Imperial College London

ProfessorPhilippeFroguel

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Genomic Medicine
 
 
 
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Contact

 

+44 (0)20 7594 6520p.froguel

 
 
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Assistant

 

Mrs Patricia Murphy +44 (0)20 7594 1603

 
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Location

 

E306Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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1181 results found

Folon L, Baron M, Scherrer V, Toussaint B, Vaillant E, Loiselle H, Dechaume A, De Pooter F, Boutry R, Boissel M, Diallo A, Ning L, Balkau B, Charpentier G, Franc S, Marre M, Derhourhi M, Froguel P, Bonnefond Aet al., 2024, Pathogenic, Total Loss-of-Function DYRK1B Variants Cause Monogenic Obesity Associated With Type 2 Diabetes., Diabetes Care, Vol: 47, Pages: 444-451

OBJECTIVE: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated. RESEARCH DESIGN AND METHODS: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes. Each DYRK1B variant was functionally assessed in vitro. Variant pathogenicity was determined using criteria from the American College of Medical Genetics and Genomics (ACMG). The effect of pathogenic or likely pathogenic (P/LP) variants on metabolic traits was assessed using adjusted mixed-effects score tests. RESULTS: Sixty-five rare, heterozygous DYRK1B variants were identified and were not associated with obesity or type 2 diabetes. Following functional analyses, 20 P/LP variants were pinpointed, including 6 variants that exhibited a fully inhibitory effect (P/LP-null) on DYRK1B activity. P/LP and P/LP-null DYRK1B variants were associated with increased BMI and obesity risk; however, the impact was notably more pronounced for the P/LP-null variants (effect of 8.0 ± 3.2 and odds ratio of 7.9 [95% CI 1.2-155]). Furthermore, P/LP-null variants were associated with higher fasting glucose and type 2 diabetes risk (effect of 2.9 ± 1.0 and odds ratio of 4.8 [95% CI 0.85-37]), while P/LP variants had no effect on glucose homeostasis. CONCLUSIONS: P/LP, total loss-of-function DYRK1B variants cause monogenic obesity associated with type 2 diabetes. This study underscores the significance of conducting functional assessments in order to accurately ascertain the tangible effects of P/LP DYRK1B variants.

Journal article

Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, Mandla R, Huerta-Chagoya A, Melloni GEM, Kanoni S, Rayner NW, Bocher O, Arruda AL, Sonehara K, Namba S, Lee SSK, Preuss MH, Petty LE, Schroeder P, Vanderwerff B, Kals M, Bragg F, Lin K, Guo X, Zhang W, Yao J, Kim YJ, Graff M, Takeuchi F, Nano J, Lamri A, Nakatochi M, Moon S, Scott RA, Cook JP, Lee J-J, Pan I, Taliun D, Parra EJ, Chai J-F, Bielak LF, Tabara Y, Hai Y, Thorleifsson G, Grarup N, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Kwak S-H, Long J, Sun M, Tong L, Chen W-M, Nongmaithem SS, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen C-H, Raffield LM, Prins BP, Nicolas A, Yanek LR, Chen G, Brody JA, Kabagambe E, An P, Xiang AH, Choi HS, Cade BE, Tan J, Broadaway KA, Williamson A, Kamali Z, Cui J, Thangam M, Adair LS, Adeyemo A, Aguilar-Salinas CA, Ahluwalia TS, Anand SS, Bertoni A, Bork-Jensen J, Brandslund I, Buchanan TA, Burant CF, Butterworth AS, Canouil M, Chan JCN, Chang L-C, Chee M-L, Chen J, Chen S-H, Chen Y-T, Chen Z, Chuang L-M, Cushman M, Danesh J, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt K-U, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Franco OH, Frayling TM, Freedman BI, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Gordon-Larsen P, Gross M, Guare LA, Hackinger S, Hakaste L, Han S, Hattersley AT, Herder C, Horikoshi M, Howard A-G, Hsueh W, Huang M, Huang W, Hung Y-J, Hwang MY, Hwu C-M, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang H-M, Jasmine F, Jiang G, Jonas JB, Jørgensen T, Kamanu FK, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor C-C, Kibriya MG, Kim D-H, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee KM, Lee M-S, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Ligthart S, Lindgren CM, Linneberg A, Liu C-T, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lynch JA, Lyssenko V, Maeda S, Mamakou V, Mansuri SR, Matsuda K, Meitet al., 2024, Genetic drivers of heterogeneity in type 2 diabetes pathophysiology., Nature, Vol: 627, Pages: 347-357

