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We focus on the use of human genetics to drive a mechanistic understanding of type 2 diabetes, and to identify novel translational opportunities.

Mccarthy

About the research 

We combine experimental and computational strategies, assembling diverse types of large-scale genetic genomic, molecular and clinical data, and deploying a wide range of statistical and computational approaches to mine them. We have a strong track record of providing postgraduate training in the analysis and interpretation of large-scale biomedical data sets, and several of our students have taken on projects that combine experimental and computational components. We interact closely with the research group led by Professor Anna Gloyn, and many of our students have been jointly supervised.

The foundation of our group’s work lies in the identification of DNA sequence variants influencing risk of T2D and related traits. I lead international consortia that have used large-scale genome wide association (~1.5M people) and exome sequencing analyses (~50,000) to uncover over 400 T2D-association signals: further expansion of these efforts is planned. We integrate genomic information from diabetes-relevant tissues (islet, fat, muscle) to understand the molecular and cellular impact of these variants, and to identify the effector transcripts through which they mediate their effects. In collaboration with Prof Gloyn, we seek to functionally validate these findings, using diverse techniques, including genome-editing and high-throughput screens. We aim to identify the shared pathways and networks through which multiple association signals operate.

A major focus of our activities lies in the development of partitioned polygenic risk scores: these set out to deconstruct T2D genetic risk into components mediated through particular pathophysiological defects (such as defective insulin secretion, insulin resistance or adiposity). These partitioned risk scores allow us to capture the clinical and phenotypic heterogeneity within T2D, and to determine whether these offer clinical utility with respect to the prediction of relevant clinical outcomes (such as drug response and complication risk). 

Students accepted within the group could be engaged in any of these research areas, and the examples which follow are illustrative:

  • Developing and implementing single-cell analyses of molecular phenotypes including assays of open chromatin, and the transcriptomic responses to gene perturbation (e.g. using CROP-Seq);
  • Identifying process-specific metabolomic and proteomic biomarkers, able to provide a “real time” complement to the predictive inference available from partitioned polygenic risk scores;
  • Exploring the impact of selection on variants associated with T2D and obesity;
  • Mapping tissue-specific differences in allelic imbalance at open chromatin sites to known/presumed tissues of action at GWAS loci  

Training Opportunities

Students within the lab will receive training in the analysis and interpretation of large biomedical data sets including (dependent on their decided project) genome-wide association analysis, exome sequencing, whole genome sequencing, NGS readouts of regulatory function (eg ATAC-Seq), RNA-Seq, network analysis and protein-protein interaction data. There are also opportunities to be trained in relevant experimental techniques (again dependent on the project) including cell-culture, genome-editing, stem-cell differentiation, single-cell analysis and high throughput genetic screens.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Publications

