Timothy M Frayling

University of Exeter, Exeter, England, United Kingdom

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Publications (192)2455.64 Total impact

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    ABSTRACT: Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.
    The Journal of clinical investigation 03/2015; DOI:10.1172/JCI74692 · 13.77 Impact Factor
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    ABSTRACT: Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity (e.g. body mass index [BMI]≥40 kg/m(2)), but their contribution to common obesity (BMI≥30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331,175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CI) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR=1.15, 95% CI 1.06-1.24, P=6.08x10(-6)) and rs6234/rs6235 (OR=1.07, 95% CI 1.04-1.10, P=3.00x10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (beta=0.03, 95% CI 0.00-0.07; P=0.047) and rs6234/rs6235 (beta=0.02, 95% CI 0.00-0.03; P=5.57x10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 03/2015; DOI:10.1093/hmg/ddv097 · 6.68 Impact Factor
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    ABSTRACT: Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis
    Nature 02/2015; 518(7538). DOI:10.1038/nature14177 · 42.35 Impact Factor
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    ABSTRACT: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
    Nature 02/2015; 518(7538-7538):187-96. DOI:10.1038/nature14132 · 42.35 Impact Factor
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    ABSTRACT: Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
    Nature Communications 01/2015; 6:5897. DOI:10.1038/ncomms6897 · 10.74 Impact Factor
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    ABSTRACT: MicroRNAs (miRNA) play a crucial role in the regulation of diverse biological processes by post-transcriptional modulation of gene expression. Genetic polymorphisms in miRNA-related genes can potentially contribute to a wide range of phenotypes. The effect of such variants on cardiometabolic diseases has not yet been defined. We systematically investigated the association of genetic variants in the seed regions of miRNAs with cardiometabolic phenotypes, using the thus far largest genome wide association studies on 17 cardiometabolic traits/diseases. We found that rs2168518:G>A, a seed region variant of miR-4513, associates with fasting glucose, LDL-cholesterol and total cholesterol, systolic and diastolic blood pressure and risk of coronary artery disease. We experimentally showed that miR-4513 expression is significantly reduced in presence of the rs2168518 mutant allele. We sought to identify miR-4513 target genes that may mediate these associations and revealed five genes (PCSK1, BNC2, MTMR3, ANK3 and GOSR2) through which these effects might be taking place. Using luciferase reporter assays we validated GOSR2 as a target of miR-4513 and further demonstrated that the miRNA mediated regulation of this gene is changed by rs2168518. Our findings indicate a pleiotropic effect of miR-4513 on cardiometabolic phenotypes and may improve our understanding of the pathophysiology of cardiometabolic diseases.This article is protected by copyright. All rights reserved
    Human Mutation 12/2014; 35(12). DOI:10.1002/humu.22706 · 5.05 Impact Factor
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    ABSTRACT: Initial results from sequencing studies suggest that there are relatively few low frequency (<5%) variants associated with large effects on common phenotypes. We performed low pass whole genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: i) that sequencing would detect single low frequency - large effect variants that explained similar amounts of phenotypic variance as single common variants, and ii) that some common variant associations could be explained by low frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant - common phenotype associations - 11,132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11,657,229 high quality variants of which 6,129,221 and 5,528,008 were common and low frequency (<5%) respectively, low frequency - large effect associations comprised 7% of detectable cis-gene expression traits (89 of 1,314 cis-eQTLs at P<1x10(-06) (FDR ∼5%)) and 1 of 8 biomarker associations at P<8x10(-10). Very few (30 of 1,232; 2%) common variant associations were fully explained by low frequency variants. Our data show that whole genome sequencing can identify low frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low frequency variants of large effect.
    Human Molecular Genetics 11/2014; 24(5). DOI:10.1093/hmg/ddu560 · 6.68 Impact Factor
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    ABSTRACT: Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N=28,459). We identified 7 independent top SNPs (P<1x10(-6)) for birth length, of which 3 were novel and 4 were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The 3 novel SNPs were followed-up in 9 replication studies (Stage 2; N=11,995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1+2; ß=0.046, S.E.=0.008, P=2.46x10(-8), explained variance=0.05%). Rs905938 was also associated with infant length (N=28,228; P=5.54x10(-4)) and adult height (N=127,513; P=1.45x10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
    Human Molecular Genetics 10/2014; DOI:10.1093/hmg/ddu510 · 6.68 Impact Factor
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    ABSTRACT: Arising from G. Hemani et al. 508, 249-253 (2014); doi:10.1038/nature13005Epistasis occurs when the effect of a genetic variant on a trait is dependent on genotypes of other variants elsewhere in the genome. Hemani et al. recently reported the detection and replication of many instances of epistasis between pairs of variants influencing gene expression levels in humans. Using whole-genome sequencing data from 450 individuals we strongly replicated many of the reported interactions but, in each case, a single third variant captured by our sequencing data could explain all of the apparent epistasis. Our results provide an alternative explanation for the apparent epistasis observed for gene expression in humans. There is a Reply to this Brief Communication Arising by Hemani, G. et al. Nature 514, http://dx.doi.org/10.1038/nature13692 (2014).
    Nature 10/2014; 514(7520):E3-5. DOI:10.1038/nature13691 · 42.35 Impact Factor
