Imperial College London

ProfessorPhilippeFroguel

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Genomic Medicine
 
 
 
//

Contact

 

+44 (0)20 7594 6520p.froguel

 
 
//

Assistant

 

Mrs Patricia Murphy +44 (0)20 7594 1603

 
//

Location

 

E306Burlington DanesHammersmith Campus

//

Summary

 

Publications

Publication Type
Year
to

801 results found

Porcu E, Gilardi F, Darrous L, Yengo L, Bararpour N, Gasser M, Marques-Vidal P, Froguel P, Waeber G, Thomas A, Kutalik Zet al., 2021, Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes., Sci Rep, Vol: 11

The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.

Journal article

Hu M, Cebola I, Carrat G, Jiang S, Nawaz S, Khamis A, Canouil M, Froguel P, Schulte A, Solimena M, Ibberson M, Marchetti P, Cardenas-Diaz FL, Gadue PJ, Hastoy B, Almeida-Souza L, McMahon H, Rutter GAet al., 2021, Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion., Cell Research, Vol: 34, Pages: 1-1, ISSN: 1001-0602

Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-βH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function.

Journal article

Bonnefond A, Froguel P, 2021, Clustering for a better prediction of type 2 diabetes mellitus, NATURE REVIEWS ENDOCRINOLOGY, Vol: 17, Pages: 193-194, ISSN: 1759-5029

Journal article

Lagou V, Maegi R, Hottenga J-J, Grallert H, Perry JRB, Bouatia-Naji N, Marullo L, Rybin D, Jansen R, Min JL, Dimas AS, Ulrich A, Zudina L, Gadin JR, Jiang L, Faggian A, Bonnefond A, Fadista J, Stathopoulou MG, Isaacs A, Willems SM, Navarro P, Tanaka T, Jackson AU, Montasser ME, O'Connell JR, Bielak LF, Webster RJ, Saxena R, Stafford JM, Pourcain BS, Timpson NJ, Salo P, Shin S-Y, Amin N, Smith AV, Li G, Verweij N, Goel A, Ford I, Johnson PCD, Johnson T, Kapur K, Thorleifsson G, Strawbridge RJ, Rasmussen-Torvik LJ, Esko T, Mihailov E, Fall T, Fraser RM, Mahajan A, Kanoni S, Giedraitis V, Kleber ME, Silbernagel G, Meyer J, Mueller-Nurasyid M, Ganna A, Sarin A-P, Yengo L, Shungin D, Luan J, Horikoshi M, An P, Sanna S, Boettcher Y, Rayner NW, Nolte IM, Zemunik T, Iperen EV, Kovacs P, Hastie ND, Wild SH, McLachlan S, Campbell S, Polasek O, Carlson O, Egan J, Kiess W, Willemsen G, Kuusisto J, Laakso M, Dimitriou M, Hicks AA, Rauramaa R, Bandinelli S, Thorand B, Liu Y, Miljkovic I, Lind L, Doney A, Perola M, Hingorani A, Kivimaki M, Kumari M, Bennett AJ, Groves CJ, Herder C, Koistinen HA, Kinnunen L, Faire UD, Bakker SJL, Uusitupa M, Palmer CNA, Jukema JW, Sattar N, Pouta A, Snieder H, Boerwinkle E, Pankow JS, Magnusson PK, Krus U, Scapoli C, de Geus EJCN, Blueher M, Wolffenbuttel BHR, Province MA, Abecasis GR, Meigs JB, Hovingh GK, Lindstroem J, Wilson JF, Wright AF, Dedoussis GV, Bornstein SR, Schwarz PEH, Toenjes A, Winkelmann BR, Boehm BO, Maerz W, Metspalu A, Price JF, Deloukas P, Koerner A, Lakka TA, Keinanen-Kiukaanniemi SM, Saaristo TE, Bergman RN, Tuomilehto J, Wareham NJ, Langenberg C, Maennistoe S, Franks PW, Hayward C, Vitart V, Kaprio J, Visvikis-Siest S, Balkau B, Altshuler D, Rudan I, Stumvoll M, Campbell H, van Duijn CM, Gieger C, Illig T, Ferrucci L, Pedersen NL, Pramstaller PP, Boehnke M, Frayling TM, Shuldiner AR, Peyser PA, Kardia SLR, Palmer LJ, Penninx BW, Meneton P, Harris TB, Navis G, Harst PVD, Smith GD, Forouhi NG, Loos RJF, Salomaa V, Soranzo N Bet al., 2021, Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability, NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723