              
Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW,    Steinthorsdottir V, Scott RA, Grarup N, Cook JP, Schmidt EM, Wuttke M,    Sarnowski C, Mägi R, Nano J, Gieger C, Trompet S, Lecoeur C, Preuss M, Prins    BP, Guo X, Bielak LF, DIAMANTE Consortium, Bennett AJ, Bork-Jensen J,    Brummett CM, Canouil M, Eckardt K-U, Fischer K, Kardia SLR, Kronenberg F,    Läll K, Liu C-T, Locke AE, Luan J, Ntalla I, Nylander V, Schönherr S,    Schurmann C, Yengo L, Bottinger EP, Brandslund I, Christensen C, Dedoussis    G, Florez JC, Ford I, Franco OH, Frayling TM, Giedraitis V, Hackinger S,    Hattersley AT, Herder C, Ikram MA, Ingelsson M, Jørgensen ME, Jørgensen T,    Kriebel J, Kuusisto J, Ligthart S, Lindgren CM, Linneberg A, Lyssenko V,    Mamakou V, Meitinger T, Mohlke KL, Morris AD, Nadkarni G, Pankow JS, Peters    A, Sattar N, Stančáková A, Strauch K, Taylor KD, Thorand B, Thorleifsson G,    Thorsteinsdottir U, Tuomilehto J, Witte DR, Dupuis J, Peyser PA, Zeggini E,    Loos RJF, Froguel P, Ingelsson E, Lind L, Groop L, Laakso M, Collins FS,    Jukema JW, Palmer CNA, Grallert H, Metspalu A, Dehghan A, Köttgen A,    Abecasis G, Meigs JB, Rotter JI, Marchini J, Pedersen O, Hansen T,    Langenberg C, Wareham NJ, Stefansson K, Gloyn AL, Morris AP, Boehnke M,    McCarthy MI. Fine-mapping of an expanded set of type 2 diabetes loci to    single-variant resolution using high-density imputation and islet-specific    epigenome maps bioRxiv 245506; doi: https://doi.org/10.1101/245506; (Nature Genetics, in press) 
Thomsen SK, Raimondo A, Hastoy B, Sengupta S, Dia X-Q, Bautista A,    Censin J, Payne A, Umapathysivam MM, Spigelman A, Barrett A, Groves CJ, Beer    BL, Manning Fox E, McCarthy MI, Clark A, Mahajan A, Rorsman P, MacDonald PE,    Gloyn AL. Type 2 Diabetes Risk Alleles in PAM Impact on Human Beta Cell Function Nature Genetics 2018;50:1122-1131. PMID: 30054598 
Mahajan A, Wessel J, Willems SM, Zhao W, Robertson NR,    Chu AY, Gan W, Kitajima H, Taliun D, Rayner NW, Guo X, Lu Y, Li M, Jensen    RA, Hu Y, Huo S, Lohman KK, Zhang W, Cook JP, Prins BP, Flannick J, Grarup    N, Trubetskoy VV, Kravic J, Kim YJ, Rybin DV, Yaghootkar H, Müller-Nurasyid    M, Meidtner K, Li-Gao R, Varga TV, Marten J, Li J, Smith AV, An P, Ligthart    S, Gustafsson S, Malerba G, Demirkan A, Tajes JF, Steinthorsdottir V, Wuttke    M, Lecoeur C, Preuss M, Bielak LF, Graff M, Highland HM, Justice AE, Liu DJ,    Marouli E, Peloso GM, Warren HR; ExomeBP Consortium; MAGIC Consortium; GIANT    Consortium, Afaq S, Afzal S, Ahlqvist E, Almgren P, Amin N, Bang LB, Bertoni    AG, Bombieri C, Bork-Jensen J, Brandslund I, Brody JA, Burtt NP, Canouil M,    Chen YI, Cho YS, Christensen C, Eastwood SV, Eckardt KU, Fischer K, Gambaro    G, Giedraitis V, Grove ML, de Haan HG, Hackinger S, Hai Y, Han S,    Tybjærg-Hansen A, Hivert MF, Isomaa B, Jäger S, Jørgensen ME, Jørgensen T,    Käräjämäki A, Kim BJ, Kim SS, Koistinen HA, Kovacs P, Kriebel J, Kronenberg    