Publications
887 results found
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
Garcia-Perez I, Villaseñor A, Wijeyesekera A, et al., 2012, Urinary metabolic phenotyping the slc26a6 (chloride-oxalate exchanger) null mouse model, Journal of Proteome Research, Vol: 11, Pages: 4425-4435, ISSN: 1535-3893
The prevalence of renal stone disease is increasing, although it remains higher in men than in women when matched for age. While still somewhat controversial, several studies have reported an association between renal stone disease and hypertension, but this may be confounded by a shared link with obesity. However, independent of obesity, hyperoxaluria has been shown to be associated with hypertension in stone-formers and the most common type of renal stone is composed of calcium oxalate. The chloride-oxalate exchanger slc26a6 (also known as CFEX or PAT-1), located in the renal proximal tubule, was originally thought to have an important role in sodium homeostasis and thereby blood pressure control, but it has recently been shown to have a key function in oxalate balance by mediating oxalate secretion in the gut. We have applied two orthogonal analytical platforms (NMR spectroscopy and capillary-electrophoresis with UV detection) in parallel to characterize the urinary metabolic signatures related to the loss of the renal chloride-oxalate exchanger in slc26a6 null mice. Clear metabolic differentiation between the urinary profiles of the slc26a6 null and the wild type mice were observed using both methods, with the combination of NMR and CE-UV providing extensive coverage of the urinary metabolome. Key discriminating metabolites included oxalate, m-hydroxyphenylpropionylsulfate (m-HPPS), trimethylamine-N-oxide, glycolate and scyllo-inositol (higher in CFEX null mice) and hippurate, taurine, trimethylamine, and citrate (lower in slc26a6 null mice). In addition to the reduced efficiency of anion transport, several of these metabolites (hippurate, m-HPPS, methylamines) reflect alteration in gut microbial co-metabolic activities. Gender-related metabotypes were also observed in both wild type and slc26a6 null groups. Other urinary chemicals that showed a gender-specific pattern included trimethylamine, trimethylamine-N-oxide, citrate, spermidine, guanidinoacetate, and 2-
Fox CS, Liu Y, White CC, et al., 2012, Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women., PLOS Genetics, Vol: 8, ISSN: 1553-7390
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat reveale
O'Reilly PF, Hoggart CJ, Pomyen Y, et al., 2012, MultiPhen: Joint Model of Multiple Phenotypes Can Increase Discovery in GWAS, PLOS One, Vol: 7, ISSN: 1932-6203
The genome-wide association study (GWAS) approach has discovered hundreds of genetic variants associated with diseasesand quantitative traits. However, despite clinical overlap and statistical correlation between many phenotypes, GWAS aregenerally performed one-phenotype-at-a-time. Here we compare the performance of modelling multiple phenotypes jointlywith that of the standard univariate approach. We introduce a new method and software, MultiPhen, that models multiplephenotypes simultaneously in a fast and interpretable way. By performing ordinal regression, MultiPhen tests the linearcombination of phenotypes most associated with the genotypes at each SNP, and thus potentially captures effects hiddento single phenotype GWAS. We demonstrate via simulation that this approach provides a dramatic increase in power inmany scenarios. There is a boost in power for variants that affect multiple phenotypes and for those that affect only onephenotype. While other multivariate methods have similar power gains, we describe several benefits of MultiPhen overthese. In particular, we demonstrate that other multivariate methods that assume the genotypes are normally distributed,such as canonical correlation analysis (CCA) and MANOVA, can have highly inflated type-1 error rates when testing casecontrolor non-normal continuous phenotypes, while MultiPhen produces no such inflation. To test the performance ofMultiPhen on real data we applied it to lipid traits in the Northern Finland Birth Cohort 1966 (NFBC1966). In these dataMultiPhen discovers 21% more independent SNPs with known associations than the standard univariate GWAS approach,while applying MultiPhen in addition to the standard approach provides 37% increased discovery. The most associatedlinear combinations of the lipids estimated by MultiPhen at the leading SNPs accurately reflect the Friedewald Formula,suggesting that MultiPhen could be used to refine the definition of existing phenotypes or uncover novel heritablepheno
Ikram MA, Fornage M, Smith AV, et al., 2012, Common variants at 6q22 and 17q21 are associated with intracranial volume, NATURE GENETICS, Vol: 44, Pages: 539-+, ISSN: 1061-4036
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- Citations: 105
, 2012, A genome-wide association meta-analysis identifies new childhood obesity loci, Nat Genet, Vol: 44, Pages: 526-531, ISSN: 1061-4036
Chambers JC, Tan ST, Zhang WH, et al., 2012, WHOLE GENOME SEQUENCING TO IDENTIFY GENETIC VARIANTS UNDERLYING CARDIOVASCULAR DISEASE AMONG INDIAN ASIANS, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: B M J PUBLISHING GROUP, Pages: A64-A64, ISSN: 1355-6037