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Journal article

Dance A, Fernandes J, Toussaint B, Vaillant E, Boutry R, Baron M, Loiselle H, Balkau B, Charpentier G, Franc S, Ibberson M, Marre M, Gernay M, Fadeur M, Paquot N, Vaxillaire M, Boissel M, Amanzougarene S, Derhourhi M, Khamis A, Froguel P, Bonnefond Aet al., 2024, Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics., Mol Metab, Vol: 79

OBJECTIVE: Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D). METHODS: P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D. In vitro analyses were then performed to assess the functional effect of each variant. Expression quantitative trait loci (eQTL) analysis was performed in pancreatic islets from 103 pancreatectomized individuals. The effect of P2RY1 on glucose-stimulated insulin secretion was finally assessed in human pancreatic beta cells (EndoCβH5), and RNA sequencing was performed on these cells. RESULTS: Sequencing P2YR1 in 9,266 participants revealed 22 rare variants, seven of which were loss-of-function according to our in vitro analyses. Carriers, except one, exhibited impaired glucose control. Our eQTL analysis of human islets identified P2RY1 variants, in a beta-cell enhancer, linked to increased P2RY1 expression and reduced T2D risk, contrasting with variants located in a silent region associated with decreased P2RY1 expression and increased T2D risk. Additionally, a P2RY1-specific agonist increased insulin secretion upon glucose stimulation, while the antagonist led to decreased insulin secretion. RNA-seq highlighted TXNIP as one of the main transcriptomic markers of insulin secretion triggered by P2RY1 agonist. CONCLUSION: Our findings suggest that P2RY1 inherited or acquired dysfunction increases T2D risk and that P2RY1 activation stimulates insulin secretion. Selective P2RY1 agonists, impermeable to the blood-brain barrier, could serve as potential insulin secretagogues.

Journal article

Kouidrat Y, Le Collen L, Vaxillaire M, Dechaume A, Toussaint B, Vaillant E, Amanzougarene S, Derhourhi M, Delemer B, Azahaf M, Froguel P, Bonnefond Aet al., 2024, Dominant PDX1 deficiency causes highly penetrant diabetes at different ages, associated with obesity and exocrine pancreatic deficiency: Lessons for precision medicine., Diabetes Metab, Vol: 50

OBJECTIVE: Heterozygous pathogenic or likely pathogenic (P/LP) PDX1 variants cause monogenic diabetes. We comprehensively examined the phenotypes of carriers of P/LP PDX1 variants, and delineated potential treatments that could be efficient in an objective of precision medicine. METHODS: The study primarily involved a family harboring a novel P/LP PDX1 variant. We then conducted an analysis of documented carriers of P/LP PDX1 variants, from the Human Gene Mutation Database (HGMD), RaDiO study, and Type 2 Diabetes Knowledge Portal (T2DKP) including 87 K participants. RESULTS: Within the family, we identified a P/LP PDX1 variant encoding p.G232S in four relatives. All of them exhibited diabetes, albeit with very different ages of onset (10-40 years), along with caudal pancreatic agenesis and childhood-onset obesity. In the HGMD, 79 % of carriers of a P/LP PDX1 variant displayed diabetes (with differing ages of onset from eight days of life to 67 years), 63 % exhibited pancreatic insufficiency and surprisingly 40 % had obesity. The impact of P/LP PDX1 variants on increased risk of type 2 diabetes mellitus was confirmed in the T2DKP. Dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), enabled good glucose control without hypoglycemia and weight management. CONCLUSIONS: This study reveals diverse clinical presentations among the carriers of a P/LP PDX1 variant, highlighting strong variations in diabetes onset, and unexpectedly high prevalence of obesity and pancreatic development abnormalities. Clinical data suggest that DPP4i and GLP1-RA may be the best effective treatments to manage both glucose and weight controls, opening new avenue in precision diabetic medicine.