F, Läll K, Lange LA, Lee JJ, Lehne B, Li H, Lin KH, Linneberg A, Liu CT, Liu    J, Loh M, Mägi R, Mamakou V, McKean-Cowdin R, Nadkarni G, Neville M, Nielsen    SF, Ntalla I, Peyser PA, Rathmann W, Rice K, Rich SS, Rode L, Rolandsson O,    Schönherr S, Selvin E, Small KS, Stančáková A, Surendran P, Taylor KD,    Teslovich TM, Thorand B, Thorleifsson G, Tin A, Tönjes A, Varbo A, Witte DR,    Wood AR, Yajnik P, Yao J, Yengo L, Young R, Amouyel P, Boeing H, Boerwinkle    E, Bottinger EP, Chowdhury R, Collins FS, Dedoussis G, Dehghan A, Deloukas    P, Ferrario MM, Ferrières J, Florez JC, Frossard P, Gudnason V, Harris TB,    Heckbert SR, Howson JMM, Ingelsson M, Kathiresan S, Kee F, Kuusisto J,    Langenberg C, Launer LJ, Lindgren CM, Männistö S, Meitinger T, Melander O,    Mohlke KL, Moitry M, Morris AD, Murray AD, de Mutsert R, Orho-Melander M,    Owen KR, Perola M, Peters A, Province MA, Rasheed A, Ridker PM, Rivadineira    F, Rosendaal FR, Rosengren AH, Salomaa V, Sheu WH, Sladek R, Smith BH,    Strauch K, Uitterlinden AG, Varma R, Willer CJ, Blüher M, Butterworth AS,    Chambers JC, Chasman DI, Danesh J, van Duijn C, Dupuis J, Franco OH, Franks    PW, Froguel P, Grallert H, Groop L, Han BG, Hansen T, Hattersley AT, Hayward    C, Ingelsson E, Kardia SLR, Karpe F, Kooner JS, Köttgen A, Kuulasmaa K,    Laakso M, Lin X, Lind L, Liu Y, Loos RJF, Marchini J, Metspalu A,    Mook-Kanamori D, Nordestgaard BG, Palmer CNA, Pankow JS, Pedersen O, Psaty    BM, Rauramaa R, Sattar N, Schulze MB, Soranzo N, Spector TD, Stefansson K,    Stumvoll M, Thorsteinsdottir U, Tuomi T, Tuomilehto J, Wareham NJ, Wilson    JG, Zeggini E, Scott RA, Barroso I, Frayling TM, Goodarzi MO, Meigs JB,    Boehnke M, Saleheen D, Morris AP, Rotter JI, McCarthy MI. Refining the accuracy    of validated target identification through coding variant fine-mapping in    type 2 diabetes. Nature Genetics 2018;50:559-571. PMID: 29632382; PMCID: PMC5898373.
Small KS, Todorčević M, Civelek M, El-Sayed Moustafa    JS, Wang X, Simon MM, Fernandez-Tajes J, Mahajan A, Horikoshi M, Hugill A,    Glastonbury CA, Quaye L, Neville MJ, Sethi S, Yon M, Pan C, Che N, Viñuela    A, Tsai PC, Nag A, Buil A, Thorleifsson G, Raghavan A, Ding Q, Morris AP,    Bell JT, Thorsteinsdottir U, Stefansson K, Laakso M, Dahlman I, Arner P,    Gloyn AL, Musunuru K, Lusis AJ, Cox RD, Karpe F, McCarthy MI. Regulatory    variants at KLF14 influence type 2 diabetes risk via a female-specific    effect on adipocyte size and body composition. Nature Genetics 2018;50:572-580. PMID: 29632379. PMCID: PMC5935235  
Thurner M, van de Bunt M, Gaulton K, Barrett A, Bennett    AJ, Torres JM, Nylander V, Mahajan A, Bell CG, Lowe R, Beck S, Rakyan VK,    Gloyn AL, McCarthy MI. Integration of human pancreatic islet genomic data    refines regulatory mechanisms at Type 2 Diabetes susceptibility loci bioRxiv    190892; doi: https://doi.org/10.1101/190892.    Elife 2018;7:e31977. PMID:    29412141 PMCID: PMC5828664 
  

