Publications
368 results found
Locke AE, Kahali B, Berndt SI, et al., 2015, Genetic studies of body mass index yield new insights for obesity biology, Nature, Vol: 518, Pages: 197-206, ISSN: 0028-0836
Yaghootkar H, Scott RA, White CC, et al., 2014, Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes, Diabetes, Vol: 63, Pages: 4369-4377, ISSN: 0012-1797
The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy—a reduction in subcutaneous adipose tissue—it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin–based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10−29), lower HDL cholesterol (β = −0.020; P = 7 × 10−37), greater hepatic steatosis (β = 0.021; P = 3 × 10−4), higher alanine transaminase (β = 0.002; P = 3 × 10−5), lower sex-hormone-binding globulin (β = −0.010; P = 9 × 10−13), and lower adiponectin (β = −0.015; P = 2 × 10−26). The same risk alleles were associated with lower BMI (per-allele β = −0.008; P = 7 × 10−8) and increased visceral-to-subcutaneous adipose tissue ratio (β = −0.015; P = 6 × 10−7). Individuals carrying ≥17 fasting insulin–raising alleles (5.5% population) were slimmer (0.30 kg/m2) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5
Wood AR, Esko T, Yang J, et al., 2014, Defining the role of common variation in the genomic and biological architecture of adult human height, Nature Genetics, Vol: 46, Pages: 1173-1186, ISSN: 1546-1718
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate–related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Xi B, Takeuchi F, Meirhaeghe A, et al., 2014, Associations of genetic variants in/near body mass index-associated genes with type 2 diabetes: a systematic meta-analysis, CLINICAL ENDOCRINOLOGY, Vol: 81, Pages: 702-710, ISSN: 0300-0664
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- Citations: 29
Chen L, Kostadima M, Martens JHA, et al., 2014, Transcriptional diversity during lineage commitment of human blood progenitors, SCIENCE, Vol: 345, Pages: 1580-+, ISSN: 0036-8075
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- Citations: 185
Chambers JC, Abbott J, Zhang W, et al., 2014, The South Asian Genome, PLOS One, Vol: 9, ISSN: 1932-6203
The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.
Hoggart CJ, Venturini G, Mangino M, et al., 2014, Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index, PLOS Genetics, Vol: 10, ISSN: 1553-7390
The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present anovel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. Themethod exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups.We applied the method to .56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six leadSNPs were carried forward for replication in five family-based studies (of ,4,000 trios). Two SNPs replicated: the paternalrs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10gene) increased BMI equally (beta = 0.11 (SD), P,0.0027) compared to the respective maternal alleles. Real-time PCRexperiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent onparental origin of the SNPs alleles (P,0.01). Our scheme opens new opportunities to exploit GWAS data of unrelatedindividuals to identify POEs and demonstrates that they play an important role in adult obesity.
Ganesh SK, Chasman DI, Larson MG, et al., 2014, Effects of Long-Term Averaging of Quantitative Blood Pressure Traits on the Detection of Genetic Associations, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 95, Pages: 49-65, ISSN: 0002-9297
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- Citations: 55
Yaghootkar H, Scott R, White CC, et al., 2014, Genetic Evidence for a Metabolically Obese, Normal Weight Phenotype That Links Insulin Resistance with Type 2 Diabetes, Hypertension, and Coronary Artery Disease, Publisher: AMER DIABETES ASSOC, Pages: A414-A414, ISSN: 0012-1797
Flannick J, Thorleifsson G, Beer NL, et al., 2014, Loss-of-function mutations in SLC30A8 protect against type 2 diabetes., Nat Genet, Vol: 46, Pages: 357-363
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
Mahajan A, Go MJ, Zhang W, et al., 2014, Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility, Nature Genetics, Vol: 46, Pages: 234-244, ISSN: 1061-4036
To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
Williams AL, Jacobs SBR, Moreno-Macias H, et al., 2014, Sequence variants in <i>SLC16A11</i> are a common risk factor for type 2 diabetes in Mexico, NATURE, Vol: 506, Pages: 97-+, ISSN: 0028-0836
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- Citations: 61
Dichgans M, Malik R, Koenig IR, et al., 2014, Shared Genetic Susceptibility to Ischemic Stroke and Coronary Artery Disease A Genome-Wide Analysis of Common Variants, STROKE, Vol: 45, Pages: 24-36, ISSN: 0039-2499
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- Citations: 249
