012, C-Reactive Protein, Fibrinogen, and Cardiovascular Disease Prediction, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 367, Pages: 1310-1320, ISSN: 0028-4793
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- Citations: 786
Okada Y, Sim X, Go MJ, et al., 2012, Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations, NATURE GENETICS, Vol: 44, Pages: 904-+, ISSN: 1061-4036
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- Citations: 220
Brautbar A, Pompeii LA, Dehghan A, et al., 2012, A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies, ATHEROSCLEROSIS, Vol: 223, Pages: 421-426, ISSN: 0021-9150
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- Citations: 58
Sarwar N, Butterworth AS, Freitag DF, et al., 2012, Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies, LANCET, Vol: 379, Pages: 1205-1213, ISSN: 0140-6736
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- Citations: 580
Dastani Z, Hivert M-F, Timpson N, et al., 2012, Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals, PLOS Genetics, Vol: 8, ISSN: 1553-7390
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inverselyassociated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wideassociation studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. Weidentified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.561028–1.2610243). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, andN = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samplesrevealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations afteraccounting for multiple testing (p,361024). We next developed a multi-SNP genotypic risk score to test the associationof adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This riskscore was associated with increased risk of T2D (p = 4.361023, n = 22,044), increased triglycerides (p = 2.6610214,n = 93,440), increased waist-to-hip ratio (p = 1.861025, n = 77,167), increased glucose two hours post oral glucosetolerance testing (p = 4.461023, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDLcholesterolconcentrations (p = 4.5610213, n = 96,748) and decreased BMI (p = 1.461024, n = 121,335). These findingsidentify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers ofinsulin resistance.
Pattaro C, Koettgen A, Teumer A, et al., 2012, Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function, PLOS GENETICS, Vol: 8, ISSN: 1553-7404
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- Citations: 144
Mitchell GF, Verwoert GC, Tarasov KV, et al., 2012, Common Genetic Variation in the 3′-<i>BCL11B</i> Gene Desert Is Associated With Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk The AortaGen Consortium, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 5, Pages: 81-90, ISSN: 1942-325X
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- Citations: 71
Murabito JM, White CC, Kavousi M, et al., 2012, Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 5, Pages: 100-112, ISSN: 1942-325X
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- Citations: 82
Palmer ND, McDonough CW, Hicks PJ, et al., 2012, A genome-wide association search for type 2 diabetes genes in African Americans., PLOS One, Vol: 7, ISSN: 1932-6203
African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
Grallert H, Dupuis J, Bis JC, et al., 2012, Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies, EUROPEAN HEART JOURNAL, Vol: 33, Pages: 238-251, ISSN: 0195-668X
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- Citations: 85
O'Donnell CJ, Kavousi M, Smith AV, et al., 2011, Genome-Wide Association Study for Coronary Artery Calcification With Follow-Up in Myocardial Infarction, CIRCULATION, Vol: 124, Pages: 2855-U255, ISSN: 0009-7322
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- Citations: 223
Herder C, Peeters W, Illig T, et al., 2011, RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies, PLOS ONE, Vol: 6, ISSN: 1932-6203
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- Citations: 38
Kiechl S, Pare G, Barbalic M, et al., 2011, Association of Variation at the <i>ABO</i> Locus With Circulating Levels of Soluble Intercellular Adhesion Molecule-1, Soluble P-selectin, and Soluble E-selectin A Meta-Analysis, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 4, Pages: 681-U436, ISSN: 1942-325X
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- Citations: 65
Leebeek FWG, Dehghan A, Kruip MJHA, et al., 2011, The presumed increased bleeding tendency in red-haired individuals is not associated with von Willebrand factor antigen levels in older individuals, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 9, Pages: 2509-2511, ISSN: 1538-7933
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- Citations: 1
Bown MJ, Jones GT, Harrison SC, et al., 2011, Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 89, Pages: 619-627, ISSN: 0002-9297
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- Citations: 141
Chambers JC, Zhang W, Sehmi J, et al., 2011, Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma, NATURE GENETICS, Vol: 43, Pages: 1131-1138, ISSN: 1061-4036
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- Citations: 409
Ehret GB, Munroe PB, Rice KM, et al., 2011, Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk, NATURE, Vol: 478, Pages: 103-109, ISSN: 0028-0836
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- Citations: 1509
Strawbridge RJ, Dupuis J, Prokopenko I, et al., 2011, Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes, Diabetes, Vol: 60, Pages: 2624-2634, ISSN: 0012-1797
OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
Bis JC, Kavousi M, Franceschini N, et al., 2011, Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque, NATURE GENETICS, Vol: 43, Pages: 940-U40, ISSN: 1061-4036
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- Citations: 162
Wain LV, Verwoert GC, O'Reilly PF, et al., 2011, Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure, NATURE GENETICS, Vol: 43, Pages: 1005-U122, ISSN: 1061-4036
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans1,2,3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10−8 to P = 2.3 × 10−13) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Butterworth AS, Braund PS, Farrall M, et al., 2011, Large-scale gene-centric analysis identifies novel variants for coronary Artery disease, PLoS Genetics, Vol: 7, ISSN: 1553-7390
Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10−33; LPA:p<10−19; 1p13.3:p<10−17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10−7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse bioc
Boeger CA, Gorski M, Li M, et al., 2011, Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD, PLOS GENETICS, Vol: 7, ISSN: 1553-7404
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- Citations: 153
Ricketts SL, Rensing KL, Holly JM, et al., 2011, Prospective study of insulin-like growth factor-I, insulinlike growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease, International Journal of Molecular Epidemiology and Genetics, Vol: 2, Pages: 261-285
Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% CI 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% CI 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.
Smith NL, Rice KM, Bovill EG, et al., 2011, Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis, BLOOD, Vol: 117, Pages: 6007-6011, ISSN: 0006-4971
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- Citations: 84
Arking DE, Junttila MJ, Goyette P, et al., 2011, Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals, PLOS GENETICS, Vol: 7, ISSN: 1553-7390
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- Citations: 98
van Hoek M, van Herpt TW, Dehghan A, et al., 2011, Association of an APOC3 promoter variant with type 2 diabetes risk and need for insulin treatment in lean persons, DIABETOLOGIA, Vol: 54, Pages: 1360-1367, ISSN: 0012-186X
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- Citations: 17
Nalls MA, Couper DJ, Tanaka T, et al., 2011, Multiple Loci Are Associated with White Blood Cell Phenotypes, PLOS GENETICS, Vol: 7, ISSN: 1553-7390
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- Citations: 82
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