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- Citations: 2
Tan ST, Sehmi J, Al-Hussaini A, et al., 2012, NUCLEAR MAGNETIC RESONANCE PROFILING OF SERUM IDENTIFIES NOVEL BIOMARKER ASSOCIATED WITH CORONARY ATHEROSCLEROSIS, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: B M J PUBLISHING GROUP, Pages: A83-A83, ISSN: 1355-6037
Taal HR, St Pourcain B, Thiering E, et al., 2012, Common variants at 12q15 and 12q24 are associated with infant head circumference, Nat Genet, Vol: 44, Pages: 532-538, ISSN: 1061-4036
Repacholi MH, Lerchl A, Roosli M, et al., 2012, Systematic review of wireless phone use and brain cancer and other head tumors, BIOELECTROMAGNETICS, Vol: 33, Pages: 187-206, ISSN: 0197-8462
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- Citations: 61
Khan SA, Emadossadaty S, Ladep NG, et al., 2012, Rising trends in cholangiocarcinoma: Is the ICD classification system misleading us?, JOURNAL OF HEPATOLOGY, Vol: 56, Pages: 848-854, ISSN: 0168-8278
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- Citations: 213
Ichimura A, Hirasawa A, Poulain-Godefroy O, et al., 2012, Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human, NATURE, Vol: 483, Pages: 350-U149, ISSN: 0028-0836
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- Citations: 498
Froguel P, Ndiaye NC, Bonnefond A, et al., 2012, A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels, PLOS One, Vol: 7, ISSN: 1932-6203
Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes toaid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobinlevels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases,including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acutemyocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulatinghaptoglobin levels has not been conducted so far. We used a genome-wide association study initially conducted in 631French children followed by a replication in three additional European sample sets and we identified a common singlenucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulatingHaptoglobin levels (Poverall = 8.1610259), explaining 45.4% of its genetic variability (11.8% of Hp global variance). Thefunctional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (b = 0.2360.08,P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789European children (Ptotal cholesterol = 0.002 and PLDL = 0.0008). Given the central position of haptoglobin in manyinflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobinconcentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.
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.
Loo RL, Chan Q, Brown IJ, et al., 2012, A Comparison of Self-Reported Analgesic Use and Detection of Urinary Ibuprofen and Acetaminophen Metabolites by Means of Metabonomics The INTERMAP Study, AMERICAN JOURNAL OF EPIDEMIOLOGY, Vol: 175, Pages: 348-358, ISSN: 0002-9262
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- Citations: 27
Creemers JWM, Choquet H, Stijnen P, et al., 2012, Heterozygous Mutations Causing Partial Prohormone Convertase 1 Deficiency Contribute to Human Obesity, Diabetes, Vol: 61, Pages: 383-390, ISSN: 0012-1797
Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.
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
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.
Wijeyesekera A, Clarke PA, Bictash M, et al., 2012, Quantitative UPLC-MS/MS analysis of the gut microbial co-metabolites phenylacetylglutamine, 4-cresyl sulphate and hippurate in human urine: INTERMAP Study, ANALYTICAL METHODS, Vol: 4, Pages: 65-72, ISSN: 1759-9660
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- Citations: 28
Ward H, Toledano MB, Shaddick G, et al., 2012, Oxford Handbook of Epidemiology for Clinicians, Oxford Handbook of Epidemiology for Clinicians, Editors: Ward, Toledano, Shaddick, Davies, Elliott, Oxford UK, Publisher: Oxford University Press, Pages: 1-388, ISBN: 978-0-19-852988-0
Ward H, Toledano MB, Shaddick G, et al., 2012, Oxford Handbook of Epidemiology for Clinicians 978-0-19-852988-0, Oxford UK, Publisher: Oxford University Press, ISBN: 978-0-19-852988-0
Johnson T, Gaunt TR, Newhouse SJ, et al., 2011, Blood Pressure Loci Identified with a Gene-Centric Array, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 89, Pages: 688-700, ISSN: 0002-9297
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- Citations: 130
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
Pitcher A, Ashby D, Elliott P, et al., 2011, Cardiac MRI as end point in clinical trials reply, HEART, Vol: 97, Pages: 1991-1991, ISSN: 1355-6037
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
Heid IM, Jackson AU, Randall JC, et al., 2011, Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution, NATURE GENETICS, Vol: 43, Pages: 1164-1164, ISSN: 1061-4036
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- Citations: 9
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.
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
Soler Artigas M, Loth DW, Wain LV, et al., 2011, Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function, NATURE GENETICS, Vol: 43, Pages: 1082-1090, ISSN: 1061-4036
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