Journal article

Saeed S, Arslan M, Manzoor J, Janjua QM, Ayesha H, Durand E, Khan WI, Butt TA, Bonnefond A, Froguel Pet al., 2020, Genetic aetiology of early onset severe obesity revealed in half of the affected cases from a consanguineous population of Pakistan, Publisher: SPRINGERNATURE, Pages: 568-569, ISSN: 1018-4813

Conference paper

Imam A, Winnebeck EC, Buchholz N, Froguel P, Bonnefond A, Solimena M, Ivanova A, Bouvier M, Plouffe B, Charpentier G, Karamitri A, Jockers R, Roenneberg T, Vetter Cet al., 2020, Circadian, Sleep and Caloric Intake Phenotyping in Type 2 Diabetes Patients With Rare Melatonin Receptor 2 Mutations and Controls: A Pilot Study, FRONTIERS IN PHYSIOLOGY, Vol: 11, ISSN: 1664-042X

Journal article

Baron M, Froguel P, Bonnefond A, 2020, Something new in the genetics of monogenic obesity and its insights into pathophysiology, M S-MEDECINE SCIENCES, Vol: 36, Pages: 859-865, ISSN: 0767-0974

Journal article

Bonnefond A, Boissel M, Bolze A, Durand E, Toussaint B, Vaillant E, Gaget S, De Graeve F, Dechaume A, Allegaert F, Le Guilcher D, Yengo L, Dhennin V, Borys J-M, Lu JT, Cirulli ET, Elhanan G, Roussel R, Balkau B, Marre M, Franc S, Charpentier G, Vaxillaire M, Canouil M, Washington NL, Grzymski JJ, Froguel Pet al., 2020, Pathogenic variants in actionable MODY genes are associated with type 2 diabetes, NATURE METABOLISM, Vol: 2, Pages: 1126-+

Journal article

Jacob A, Pasquier J, Carapito R, Aurade F, Molitor A, Froguel P, Fakhro K, Halabi N, Viot G, Bahram S, Rafii Aet al., 2020, A de novo synonymous variant inEFTUD2disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report, BMC MEDICAL GENETICS, Vol: 21

Journal article

Kahoul Y, Oger F, Montaigne J, Froguel P, Breton C, Annicotte J-Set al., 2020, Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes, BIOMOLECULES, Vol: 10

Journal article

Saeed S, Arslan M, Manzoor J, Din SM, Janjua QM, Ayesha H, Ain Q-T, Inam L, Lobbens S, Vaillant E, Durand E, Derhourhi M, Amanzougarene S, Badreddine A, Berberian L, Gaget S, Khan WI, Butt TA, Bonnefond A, Froguel Pet al., 2020, Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence in an Inbred Population of Pakistan, DIABETES, Vol: 69, Pages: 1424-1438, ISSN: 0012-1797

Journal article

Lemoine S, Eladari D, Juillard L, Bonnefond A, Froguel P, Dubourg Let al., 2020, Hypokalemia and severe renal loss of sodium - Pendred syndrome mimicking Gitelman syndrome, KIDNEY INTERNATIONAL, Vol: 97, Pages: 1305-1306, ISSN: 0085-2538

Journal article

Khamis A, Boutry R, Canouil M, Mathew S, Lobbens S, Crouch H, Andrew T, Abderrahmani A, Tamanini F, Froguel Pet al., 2020, Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect, CLINICAL EPIGENETICS, Vol: 12, ISSN: 1868-7075

Journal article

Mishra R, Akerlund M, Cousminer DL, Ahlqvist E, Bradfield JP, Chesi A, Hodge KM, Guy VC, Brillon DJ, Pratley RE, Rickels MR, Vella A, Ovalle F, Harris RI, Melander O, Varvel S, Hakonarson H, Froguel P, Lonsdale JT, Mauricio D, Schloot NC, Khunti K, Greenbaum CJ, Yderstraede KB, Tuomi T, Voight BF, Schwartz S, Boehm BO, Groop L, Leslie RD, Grant SFAet al., 2020, Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC, DIABETES CARE, Vol: 43, Pages: 418-425, ISSN: 0149-5992

Journal article

Canouil M, Bouland GA, Bonnefond A, Froguel P, 't Hart LM, Slieker RCet al., 2020, NACHO: an R package for quality control of NanoString nCounter data, BIOINFORMATICS, Vol: 36, Pages: 970-971, ISSN: 1367-4803