Journal article

Johanns M, Haas JT, Raverdy V, Vandel J, Chevalier-Dubois J, Guille L, Derudas B, Legendre B, Caiazzo R, Verkindt H, Gnemmi V, Leteurtre E, Derhourhi M, Bonnefond A, Froguel P, Eeckhoute J, Lassailly G, Mathurin P, Pattou F, Staels B, Lefebvre Pet al., 2024, Time-of-day-dependent variation of the human liver transcriptome and metabolome is disrupted in MASLD., JHEP Rep, Vol: 6

BACKGROUND & AIMS: Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers. METHODS: Liver biopsies, collected within an 8 h-window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, steatotic or MASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, steatotic and MASH livers. RESULTS: Herein, we provide a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in MASLD. Transcriptomic analysis showed a robustness of core molecular clock components in steatotic and MASH livers. It also revealed stage-specific, time-of-day-dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intracellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFα and PPARγ signaling were predicted as important contributors to altered rhythmicity. CONCLUSION: MASLD progression to MASH perturbs time-of-day-dependent processes in human livers, while the differential expression of core molecular clock components is maintained. IMPACT AND IMPLICATIONS: This work characterizes the rhythmic patterns of the transcriptome and metabolome in the human liver. Using a cohort of well-phenotyped patients (n = 290) for whom the time-of-day at biopsy

Journal article

Meulebrouck S, Scherrer V, Boutry R, Toussaint B, Vaillant E, Dechaume A, Loiselle H, Balkau B, Charpentier G, Franc S, Marre M, Baron M, Vaxillaire M, Derhourhi M, Boissel M, Froguel P, Bonnefond Aet al., 2023, Pathogenic monoallelic variants in <i>GLIS3</i> increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas, DIABETOLOGIA, ISSN: 0012-186X

Journal article

Fumeron F, Velho G, Alzaid F, El Boustany R, Vandiedonck C, Bonnefond A, Froguel P, Potier L, Marre M, Balkau B, Roussel R, Venteclef Net al., 2023, Genetic variants of interferon-response factor 5 are associated with the incidence of chronic kidney disease: the DESIR study, GENES AND IMMUNITY, ISSN: 1466-4879

Journal article

Hu M, Kim I, Morán I, Peng W, Sun O, Bonnefond A, Khamis A, Bonas-Guarch S, Froguel P, Rutter GAet al., 2023, Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function., bioRxiv

Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers. In the present study, combined allele-specific expression (cASE) analysis in human islets revealed multiple variants that influence SLC30A8 expression. Epigenomic mapping identified an islet-selective enhancer cluster at the SLC30A8 locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the SLC30A8 promoter and additional neighbouring genes. Deletions of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-βH3 cells lowered the expression of SLC30A8 and several neighbouring genes, and improved insulin secretion. Whilst down-regulation of SLC30A8 had no effect on beta cell survival, loss of UTP23, RAD21 or MED30 markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the SLC30A8 locus and enhanced stimulated insulin secretion.

Journal article

Puig-Castellvi F, Pacheco-Tapia R, Deslande M, Jia M, Andrikopoulos P, Chechi K, Bonnefond A, Froguel P, Dumas M-Eet al., 2023, Advances in the integration of metabolomics and metagenomics for human gut microbiome and their clinical applications, TRAC-TRENDS IN ANALYTICAL CHEMISTRY, Vol: 167, ISSN: 0165-9936

Journal article

Andrikopoulos P, Aron-Wisnewsky J, Chakaroun R, Myridakis A, Forslund S, Nielsen T, Adriouch S, Holmes B, Chilloux J, Vieira-Silva S, Falony G, Salem J-E, Andreelli F, Belda E, Kieswich J, Chechi K, Puig-Castellvi F, Chevalier M, Le Chatelier E, Olanipekun M, Hoyles L, Alves R, Helft G, Isnard R, Køber L, Coelho LP, Rouault C, Gauguier D, Gøtze JP, Prifti E, Froguel P, The MetaCardis C, Zucker J-D, Bäckhed F, Vestergaard H, Hansen T, Oppert J-M, Blüher M, Nielsen J, Raes J, Bork P, Yaqoob M, Stumvoll M, Pedersen O, Ehrlich SD, Clément K, Dumas M-Eet al., 2023, Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide, Nature Communications, Vol: 14, Pages: 1-18, ISSN: 2041-1723

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied “explainable” machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.