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    Timothy M Frayling
    The Lancet 09/2014; 385(9965). DOI:10.1016/S0140-6736(14)61639-1 · 39.21 Impact Factor
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    ABSTRACT: 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, coronary artery disease and type 2 diabetes. We aimed to test the hypothesis that common alleles associated with insulin resistance also influence the wider clinical and biochemical profile of monogenic insulin resistance. We selected 19 common genetic variants associated with fasting insulin based measures of insulin resistance. We used hierarchical clustering and results from genome wide association studies of 8 non-disease outcomes of monogenic insulin resistance, to group these variants. We analysed 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 (ß=0.018; p=4x10(-29)), lower HDL cholesterol (ß=-0.020; p=7x10(-37)), greater hepatic steatosis (ß=0.021; p=3x10(-4)) higher alanine transaminase (ß=0.002; p=3x10(-5)), lower SHBG (ß=-0.010; p=9x10(-13)) and lower adiponectin (ß=-0.015; p=2x10(-26)). The same risk alleles were associated with lower BMI (per-allele ß=-0.008; p=7x10(-8)), and increased visceral-to-subcutaneous adipose tissue ratio (ß=-0.015; p=6x10(-7)). Individuals carrying >= 17 fasting insulin raising alleles (5.5% population) were slimmer (0.30 kgm(-2)) but at increased risk of T2D (odds ratio [OR] 1.46, per-allele p=5x10(-13)), CAD (OR 1.12, per-allele p=1x10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg (per-allele p=2x10(-5)), and 0.67 mmHg (per-allele p=2x10(-4)), respectively, compared to individuals carrying <=9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.
    Diabetes 07/2014; 63(12). DOI:10.2337/db14-0318 · 8.47 Impact Factor
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    ABSTRACT: Background Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97—0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96—0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87—0·97; p=0·002). Interpretation Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
    06/2014; DOI:10.1016/S2213-8587(14)70113-5
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    ABSTRACT: Most studies seeking common variant associations with type 2 diabetes (T2D) have focused on individuals of European ancestry. These discoveries need to be evaluated in other major ancestral groups, to understand ethnic differences in predisposition, and establish whether these contribute to variation in T2D prevalence and presentation. This study aims to establish whether common variants conferring T2D-risk in Europeans contribute to T2D-susceptibility in the South Asian population of Sri Lanka.
    PLoS ONE 06/2014; 9(6):e98608. DOI:10.1371/journal.pone.0098608 · 3.53 Impact Factor
  • Timothy M Frayling, Andrew T Hattersley
    Diabetes 06/2014; 63(6):1836-7. DOI:10.2337/db14-0130 · 8.47 Impact Factor
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    ABSTRACT: Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
    PLoS Genetics 04/2014; 10(4):e1004235. DOI:10.1371/journal.pgen.1004235 · 8.17 Impact Factor
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    ABSTRACT: 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.
    Nature Genetics 03/2014; · 29.65 Impact Factor
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    ABSTRACT: Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
    PLoS Genetics 02/2014; 10(2):e1004123. DOI:10.1371/journal.pgen.1004123 · 8.17 Impact Factor
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    ABSTRACT: Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10−13; odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10−4; OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.
    Nature 12/2013; DOI:10.1038/nature12828 · 42.35 Impact Factor
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    ABSTRACT: The UK Biobank study provides a unique opportunity to study the causes and consequences of disease. We aimed to use the UK Biobank data to study the well-established, but poorly understood, association between low birthweight and type 2 diabetes. We used logistic regression to calculate the odds ratio for participants' risk of type 2 diabetes given a one standard deviation increase in birthweight. To test for an association between parental diabetes and birthweight, we performed linear regression of self-reported parental diabetes status against birthweight. We performed path and mediation analyses to test the hypothesis that birthweight partly mediates the association between parental diabetes and participant type 2 diabetes status. Of the UK Biobank participants, 277 261 reported their birthweight. Of 257 715 individuals of White ethnicity and singleton pregnancies, 6576 had type 2 diabetes, 19 478 reported maternal diabetes (but not paternal), 20 057 reported paternal diabetes (but not maternal) and 2754 participants reported both parents as having diabetes. Lower birthweight was associated with type 2 diabetes in the UK Biobank participants. A one kilogram increase in birthweight was associated with a lower risk of type 2 diabetes (odds ratio: 0.74; 95% CI: 0.71, 0.76; P = 2 × 10(-57)). Paternal diabetes was associated with lower birthweight (45 g lower; 95% CI: 36, 54; P = 2 × 10(-23)) relative to individuals with no parental diabetes. Maternal diabetes was associated with higher birthweight (59 g increase; 95% CI: 50, 68; P = 3 × 10(-37)). Participants' lower birthweight was a mediator of the association between reported paternal diabetes and participants' type 2 diabetes status, explaining 1.1% of the association, and participants' higher birthweight was a mediator of the association between reported maternal diabetes and participants' type 2 diabetes status, explaining 1.2% of the association. Data from the UK Biobank provides the strongest evidence by far that paternal diabetes is associated with lower birthweight, whereas maternal diabetes is associated with increased birthweight. Our findings with paternal diabetes are consistent with a role for the same genetic factors influencing foetal growth and type 2 diabetes.
    International Journal of Epidemiology 12/2013; 42(6). DOI:10.1093/ije/dyt220 · 9.20 Impact Factor
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Publication Stats