Journal article

Ndiaye FK, Huyvaert M, Ortalli A, Canouil M, Lecoeur C, Verbanck M, Lobbens S, Khamis A, Marselli L, Marchetti P, Kerr-Conte J, Pattou F, Marre M, Roussel R, Balkau B, Froguel P, Bonnefond Aet al., 2020, The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward, INTERNATIONAL JOURNAL OF OBESITY, Vol: 44, Pages: 539-543, ISSN: 0307-0565

Journal article

Gloaguen E, Dizier M-H, Boissel M, Rocheleau G, Canouil M, Froguel P, Tichet J, Roussel R, Julier C, Balkau B, Mathieu F, Ducimetiere P, Eschwege E, Alhenc-Gelas F, Fumeron F, Marre M, Gallois Y, Girault A, Bonnet F, Bonnefond A, Cauchi S, Alencon A, Blois C, Chartres C, Cholet LM, Orleans T, Cogneau J, Born C, Caces E, Cailleau M, Copin N, Lantieri O, Moreau J-G, Rakotozafy F, Vol Set al., 2019, General regression model: A "model-free" association test for quantitative traits allowing to test for the underlying genetic model, ANNALS OF HUMAN GENETICS, Vol: 84, Pages: 280-290, ISSN: 0003-4800

Journal article

Imam A, Winnebeck E, Buchholz N, Froguel P, Bonnefond A, Solimena M, Ivanova A, Bouvier M, Plouffe B, Charpentier G, Karamitri A, Jockers R, Roenneberg T, Vetter Cet al., 2019, FUNCTIONAL CIRCADIAN AND SLEEP PHENOTYPING OF TYPE 2 DIABETES PATIENTS WITH MELATONIN RECEPTOR 2 MUTATIONS AND CONTROLS: A PILOT STUDY, Publisher: ELSEVIER, Pages: S166-S167, ISSN: 1389-9457

Conference paper

Lecoutre S, Montel V, Vallez E, Pourpe C, Delmont A, Eury E, Verbanck M, Dickes-Coopman A, Daubersies P, Lesage J, Laborie C, Tailleux A, Staels B, Froguel P, Breton C, Vieau Det al., 2019, Transcription profiling in the liver of undernourished male rat offspring reveals altered lipid metabolism pathways and predisposition to hepatic steatosis, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, Vol: 317, Pages: E1094-E1107, ISSN: 0193-1849

Journal article

Mitchell RN, Ashar FN, Jarvelin M-R, Froguel P, Sotoodehnia N, Brody JA, Sebert S, Huikuri H, Rioux J, Goyette P, Newcomb CE, Junttila MJ, Arking DEet al., 2019, Effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death, Journal of the American Heart Association, Vol: 8, Pages: 1-27, ISSN: 2047-9980

BackgroundSudden cardiac death (SCD) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex‐ and coronary artery disease–stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk.Methods and ResultsWe examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval–associated single‐nucleotide polymorphism, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non‐ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate (P=0.036 for difference). Similar trends were observed for the Mendelian randomization analysis.ConclusionsWhile individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.

Journal article

Meyre D, Andress EJ, Sharma T, Snippe M, Asif H, Maharaj A, Vatin V, Gaget S, Besnard P, Choquet H, Froguel P, Linton KJet al., 2019, Contribution of rare coding mutations in CD36 to type 2 diabetes and cardio-metabolic complications, SCIENTIFIC REPORTS, Vol: 9, ISSN: 2045-2322

Journal article

Baron M, Maillet J, Huyvaert M, Dechaume A, Boutry R, Loiselle H, Durand E, Toussaint B, Vaillant E, Philippe J, Thomas J, Ghulam A, Franc S, Charpentier G, Borys J-M, Levy-Marchal C, Tauber M, Scharfmann R, Weill J, Aubert C, Kerr-Conte J, Pattou F, Roussel R, Balkau B, Marre M, Boissel M, Derhourhi M, Gaget S, Canouil M, Froguel P, Bonnefond Aet al., 2019, Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension, NATURE MEDICINE, Vol: 25, Pages: 1733-+, ISSN: 1078-8956