Journal article

Saeed S, Khanam R, Janjua QM, Manzoor J, Ning L, Hanook S, Canouil M, Ali M, Ayesha H, Khan WI, Farooqi IS, Yeo GSH, O'Rahilly S, Bonnefond A, Butt TA, Arslan M, Froguel Pet al., 2023, High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor, CELL REPORTS MEDICINE, Vol: 4, ISSN: 2666-3791

Journal article

Gao W, Liu L, Huh E, Gbahou F, Cecon E, Oshima M, Houze L, Katsonis P, Hegron A, Fan Z, Hou G, Charpentier G, Boissel M, Derhourhi M, Marre M, Balkau B, Froguel P, Scharfmann R, Lichtarge O, Dam J, Bonnefond A, Liu J, Jockers Ret al., 2023, Human <i>GLP1R</i> variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity, NATURE METABOLISM

Journal article

Lagou V, Jiang L, Ulrich A, Zudina L, González KSG, Balkhiyarova Z, Faggian A, Maina JG, Chen S, Todorov PV, Sharapov S, David A, Marullo L, Mägi R, Rujan R-M, Ahlqvist E, Thorleifsson G, Gao Η, Εvangelou Ε, Benyamin B, Scott RA, Isaacs A, Zhao JH, Willems SM, Johnson T, Gieger C, Grallert H, Meisinger C, Müller-Nurasyid M, Strawbridge RJ, Goel A, Rybin D, Albrecht E, Jackson AU, Stringham HM, Corrêa IR, Farber-Eger E, Steinthorsdottir V, Uitterlinden AG, Munroe PB, Brown MJ, Schmidberger J, Holmen O, Thorand B, Hveem K, Wilsgaard T, Mohlke KL, Wang Z, GWA-PA Consortium, Shmeliov A, den Hoed M, Loos RJF, Kratzer W, Haenle M, Koenig W, Boehm BO, Tan TM, Tomas A, Salem V, Barroso I, Tuomilehto J, Boehnke M, Florez JC, Hamsten A, Watkins H, Njølstad I, Wichmann H-E, Caulfield MJ, Khaw K-T, van Duijn CM, Hofman A, Wareham NJ, Langenberg C, Whitfield JB, Martin NG, Montgomery G, Scapoli C, Tzoulaki I, Elliott P, Thorsteinsdottir U, Stefansson K, Brittain EL, McCarthy MI, Froguel P, Sexton PM, Wootten D, Groop L, Dupuis J, Meigs JB, Deganutti G, Demirkan A, Pers TH, Reynolds CA, Aulchenko YS, Kaakinen MA, Jones B, Prokopenko I, Meta-Analysis of Glucose and Insulin-Related Traits Consortium MAGICet al., 2023, GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification, Nature Genetics, Vol: 55, Pages: 1448-1461, ISSN: 1061-4036

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Journal article

Orioli L, Canouil M, Sawadogo K, Ning L, Deldicque L, Lause P, de Barsy M, Froguel P, Loumaye A, Deswysen Y, Navez B, Bonnefond A, Thissen J-Pet al., 2023, Identification of myokines susceptible to improve glucose homeostasis after bariatric surgery, EUROPEAN JOURNAL OF ENDOCRINOLOGY, Vol: 189, Pages: 409-421, ISSN: 0804-4643

Journal article

Maina JG, Balkhiyarova Z, Nouwen A, Pupko I, Ulrich A, Boissel M, Bonnefond A, Froguel P, Khamis A, Prokopenko I, Kaakinen Met al., 2023, Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes., Diabetes Care, Vol: 46, Pages: 1707-1714

OBJECTIVE: Depression is a common comorbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them. RESEARCH DESIGN AND METHODS: We applied two-sample, bidirectional Mendelian randomization (MR) to assess causality between type 2 diabetes and depression. We investigated potential mediation using two-step MR. To identify shared genetics, we performed 1) genome-wide association studies (GWAS) separately and 2) multiphenotype GWAS (MP-GWAS) of type 2 diabetes (19,344 case subjects, 463,641 control subjects) and depression using major depressive disorder (MDD) (5,262 case subjects, 86,275 control subjects) and self-reported depressive symptoms (n = 153,079) in the UK Biobank. We analyzed expression quantitative trait locus (eQTL) data from public databases to identify target genes in relevant tissues. RESULTS: MR demonstrated a significant causal effect of depression on type 2 diabetes (odds ratio 1.26 [95% CI 1.11-1.44], P = 5.46 × 10-4) but not in the reverse direction. Mediation analysis indicated that 36.5% (12.4-57.6%, P = 0.0499) of the effect from depression on type 2 diabetes was mediated by BMI. GWAS of type 2 diabetes and depressive symptoms did not identify shared loci. MP-GWAS identified seven shared loci mapped to TCF7L2, CDKAL1, IGF2BP2, SPRY2, CCND2-AS1, IRS1, CDKN2B-AS1. MDD has not brought any significant association in either GWAS or MP-GWAS. Most MP-GWAS loci had an eQTL, including single nucleotide polymorphisms implicating the cell cycle gene CCND2 in pancreatic islets and brain and the insulin signaling gene IRS1 in adipose tissue, suggesting a multitissue and pleiotropic underlying mechanism. CONCLUSIONS: Our results highlight the importance to prevent type 2 diabetes at the onset of depressive symptoms and the need to maintain a healthy weight in the context of its effect on depression and type 2 diabetes comorbidity.