Dichgans M, Malik R, Koenig IR, et al., 2013, Evidence for a shared genetic determination of Ischemic Stroke And Coronary Artery Disease - a genome-wide analysis, Scientific Sessions of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E160-E161, ISSN: 0009-7330
Walker DG, Williams HRT, Bancil AS, et al., 2013, Ethnicity Differences in Genetic Susceptibility to Ulcerative Colitis: A Comparison of Indian Asians and White Northern Europeans, INFLAMMATORY BOWEL DISEASES, Vol: 19, Pages: 2888-2894, ISSN: 1078-0998
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- Citations: 10
Tan S-T, Rai B, Boustead L, et al., 2013, Assessing the Contribution of Dietary Factors to the Increased Prevalence of Insulin Resistance Amongst Uk Indian Asians Compared to Europeans, Scientific Sessions and Resuscitation Science Symposium of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Do R, Willer CJ, Schmidt EM, et al., 2013, Common variants associated with plasma triglycerides and risk for coronary artery disease, Nature Genetics, Vol: 45, Pages: 1345-1352, ISSN: 1061-4036
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10−8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
Willer CJ, Schmidt EM, Sengupta S, et al., 2013, Discovery and refinement of loci associated with lipid levels, Nature Genetics, Vol: 45, Pages: 1274-1283, ISSN: 1061-4036
Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
O'Seaghdha CM, Wu H, Yang Q, et al., 2013, Meta-analysis of genome-wide association studies identifies six new loci for serum calcium concentrations, PLoS Genetics, Vol: 9, Pages: 1-13, ISSN: 1553-7390
Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
Sabater-Lleal M, Huang J, Chasman D, et al., 2013, Multiethnic Meta-Analysis of Genome-Wide Association Studies in > 100 000 Subjects Identifies 23 FibrinogenAssociated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease, CIRCULATION, Vol: 128, Pages: 1310-1324, ISSN: 0009-7322
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- Citations: 113
van Meurs JBJ, Pare G, Schwartz SM, et al., 2013, Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol: 98, Pages: 668-676, ISSN: 0002-9165
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- Citations: 143
Sabharwal S, Patel V, Nijjer SS, et al., 2013, Guidelines in cardiac clinical practice: evaluation of their methodological quality using the AGREE II instrument, JOURNAL OF THE ROYAL SOCIETY OF MEDICINE, Vol: 106, Pages: 315-322, ISSN: 0141-0768
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- Citations: 33
Paul DS, Albers CA, Rendon A, et al., 2013, Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci, GENOME RESEARCH, Vol: 23, Pages: 1130-1141, ISSN: 1088-9051
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- Citations: 30
Paul D, Albers CA, Rendon A, et al., 2013, The epigenetic landscape of platelet and red blood cell traits, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 11, Pages: 349-349, ISSN: 1538-7933
Wang X, Chua H-X, Chen P, et al., 2013, Comparing methods for performing trans-ethnic meta-analysis of genome-wide association studies, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 2303-2311, ISSN: 0964-6906
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- Citations: 52
den Hoed M, Eijgelsheim M, Esko T, et al., 2013, Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders, NATURE GENETICS, Vol: 45, Pages: 621-+, ISSN: 1061-4036
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- Citations: 228
Saxena R, Saleheen D, Been LF, et al., 2013, Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India, Diabetes, Vol: 62, Pages: 1746-1755, ISSN: 0012-1797
We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10−3) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10−4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10−8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10−3) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10−4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10−5 to < 10−7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.
Chahal NS, Lim TK, Jain P, et al., 2013, The increased prevalence of left ventricular hypertrophy and concentric remodeling in UK Indian Asians compared with European Whites, JOURNAL OF HUMAN HYPERTENSION, Vol: 27, Pages: 288-293, ISSN: 0950-9240
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- Citations: 6
Mughal SA, Chambers JC, Kelly MA, et al., 2013, Evaluation of high sensitivity C-reactive protein as a screening tool for detecting young South Asians with maturity-onset diabetes of the young due to <i>HNF1A</i> mutations, DIABETIC MEDICINE, Vol: 30, Pages: 61-61, ISSN: 0742-3071
Koettgen A, Albrecht E, Teumer A, et al., 2013, Genome-wide association analyses identify 18 new loci associated with serum urate concentrations, NATURE GENETICS, Vol: 45, Pages: 145-154, ISSN: 1061-4036
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- Citations: 561
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