Journal article

Schmidt AF, Holmes MV, Preiss D, Swerdlow DI, Denaxas S, Fatemifar G, Faraway R, Finan C, Valentine D, Fairhurst-Hunter Z, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh K, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Lill CM, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott RA, Luan J, Bobak M, Malyutina S, Pająk A, Kubinova R, Tamosiunas A, Pikhart H, Grarup N, Pedersen O, Hansen T, Linneberg A, Jess T, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Lester KH, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, Scott R, Schofield P, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, Lifelines Cohort authors, Christen T, Mook-Kanamori DO, ICBP Consortium, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dörr M, Lerch MM, Völker U, Völzke H, Ward J, Pell JP, Meade T, Christophersen IE, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Roussel R, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Hopewell JC, Seshadri S, METASTROKE Consortium of the ISGC, Dale C, Costa RPE, Ridker PM, Chasman DI, Reiner AP, Ritchie MD, Lange LA, Cornish AJ, Dobbins SE, Hemminki K, Kinnersley B, Sanson M, Labreche K, Simon M, Bondy M, Law P, Speedy H, Allan J, Li N, Went M, Weinhold N, Morgan G, Sonneveld P, Nilsson B, Goldschmidt H, Sud A, Engert A, Hansson M, Hemingway H, Asselbergs FW, Patel RS, Keating BJ, Sattar N, Houlston R, Casas JP, Hingorani ADet al., 2019, Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9, BMC Cardiovascular Disorders, Vol: 19, ISSN: 1471-2261

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Journal article

Bradfield JP, Vogelezang S, Felix JF, Chesi A, Helgeland Ø, Horikoshi M, Karhunen V, Lowry E, Cousminer DL, Ahluwalia TS, Thiering E, Boh ET-H, Zafarmand MH, Vilor-Tejedor N, Wang CA, Joro R, Chen Z, Gauderman WJ, Pitkänen N, Parra EJ, Fernandez-Rhodes L, Alyass A, Monnereau C, Curtin JA, Have CT, McCormack SE, Hollensted M, Frithioff-Bøjsøe C, Valladares-Salgado A, Peralta-Romero J, Teo Y-Y, Standl M, Leinonen JT, Holm J-C, Peters T, Vioque J, Vrijheid M, Simpson A, Custovic A, Vaudel M, Canouil M, Lindi V, Atalay M, Kähönen M, Raitakari OT, van Schaik BDC, Berkowitz RI, Cole SA, Voruganti VS, Wang Y, Highland HM, Comuzzie AG, Butte NF, Justice AE, Gahagan S, Blanco E, Lehtimäki T, Lakka TA, Hebebrand J, Bonnefond A, Grarup N, Froguel P, Lyytikäinen L-P, Cruz M, Kobes S, Hanson RL, Zemel BS, Hinney A, Teo KK, Meyre D, North KE, Gilliland FD, Bisgaard H, Bustamante M, Bonnelykke K, Pennell CE, Rivadeneira F, Uitterlinden AG, Baier LJ, Vrijkotte TGM, Heinrich J, Sørensen TIA, Saw S-M, Pedersen O, Hansen T, Eriksson J, Widén E, McCarthy MI, Njølstad PR, Power C, Hyppönen E, Sebert S, Brown CD, Järvelin M-R, Timpson NJ, Johansson S, Hakonarson H, Jaddoe VWV, Grant SFA, Early Growth Genetics Consortiumet al., 2019, A trans-ancestral meta-analysis of Genome-wide Association Studies reveals loci associated with childhood obesity, Human Molecular Genetics, Vol: 28, Pages: 3327-3338, ISSN: 0964-6906

Although hundreds of GWAS-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity, and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of thirty studies consisting of up to 13,005 cases (≥95th percentile of BMI achieved 2-18 years old) and 15,599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1,888 cases and 4,689 controls from seven cohorts of European and North/South American ancestry. In addition to observing eighteen previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene: METTL15). The variant was nominally associated in only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than ten SNPs (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

Journal article

Wilman HR, Parisinos CA, Atabaki-Pasdar N, Kelly M, Thomas EL, Neubauer S, IMI DIRECT Consortium, Mahajan A, Hingorani AD, Patel RS, Hemingway H, Franks PW, Bell JD, Banerjee R, Yaghootkar Het al., 2019, Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration, Journal of Hepatology, Vol: 71, Pages: 594-602, ISSN: 0168-8278

BACKGROUND & AIMS: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. METHODS: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. RESULTS: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. CONCLUSION: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. LAY SUMMARY: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart

Journal article

Bourouh C, Oger F, Gromada X, Moreno M, Carney C, Kerr-Conte J, Pattou F, Froguel P, Annicotte J-Set al., 2019, The transcriptional activity of E2F1 is controlled through exendin-4 signalling in pancreatic beta cell, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S214-S214, ISSN: 0012-186X