Journal article

Saeed S, Ning L, Badreddine A, Mirza MU, Boissel M, Khanam R, Manzoor J, Janjua QM, Khan WI, Toussaint B, Vaillant E, Amanzougarene S, Derhourhi M, Trant JF, Siegert A-M, Lam BYH, Yeo GSH, Chabraoui L, Touzani A, Kulkarni A, Farooqi IS, Bonnefond A, Arslan M, Froguel Pet al., 2023, Biallelic Mutations in P4HTM Cause Syndromic Obesity., Diabetes, Vol: 72, Pages: 1228-1234

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.

Journal article

Maurin L, Ning L, Boissel M, Marselli L, Pattou F, Kerr-Conte J, Marchetti P, Bonnefond A, Froguel P, Khamis Aet al., 2023, Pnliprp1 (pancreatic lipase related protein 1) hypermethylation in the exocrine pancreas links type 2 diabetes to pancreatic cancer development: an EWAS study, 59th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S129-S129, ISSN: 0012-186X

Conference paper

Dance A, Derhourhi M, Boissel M, Marre M, Charpentier G, Khamis A, Froguel P, Bonnefond Aet al., 2023, Functional genomics highlights type 2 diabetes-associated purinergic receptor P2RY1 as a new modulator of insulin secretion in humans, 59th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S44-S45, ISSN: 0012-186X

Conference paper

Brown AA, Fernandez-Tajes JJ, Hong M-G, Brorsson CA, Koivula RW, Davtian D, Dupuis T, Sartori A, Michalettou T-D, Forgie IM, Adam J, Allin KH, Caiazzo R, Cederberg H, De Masi F, Elders PJM, Giordano GN, Haid M, Hansen T, Hansen TH, Hattersley AT, Heggie AJ, Howald C, Jones AG, Kokkola T, Laakso M, Mahajan A, Mari A, Mcdonald TJ, Mcevoy D, Mourby M, Musholt PB, Nilsson B, Pattou F, Penet D, Raverdy V, Ridderstrale M, Romano L, Rutters F, Sharma S, Teare H, 't Hart L, Tsirigos KD, Vangipurapu J, Vestergaard H, Brunak S, Franks PW, Frost G, Grallert H, Jablonka B, Mccarthy MI, Pavo I, Pedersen O, Ruetten H, Walker M, Adragni K, Allesoe RLL, Artati AA, Arumugam M, Atabaki-Pasdar N, Baltauss T, Banasik K, Barnett AL, Baum P, Bell JD, Beulens JW, Bianzano SB, Bizzotto R, Bonnefond A, Cabrelli L, Dale M, Dawed AY, de Preville N, Dekkers KF, Deshmukh HA, Dings C, Donnelly L, Dutta A, Ehrhardt B, Engelbrechtsen L, Eriksen R, Fan Y, Ferrer J, Fitipaldi H, Forman A, Fritsche A, Froguel P, Gassenhuber J, Gough S, Graefe-Mody U, Grempler R, Groeneveld L, Groop L, Gudmundsdottir V, Gupta R, Hennige AMH, Hill AV, Holl RW, Hudson M, Jacobsen UP, Jennison C, Johansen J, Jonsson A, Karaderi T, Kaye J, Kennedy G, Klintenberg M, Kuulasmaa T, Lehr T, Loftus H, Lundgaard ATT, Mazzoni G, Mcrobert N, Mcvittie I, Nice R, Nicolay C, Nijpels G, Palmer CN, Pedersen HK, Perry MH, Pomares-Millan H, Prehn CP, Ramisch A, Rasmussen S, Robertson N, Rodriquez M, Sackett P, Scherer N, Shah N, Sihinevich I, Slieker RC, Sondertoft NB, Steckel-Hamann B, Thomas MK, Thomas CEE, Thomas ELL, Thorand B, Thorne CE, Tillner J, Tura A, Uhlen M, van Leeuwen N, van Oort S, Verkindt H, Vogt J, Wad Sackett PW, Wesolowska-Andersen A, Whitcher B, White MW, Adamski J, Schwenk JM, Pearson ER, Dermitzakis ET, Vinuela Aet al., 2023, Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits, NATURE COMMUNICATIONS, Vol: 14

