Publications
887 results found
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
Heid IM, Jackson AU, Randall JC, et al., 2010, 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: 42, Pages: 949-U160, ISSN: 1061-4036
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- Citations: 690
Ikram MK, Sim X, Jensen RA, et al., 2010, Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo., PLOS Genetics, Vol: 6, ISSN: 1553-7390
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<5.0×10(-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 = 1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-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 dis
Allen HL, Estrada K, Lettre G, et al., 2010, Hundreds of variants clustered in genomic loci and biological pathways affect human height, Nature, Vol: 467, Pages: 832-838, ISSN: 0028-0836
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2, 3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate th
Speliotes EK, Willer CJ, Berndt SI, et al., 2010, Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index, Nature Genetics, Vol: 42, Pages: 937-948, ISSN: 1546-1718
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-)(8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Bouatia-Naji N, Bonnefond A, Baerenwald DA, et al., 2010, Genetic and functional assessment of the role of the rs13431652-A and rs573225-A alleles in the G6PC2 promoter that are strongly associated with elevated fasting glucose levels, Diabetes, Vol: 59, Pages: 2662-2671, ISSN: 0012-1797
OBJECTIVE Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal.RESEARCH DESIGN AND METHODS We genotyped 9,532 normal FPG participants (FPG <6.1 mmol/l) for three G6PC2 SNPs, rs13431652 (distal promoter), rs573225 (proximal promoter), rs560887 (3rd intron). We used regression analyses adjusted for age, sex, and BMI to assess the association with FPG and haplotype analyses to assess comparative SNP contributions. Fusion gene and gel retardation analyses characterized the effect of rs13431652 and rs573225 on G6PC2 promoter activity and transcription factor binding.RESULTS Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: β = 0.075, P = 3.6 × 10−35; rs573225 β = 0.073 P = 3.6 × 10−34), in addition to rs560887 (β = 0.071, P = 1.2 × 10−31). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is associated with increased FPG and elevated promoter activity, consistent with the function of G6PC2 in pancreatic islets. In contrast, the rs573225-A allele is associated with elevated FPG but reduced promoter activity.CONCLUSIONS Genetic and in situ functional data support a potential role for rs13431652, but not rs573225, as a causative SNP linking G6PC2 to variations in FPG, though a causative role for rs573225 in vivo cannot be ruled out.
Kaakinen M, Laara E, Pouta A, et al., 2010, Life-Course Analysis of a Fat Mass and Obesity-Associated (FTO) Gene Variant and Body Mass Index in the Northern Finland Birth Cohort 1966 Using Structural Equation Modeling, American Journal of Epidemiology, Vol: 172, Pages: 653-665, ISSN: 1476-6256
The association between variation in the fat mass and obesity-associated (FTO) gene and adulthood body massindex (BMI; weight (kg)/height (m)2) is well-replicated. More thorough analyses utilizing phenotypic data over thelife course may deepen our understanding of the development of BMI and thus help in the prevention of obesity.The authors used a structural equation modeling approach to explore the network of variables associated with BMIfrom the prenatal period to age 31 years (1965–1997) in 4,435 subjects from the Northern Finland Birth Cohort1966. The use of structural equation modeling permitted the easy inclusion of variables with missing values in theanalyses without separate imputation steps, as well as differentiation between direct and indirect effects. Therewas an association between the FTO single nucleotide polymorphism rs9939609 and BMI at age 31 years thatpersisted after controlling for several relevant factors during the life course. The total effect of the FTO variant onadult BMI was mostly composed of the direct effect, but a notable part was also arising indirectly via its effects onearlier BMI development. In addition to well-established genetic determinants, many life-course factors such asphysical activity, in spite of not showing mediation or interaction, had a strong independent effect on BMI.
Bictash M, Ebbels TM, Chan Q, et al., 2010, Opening up the "Black Box": Metabolic phenotyping and metabolome-wide association studies in epidemiology, JOURNAL OF CLINICAL EPIDEMIOLOGY, Vol: 63, Pages: 970-979, ISSN: 0895-4356
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- Citations: 107
Chadeau-Hyam M, Ebbels TMD, Brown IJ, et al., 2010, Metabolic Profiling and the Metabolome-Wide Association Study: Significance Level For Biomarker Identification, JOURNAL OF PROTEOME RESEARCH, Vol: 9, Pages: 4620-4627, ISSN: 1535-3893
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- Citations: 88
Schumann G, Coin L, Lourdusamy A, et al., 2010, IDENTIFICATION OF GENES ASSOCIATED WITH ALCOHOL CONSUMPTION, World Congress on International-Society-for-Biomedical-Research-on-Alcoholism, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 43A-43A, ISSN: 0145-6008
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.
