Publications
145 results found
Gieger C, Radhakrishnan A, Cvejic A, et al., 2011, New gene functions in megakaryopoiesis and platelet formation, NATURE, Vol: 480, Pages: 201-208, ISSN: 0028-0836
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- Citations: 310
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
Kooner JS, Saleheen D, Sim X, et al., 2011, Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci, NATURE GENETICS, Vol: 43, Pages: 984-U94, ISSN: 1061-4036
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- Citations: 398
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
Kilpelainen TO, Zillikens MC, Stancakova A, et al., 2011, Genetic variation near <i>IRS1</i> associates with reduced adiposity and an impaired metabolic profile, NATURE GENETICS, Vol: 43, Pages: 753-U58, ISSN: 1061-4036
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- Citations: 229
Schumann G, Coin LJ, Lourdusamy A, et al., 2011, Genome-wide association and genetic functional studies identify <i>autism susceptibility candidate 2</i> gene (AUTS2) in the regulation of alcohol consumption (vol 108, pg 7119, 2011), PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 9316-9316, ISSN: 0027-8424
Schumann G, Coin LJ, Lourdusamy A, et al., 2011, Genome-wide association and genetic functional studies identify <i>autism susceptibility candidate 2</i> gene (<i>AUTS2</i>) in the regulation of alcohol consumption, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 7119-7124, ISSN: 0027-8424
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- Citations: 208
Peden JF, Hopewell JC, Saleheen D, et al., 2011, A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease, NATURE GENETICS, Vol: 43, Pages: 339-U89, ISSN: 1061-4036
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- Citations: 532
Waterworth DM, Ricketts SL, Song K, et al., 2010, Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 30, Pages: 2264-U566, ISSN: 1079-5642
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- Citations: 319
Teslovich TM, Musunuru K, Smith AV, et al., 2010, Biological, clinical and population relevance of 95 loci for blood lipids, Nature, Vol: 466, Pages: 707-713, ISSN: 0028-0836
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10−8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Kapur K, Johnson T, Beckmann ND, et al., 2010, Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor (CASR) Gene, PLOS Genetics, Vol: 6, ISSN: 1553-7390
Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disordersof bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wideassociation study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individualsof European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near thecalcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3610-37 is rs1801725, a missense variant,explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of Europeandescent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1610-21), a SNP in strong linkagedisequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of4,126 individuals (p = 1.02610-4). This genome-wide meta-analysis shows that common CASR variants modulate serumcalcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASRlocus. This study highlights the key role of CASR in calcium regulation.
Chambers JC, Zhang W, Lord GM, et al., 2010, Genetic loci influencing kidney function and chronic kidney disease, NATURE GENETICS, Vol: 42, Pages: 373-375, ISSN: 1061-4036
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- Citations: 215
Pillas D, Hoggart CJ, Evans DM, et al., 2010, Genome-Wide Association Study Reveals Multiple Loci Associated with Primary Tooth Development during Infancy, PLOS Genetics, Vol: 6, ISSN: 1553-7390
Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.
Chambers JC, Zhao J, Terracciano CMN, et al., 2010, Genetic variation in <i>SCN10A</i> influences cardiac conduction, NATURE GENETICS, Vol: 42, Pages: 149-U80, ISSN: 1061-4036
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- Citations: 204
Chambers J, Zhao J, Terracciano C, et al., 2009, Genetic Variation in SCN10a is Associated With Cardiac Conduction, Heart Block and Risk of Ventricular Fibrillation, 82nd Scientific Session of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S579-S580, ISSN: 0009-7322
Chambers JC, Zhang W, Zabaneh D, et al., 2009, Common genetic variation near melatonin receptor mtnr1b contributes to raised plasma glucose and increased risk of type 2 diabetes among Indian Asians and European Caucasians, Diabetes, Vol: 58, Pages: 2703-2708, ISSN: 0012-1797
OBJECTIVE Fasting plasma glucose and risk of type 2 diabetes are higher among Indian Asians than among European and North American Caucasians. Few studies have investigated genetic factors influencing glucose metabolism among Indian Asians.RESEARCH DESIGN AND METHODS We carried out genome-wide association studies for fasting glucose in 5,089 nondiabetic Indian Asians genotyped with the Illumina Hap610 BeadChip and 2,385 Indian Asians (698 with type 2 diabetes) genotyped with the Illumina 300 BeadChip. Results were compared with findings in 4,462 European Caucasians.RESULTS We identified three single nucleotide polymorphisms (SNPs) associated with glucose among Indian Asians at P < 5 × 10−8, all near melatonin receptor MTNR1B. The most closely associated was rs2166706 (combined P = 2.1 × 10−9), which is in moderate linkage disequilibrium with rs1387153 (r2 = 0.60) and rs10830963 (r2 = 0.45), both previously associated with glucose in European Caucasians. Risk allele frequency and effect sizes for rs2166706 were similar among Indian Asians and European Caucasians: frequency 46.2 versus 45.0%, respectively (P = 0.44); effect 0.05 (95% CI 0.01–0.08) versus 0.05 (0.03–0.07 mmol/l), respectively, higher glucose per allele copy (P = 0.84). SNP rs2166706 was associated with type 2 diabetes in Indian Asians (odds ratio 1.21 [95% CI 1.06–1.38] per copy of risk allele; P = 0.006). SNPs at the GCK, GCKR, and G6PC2 loci were also associated with glucose among Indian Asians. Risk allele frequencies of rs1260326 (GCKR) and rs560887 (G6PC2) were higher among Indian Asians compared with European Caucasians.CONCLUSIONS Common genetic variation near MTNR1B influences blood glucose and risk of type 2 diabetes in Indian Asians. Genetic variation at the MTNR1B, GCK, GCKR, and G6PC2 loci may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians.
Chambers JC, Zhang W, Li Y, et al., 2009, Genome-wide association study identifies variants in <i>TMPRSS6</i> associated with hemoglobin levels, NATURE GENETICS, Vol: 41, Pages: 1170-1172, ISSN: 1061-4036
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- Citations: 188
Elliott P, Chambers JC, Zhang W, et al., 2009, Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease, JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, Vol: 302, Pages: 37-48, ISSN: 0098-7484
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- Citations: 485
Lindgren CM, Heid IM, Randall JC, et al., 2009, Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution, PLOS GENETICS, Vol: 5, ISSN: 1553-7404
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- Citations: 406
Chambers J, Elliott P, Zhang W, et al., 2008, Contribution Of Known Genetic Factors To Increased Risk Of Type-2 Diabetes In Indian Asians, 81st Annual Scientific Session of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S1117-S1117, ISSN: 0009-7322
Chambers J, Elliott P, Zhang W, et al., 2008, Do Known Genetic Factors Contribute to the Increased Risk of Cardiovascular Disease Amongst Indian Asians?, 81st Annual Scientific Session of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S1101-S1101, ISSN: 0009-7322
Yuan X, Waterworth D, Perry JRB, et al., 2008, Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 83, Pages: 520-528, ISSN: 0002-9297
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- Citations: 336
Chambers JC, Elliott P, Zabaneh D, et al., 2008, Common genetic variation near <i>MC4R</i> is associated with waist circumference and insulin resistance, NATURE GENETICS, Vol: 40, Pages: 716-718, ISSN: 1061-4036
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- Citations: 382
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