Journal article

van de Vegte Y, Eppinga RP, van der Ende MY, Hagemeijer Y, Mahendran YV, Salfati EY, Smith AE, Tan V, Arking DV, Ntalla I, Appel EA, Schurmann C, Brody J, Rueedi R, Polasek O, Sveinbjornsson G, Lecoeur C, Ladenvall C, Zhao JH, Isaacs A, Wang L, Luan J, Hwang S-J, Mononen NU, Auro KF, Jackson A, Bielak L, Zeng L, Shah N, Nethander M, Campbell A, Rankinen T, Pechlivanis S, Qi L, Zhao W, Rizzi F, Tanaka T, Robino A, Cocca M, Lange L, Mueller-Nurasyid M, Roselli CE, Zhang W, Kleber MJ, Guo X, Lin HE, Pavani F, Galesloot T, Noordam RE, Milaneschi Y, Schraut K, den Hoed M, Degenhardt FE, Trompet S, van den Berg M, Pistis G, Tham Y-CS, Weiss SL, Sim XJ, Li HM, van der Most P, Nolte I, Lyytikaeinen L-PR, Said MA, Witte D, Iribarren CM, Launer LS, Ring S, de Vries P, Sever PP, Linneberg A, Bottinger EM, Padmanabhan S, Psaty B, Sotoodehnia N, Kolcic I, Roshandel DD, Paterson AO, Arnar DF, Gudbjartsson D, Holm H, Balkau BT, Silva CH, Newton-Cheh C, Nikus K, Salo PL, Mohlke KA, Peyser P, Schunkert H, Lorentzon M, Lahti JC, Rao DC, Cornelis MD, Faul JA, Smith J, Stolarz-Skrzypek K, Bandinelli S, Concas MP, Sinagra G, Meitinger T, Waldenberger MF, Sinner M, Strauch KE, Delgado GD, Taylor K, Yao J, Foco L, Melander O, de Graaf J, de Mutsert R, de Geus EJC, Johansson AK, Joshi PK, Lind L, Franke AW, Macfarlane PV, Tarasov K, Tan NB, Felix S, Tai E-SQ, Quek D, Snieder H, Ormel J, Ingelsson M, Lindgren CP, Morris AT, Raitakari O, Hansen T, Assimes T, Gudnason VJ, Timpson NC, Morrison AB, Munroe PP, Strachan D, Grarup N, Loos RJFR, Heckbert S, Vollenweider P, Hayward C, Stefansson K, Froguel P, Groop LJ, Wareham NM, van Duijn CF, Feitosa MJ, O'Donnell C, Kaehoenen M, Perola M, Boehnke M, Kardia SLR, Erdmann J, Palmer CNA, Ohlsson CJ, Porteous DG, Eriksson J, Bouchard C, Moebus S, Kraft PR, Weir D, Cusi D, Ferrucci L, Ulivi S, Girotto G, Correa A, Kaeaeb S, Peters AC, Chambers JS, Kooner J, Maerz WI, Rotter JA, Hicks A, Smith JG, Kiemeney LALMO, Mook-Kanamori D, Penninx BWJH, Gyllensteet al., 2023, Genetic insights into resting heart rate and its role in cardiovascular disease, Nature Communications, Vol: 14, ISSN: 2041-1723

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Journal article

Xiao J, El Eid L, Buenaventura T, Boutry R, Bonnefond A, Jones B, Rutter GA, Froguel P, Tomas Aet al., 2023, Control of human pancreatic beta cell kinome by glucagon-like peptide-1 receptor biased agonism, Diabetes, Obesity and Metabolism, Vol: 25, Pages: 2105-2119, ISSN: 1462-8902