Heinzmann SS, Brown IJ, Chan Q, et al., 2010, Metabolic profiling strategy for discovery of nutritional biomarkers: proline betaine as a marker of citrus consumption, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol: 92, Pages: 436-443, ISSN: 0002-9165
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- Citations: 194
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.
Elliott P, Toledano MB, Bennett J, et al., 2010, Mobile phone base stations and early childhood cancers: case-control study, BMJ-BRITISH MEDICAL JOURNAL, Vol: 340, ISSN: 1756-1833
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- Citations: 30
Tzoulaki I, Sovio U, Pillas D, et al., 2010, Relation of Immediate Postnatal Growth With Obesity and Related Metabolic Risk Factors in Adulthood, AMERICAN JOURNAL OF EPIDEMIOLOGY, Vol: 171, Pages: 989-998, ISSN: 0002-9262
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- Citations: 70
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
Anderson CAM, Appel LJ, Okuda N, et al., 2010, Dietary Sources of Sodium in China, Japan, the United Kingdom, and the United States, Women and Men Aged 40 to 59 Years: The INTERMAP Study, JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION, Vol: 110, Pages: 736-745, ISSN: 0002-8223
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- Citations: 384
Dupuis J, Langenberg C, Prokopenko I, et al., 2010, New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk (vol 42, pg 105, 2010), NATURE GENETICS, Vol: 42, Pages: 464-464, ISSN: 1061-4036
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- Citations: 6
Freathy RM, Mook-Kanamori DO, Sovio U, et al., 2010, Variants in <i>ADCY5</i> and near <i>CCNL1</i> are associated with fetal growth and birth weight, NATURE GENETICS, Vol: 42, Pages: 430-U73, ISSN: 1061-4036
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- Citations: 185
Little MP, Tawn EJ, Tzoulaki I, et al., 2010, Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms, RADIATION AND ENVIRONMENTAL BIOPHYSICS, Vol: 49, Pages: 139-153, ISSN: 0301-634X
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- Citations: 93
Lindgren CM, Heid IM, Randall JC, et al., 2010, Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution, PLOS GENETICS, Vol: 6, ISSN: 1553-7390
Dugas J, Nieuwenhuijsen MJ, Martinez D, et al., 2010, Use of biocides and insect repellents and risk of hypospadias, OCCUPATIONAL AND ENVIRONMENTAL MEDICINE, Vol: 67, Pages: 196-200, ISSN: 1351-0711
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- Citations: 23
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.
Walters RG, Jacquemont S, Valsesia A, et al., 2010, A new highly penetrant form of obesity due to deletions on chromosome 16p11.2, Nature, Vol: 463, Pages: 671-675, ISSN: 1476-4687
Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
Dupuis J, Langenberg C, Prokopenko I, et al., 2010, New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk, Nature Genetics, Vol: 42, Pages: 105-U32, ISSN: 1546-1718
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.
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
Repapi E, Sayers I, Wain LV, et al., 2010, Genome-wide association study identifies five loci associated with lung function, NATURE GENETICS, Vol: 42, Pages: 36-U51, ISSN: 1061-4036
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n <= 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
Elliott P, 2010, Study of clustering and outbreaks, Teaching Epidemiology, Editors: Olsen, Saracci, Trichopoulos, Oxford, New York, Publisher: Oxford University Press, Pages: 429-439, ISBN: 9780199239474
Repapi E, Sayers I, Wain LV, et al., 2010, Genome-Wide Association Study Identifies Five New Loci Associated With Lung Function, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 181, ISSN: 1073-449X
Pillas D, Hoggart CJ, Evans DM, et al., 2010, Correction: Genome-Wide Association Study Reveals Multiple Loci Associated with Primary Tooth Development during Infancy., PLoS Genet, Vol: 6, ISSN: 1553-7404
[This corrects the article on p. e1000856 in vol. 6.].
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