Conference paper

Baron M, Maillet J, Huyvaert M, Dechaume A, Boutry R, Aubert C, Balkau B, Roussel R, Marre M, Canouil M, Froguel P, Bonnefond Aet al., 2019, Pathogenic, loss-of function mutations in MRAP2 cause monogenic metabolic syndrome, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S146-S146, ISSN: 0012-186X

Conference paper

Huang T, Wang T, Zheng Y, Ellervik C, Li X, Gao M, Fang Z, Chai J-F, Ahluwalia TVS, Wang Y, Voortman T, Noordam R, Frazier-Wood A, Scholz M, Sonestedt E, Akiyama M, Dorajoo R, Zhou A, Kilpelainen TO, Kleber ME, Crozier SR, Godfrey KM, Lemaitre R, Felix JF, Shi Y, Gupta P, Khor C-C, Lehtimaki T, Wang CA, Tiesler CMT, Thiering E, Standl M, Rzehak P, Marouli E, He M, Lecoeur C, Corella D, Lai C-Q, Moreno LA, Pitkanen N, Boreham CA, Zhang T, Saw SM, Ridker PM, Graff M, Van Rooij FJA, Uitterlinden AG, Hofman A, van Heemst D, Rosendaal FR, de Mutsert R, Burkhardt R, Schulz C-A, Ericson U, Kamatani Y, Yuan J-M, Power C, Hansen T, Sorensen TIA, Tjonneland A, Overvad K, Delgado G, Cooper C, Djousse L, Rivadeneira F, Jameson K, Zhao W, Liu J, Lee NR, Raitakari O, Kahonen M, Viikari J, Grote V, Langhendries J-P, Koletzko B, Escribano J, Verduci E, Dedoussis G, Yu C, Tham YC, Lim B, Lim SH, Froguel P, Balkau B, Fink NR, Vinding RK, Sevelsted A, Bisgaard H, Coltell O, Dallongeville J, Gottrand F, Pahkala K, Niinikoski H, Hypponen E, Pedersen O, Marz W, Inskip H, Jaddoe VV, Dennison E, YinWong T, Sabanayagam C, Tai E-S, Mohlke KL, Mackey DA, Gruszfeld D, Deloukas P, Tucker KL, Fumeron F, Bonnelykke K, Rossing P, Estruch R, Ordovas JM, Arnett DK, Meirhaeghe A, Amouyel P, Cheng C-Y, Sim X, Teo YY, van Dam RM, Koh W-P, Orho-Melander M, Loeffler M, Kubo M, Thiery J, Mook-Kanamori DO, Mozaffarian D, Psaty BM, Franco OH, Wu T, North KE, Smith GD, Chavarro JE, Chasman DI, Qi Let al., 2019, Association of Birth Weight With Type 2 Diabetes and Glycemic Traits A Mendelian Randomization Study, JAMA NETWORK OPEN, Vol: 2, ISSN: 2574-3805

Journal article

Thomas CE, Haussler RS, Hong M-G, Raverdy V, Dale M, Vinuela A, Canouil M, Dermitzakis ET, Froguel P, Brunak S, Pattou F, Schwenk JMet al., 2019, Individual effects of gastric bypass surgery on longitudinal blood protein profiles: an IMI DIRECT study, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S271-S271, ISSN: 0012-186X

Conference paper

Koivula RW, Forgie IM, Kurbasic A, Viñuela A, Heggie A, Giordano GN, Hansen TH, Hudson M, Koopman ADM, Rutters F, Siloaho M, Allin KH, Brage S, Brorsson CA, Dawed AY, De Masi F, Groves CJ, Kokkola T, Mahajan A, Perry MH, Rauh SP, Ridderstråle M, Teare HJA, Thomas EL, Tura A, Vestergaard H, White T, Adamski J, Bell JD, Beulens JW, Brunak S, Dermitzakis ET, Froguel P, Frost G, Gupta R, Hansen T, Hattersley A, Jablonka B, Kaye J, Laakso M, McDonald TJ, Pedersen O, Schwenk JM, Pavo I, Mari A, McCarthy MI, Ruetten H, Walker M, Pearson E, Franks PW, IMI DIRECT Consortiumet al., 2019, Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium., Diabetologia, Vol: 62, Pages: 1601-1615, ISSN: 0012-186X

AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enro

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00385224&limit=30&person=true