AimTo determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon-like peptide-1 receptor (GLP-1R) balanced versus biased agonist stimulations.Materials and MethodsThis study analysed the kinomic profiles of human EndoC-βh1 cells following vehicle and GLP-1R stimulation with the pharmacological agonist exendin-4, as well as exendin-4–based biased derivatives exendin-phe1 and exendin-asp3 for acute (10-minute) versus sustained (120-minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis.ResultsThe present analysis reveals that kinomic responses are distinct for acute versus sustained GLP-1R agonist exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP-1R signalling mediators, constituting potential targets for further research on biased GLP-1R downstream signalling.ConclusionThe results from this study suggest that differentially biased exendin-phe1 and exendin-asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti-type 2 diabetes therapies with optimized downstream kinomic profiles.

Journal article

Maina JG, Pascat V, Zudina L, Ulrich A, Pupko I, Bonnefond A, Balkhiyarova Z, Kaakinen M, Froguel P, Prokopenko Iet al., 2023, Abdominal obesity is a more important causal risk factor for pancreatic cancer than overall obesity, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 31, Pages: 962-966, ISSN: 1018-4813

Journal article

Oger F, Bourouh C, Friano ME, Courty E, Rolland L, Gromada X, Moreno M, Carney C, Rabhi N, Durand E, Amanzougarene S, Berberian L, Derhourhi M, Blanc E, Hannou SA, Denechaud P-D, Benfodda Z, Meffre P, Fajas L, Kerr-Conte J, Pattou F, Froguel P, Pourcet B, Bonnefond A, Collombat P, Annicotte J-Set al., 2023, β-Cell-Specific <i>E2f1</i> Deficiency Impairs Glucose Homeostasis, β-Cell Identity, and Insulin Secretion, DIABETES, Vol: 72, Pages: 1112-1126, ISSN: 0012-1797

Journal article

Oger F, Moreno M, Derhourhi M, Thiroux B, Berberian L, Bourouh C, Durand E, Amanzougarene S, Badreddine A, Blanc E, Molendi-Coste O, Pineau L, Pasquetti G, Rolland L, Carney C, Bornaque F, Courty E, Gheeraert C, Eeckhoute J, Dombrowicz D, Kerr-Conte J, Pattou F, Staels B, Froguel P, Bonneford A, Annicotte J-Set al., 2023, Pharmacological HDAC inhibition impairs pancreatic β-cell function through an epigenome-wide reprogramming, ISCIENCE, Vol: 26

Journal article

Allesoe RL, Lundgaard AT, Hernandez Medina R, Aguayo-Orozco A, Johansen J, Nissen JN, Brorsson C, Mazzoni G, Niu L, Biel JH, Leal Rodriguez C, Brasas V, Webel H, Benros ME, Pedersen AG, Chmura PJ, Jacobsen UP, Mari A, Koivula R, Mahajan A, Vinuela A, Tajes JF, Sharma S, Haid M, Hong M-GB, Musholt P, De Masi F, Vogt J, Pedersen HK, Gudmundsdottir V, Jones A, Kennedy G, Bell J, Thomas EL, Frost G, Thomsen H, Hansen E, Hansen TH, Vestergaard H, Muilwijk MT, Blom MM, 't Hart L, Pattou F, Raverdy V, Brage S, Kokkola T, Heggie A, McEvoy D, Mourby M, Kaye J, Hattersley A, McDonald T, Ridderstrale M, Walker M, Forgie IN, Giordano G, Pavo I, Ruetten H, Pedersen O, Hansen T, Dermitzakis EW, Franks PM, Schwenk J, Adamski JI, McCarthy M, Pearson E, Banasik K, Rasmussen S, Brunak Set al., 2023, Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models (vol 41, pg 399, 2023), NATURE BIOTECHNOLOGY, Vol: 41, Pages: 1026-1026, ISSN: 1087-0156

Journal article

Le Collen L, Delemer B, Poitou C, Vaxillaire M, Toussaint B, Dechaume A, Badreddine A, Boissel M, Derhourhi M, Clement K, Petit JM, Mau-Them FT, Bruel A-L, Thauvin-Robinet C, Saveanu A, Cherifi BG, Le Beyec-Le Bihan J, Froguel P, Bonnefond Aet al., 2023, Heterozygous pathogenic variants in<i> POMC</i> are not responsible for monogenic obesity: Implication for MC4R agonist use, GENETICS IN MEDICINE, Vol: 25, ISSN: 1098-3600