21k Citations
2,455.64 Total Impact Points

Institutions

  • 1997–2015
    • University of Exeter
      • • Medical School
      • • Peninsula College of Medicine and Dentistry
      Exeter, England, United Kingdom
  • 2014
    • Royal Devon and Exeter NHS Foundation Trust
      Exeter, England, United Kingdom
  • 2012
    • University of Queensland
      Brisbane, Queensland, Australia
    • Queensland Institute of Medical Research
      • Genetic Epidemiology Laboratory
      Brisbane, Queensland, Australia
    • Wellcome Trust Sanger Institute
      Cambridge, England, United Kingdom
  • 2003–2012
    • University of Oxford
      • • Wellcome Trust Centre for Human Genetics
      • • Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM)
      Oxford, ENG, United Kingdom
    • University of Helsinki
      • Department of Internal Medicine
      Helsinki, Uusimaa, Finland
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
  • 2011
    • The University of Edinburgh
      • Centre for Population Health Sciences
      Edinburgh, Scotland, United Kingdom
  • 2010
    • Imperial College London
      Londinium, England, United Kingdom
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 2008
    • Università di Pisa
      Pisa, Tuscany, Italy
  • 2007–2008
    • The Peninsula College of Medicine and Dentistry
      Plymouth, England, United Kingdom
  • 2006
    • University of London
      Londinium, England, United Kingdom
  • 2002–2006
    • Newcastle University
      Newcastle-on-Tyne, England, United Kingdom
  • 2004
    • Wellcome Trust
      Londinium, England, United Kingdom
    • University of Bergen
      Bergen, Hordaland, Norway
  • 2001
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1999
    • University of Aberdeen
      • Institute of Medical Sciences
      Aberdeen, SCT, United Kingdom