Fuchsberger C, Flannick J, Teslovich TM, Mahajan A,    Agarwala V, Gaulton KJ, Ma C, Fontanillas P, Moutsianas L, McCarthy DJ,    Rivas MA, Perry JR, Sim X, Blackwell TW, Robertson NR, Rayner NW, Cingolani    P, Locke AE, Tajes JF, Highland HM, Dupuis J, Chines PS, Lindgren CM, Hartl    C, Jackson AU, Chen H, Huyghe JR, van de Bunt M, Pearson RD, Kumar A,    Müller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen Y, Scott    RA, Below JE, Chen P, Huang J, Go MJ, Stitzel ML, Pasko D, Parker SC, Varga    TV, Green T, Beer NL, Day-Williams AG, Ferreira T, Fingerlin T, Horikoshi M,    Hu C, Huh I, Ikram MK, Kim BJ, Kim Y, Kim YJ, Kwon MS, Lee J, Lee S, Lin KH,    Maxwell TJ, Nagai Y, Wang X, Welch RP, Yoon J, Zhang W, Barzilai N, Voight    BF, Han BG, Jenkinson CP, Kuulasmaa T, Kuusisto J, Manning A, Ng MC, Palmer    ND, Balkau B, Stančáková A, Abboud HE, Boeing H, Giedraitis V, Prabhakaran    D, Gottesman O, Scott J, Carey J, Kwan P, Grant G, Smith JD, Neale BM,    Purcell S, Butterworth AS, Howson JM, Lee HM, Lu Y, Kwak SH, Zhao W, Danesh    J, Lam VK, Park KS, Saleheen D, So WY, Tam CH, Afzal U, Aguilar D, Arya R,    Aung T, Chan E, Navarro C, Cheng CY, Palli D, Correa A, Curran JE, Rybin D,    Farook VS, Fowler SP, Freedman BI, Griswold M, Hale DE, Hicks PJ, Khor CC,    Kumar S, Lehne B, Thuillier D, Lim WY, Liu J, van der Schouw YT, Loh M,    Musani SK, Puppala S, Scott WR, Yengo L, Tan ST, Taylor HA Jr, Thameem F,    Wilson G, Wong TY, Njølstad PR, Levy JC, Mangino M, Bonnycastle LL,    Schwarzmayr T, Fadista J, Surdulescu GL, Herder C, Groves CJ, Wieland T,    Bork-Jensen J, Brandslund I, Christensen C, Koistinen HA, Doney AS, Kinnunen    L, Esko T, Farmer AJ, Hakaste L, Hodgkiss D, Kravic J, Lyssenko V,    Hollensted M, Jørgensen ME, Jørgensen T, Ladenvall C, Justesen JM,    Käräjämäki A, Kriebel J, Rathmann W, Lannfelt L, Lauritzen T, Narisu N,    Linneberg A, Melander O, Milani L, Neville M, Orho-Melander M, Qi L, Qi Q,    Roden M, Rolandsson O, Swift A, Rosengren AH, Stirrups K, Wood AR, Mihailov    E, Blancher C, Carneiro MO, Maguire J, Poplin R, Shakir K, Fennell T, DePristo    M, Hrabé de Angelis M, Deloukas P, Gjesing AP, Jun G, Nilsson P, Murphy J,    Onofrio R, Thorand B, Hansen T, Meisinger C, Hu FB, Isomaa B, Karpe F, Liang    L, Peters A, Huth C, O'Rahilly SP, Palmer CN, Pedersen O, Rauramaa R,    Tuomilehto J, Salomaa V, Watanabe RM, Syvänen AC, Bergman RN, Bharadwaj D,    Bottinger EP, Cho YS, Chandak GR, Chan JC, Chia KS, Daly MJ, Ebrahim SB,    Langenberg C, Elliott P, Jablonski KA, Lehman DM, Jia W, Ma RC, Pollin TI,    Sandhu M, Tandon N, Froguel P, Barroso I, Teo YY, Zeggini E, Loos RJ, Small    KS, Ried JS, DeFronzo RA, Grallert H, Glaser B, Metspalu A, Wareham NJ,    Walker M, Banks E, Gieger C, Ingelsson E, Im HK, Illig T, Franks PW, Buck G,    Trakalo J, Buck D, Prokopenko I, Mägi R, Lind L, Farjoun Y, Owen KR, Gloyn    AL, Strauch K, Tuomi T, Kooner JS, Lee JY, Park T, Donnelly P, Morris AD,    Hattersley AT, Bowden DW, Collins FS, Atzmon G, Chambers JC, Spector TD,    Laakso M, Strom TM, Bell GI, Blangero J, Duggirala R, Tai ES, McVean G,    Hanis CL, Wilson JG, Seielstad M, Frayling TM, Meigs JB, Cox NJ, Sladek R,    Lander ES, Gabriel S, Burtt NP, Mohlke KL, Meitinger T, Groop L, Abecasis G,    Florez JC, Scott LJ, Morris AP, Kang HM, Boehnke M, Altshuler D, McCarthy    MI. The genetic architecture of type 2 diabetes. Nature. 2016;536:41-47.    PMID: 27398621. PMCID: PMC5034897

Supervisors