Journal article

Li JH, Brenner LN, Kaur V, Figueroa K, Schroeder P, Huerta-Chagoya A, MAGIC Investigators, Diabetes Prevention Program DPP Research Group, Udler MS, Leong A, Mercader JM, Florez JCet al., 2023, Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH., Diabetologia, Vol: 66, Pages: 1260-1272

AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. METHODS: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. RESULTS: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10-9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10-8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increa

Journal article

Slieker R, Donnellly L, Akalestou E, Lopez-Noriega L, Melhem R, Gunes A, Abou Azar F, Efanov A, Georgiadou E, Muniangi-Muhitu H, Shiekh M, Giordano G, Åkerlund M, Ahlqvist E, Ashfaq A, Banasik K, Brunak S, Barovic M, Bouland G, Burdet F, Canouil M, Dragan I, Elders P, Fernandez C, Festa A, Fitipaldi H, Froguel P, Gudmundsdottir V, Gudnason V, Gerl M, van der Heijden A, Jennings L, Hansen M, Kim M, Leclerc I, Klose C, Kuznetsov D, Mansour Aly D, Mehl F, Marek D, Melander O, Niknejad A, Ottosson F, Pavo I, Duffin K, Syed S, Shaw J, Cabrera O, Pullen T, Simons K, Solimena M, Suvitaival T, Wretlind A, Rossing P, Lyssenko V, Legido Quigley C, Groop L, Thorens B, Franks P, Lim G, Estall J, Ibberson M, Beulens J, t Hart L, Pearson E, Rutter Get al., 2023, Identification of biomarkers for glycaemic deterioration in type 2 diabetes, Nature Communications, Vol: 14, Pages: 1-18, ISSN: 2041-1723

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

Journal article

Balkhiyarova Z, Maina JG, Nouwen A, Pupko I, Ulrich A, Bonnefond A, Froguel P, Kaakinen M, Prokopenko Iet al., 2023, Shared genetic mechanisms and causal relationship between self-reported depression and type 2 diabetes, Publisher: WILEY, ISSN: 0742-3071

Conference paper

Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, Mandla R, Huerta-Chagoya A, Rayner NW, Bocher O, Arruda ALDSV, Sonehara K, Namba S, Lee SSK, Preuss MH, Petty LE, Schroeder P, Vanderwerff B, Kals M, Bragg F, Lin K, Guo X, Zhang W, Yao J, Kim YJ, Graff M, Takeuchi F, Nano J, Lamri A, Nakatochi M, Moon S, Scott RA, Cook JP, Lee J-J, Pan I, Taliun D, Parra EJ, Chai J-F, Bielak LF, Tabara Y, Hai Y, Thorleifsson G, Grarup N, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Kwak S-H, Long J, Sun M, Tong L, Chen W-M, Nongmaithem SS, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen C-H, Raffield LM, Prins BP, Nicolas A, Yanek LR, Chen G, Brody JA, Kabagambe E, An P, Xiang AH, Choi HS, Cade BE, Tan J, Broadaway KA, Williamson A, Kamali Z, Cui J, Adair LS, Adeyemo A, Aguilar-Salinas CA, Ahluwalia TS, Anand SS, Bertoni A, Bork-Jensen J, Brandslund I, Buchanan TA, Burant CF, Butterworth AS, Canouil M, Chan JCN, Chang L-C, Chee M-L, Chen J, Chen S-H, Chen Y-T, Chen Z, Chuang L-M, Cushman M, Danesh J, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt K-U, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Franco OH, Frayling TM, Freedman BI, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Gordon-Larsen P, Gross M, Guare LA, Hackinger S, Han S, Hattersley AT, Herder C, Horikoshi M, Howard A-G, Hsueh W, Huang M, Huang W, Hung Y-J, Hwang MY, Hwu C-M, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang H-M, Jasmine F, Jiang G, Jonas JB, Jørgensen T, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor C-C, Kibriya MG, Kim D-H, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee KM, Lee M-S, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Lithgart S, Lindgren CM, Linneberg A, Liu C-T, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lynch JA, Lyssenko V, Maeda S, Mamakou V, Mansuri SR, Matsuda K, Meitinger T, Metspalu A, Mo H, Morris AD, Nadler JL, Nallet al., 2023, Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications., medRxiv

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10-8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

Journal article

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