Dr Anna Ulrich

Research Fellow

Academic and research departments

School of Biosciences.


Vasiliki Lagou, Longda Jiang, Anna Ulrich, Liudmila Zudina, Ayse Demirkan, Karla Sofia Gutiérrez González, Marika Kaakinen, Zhanna Balkhiiarova, Inga Prokopenko, Alessia Faggian, Jared G. Maina, Shiqian Chen, Petar V. Todorov, Sodbo Sharapov, Alessia David, Letizia Marullo, Reedik Magi, Gudmar Thorleifsson, He Gao, Roxana-Maria Rujan, Emma Ahlqvist, Evangelos Evangelou, Beben Benyamin, Robert A Scott, Aaron Isaacs, Jing Hua Zhao, Sara M. Willems, Toby Johnson, Christian Gieger, Harald Grallert, Christa Meisinger, Martina Mueller-Nurasyid, Rona J Strawbridge, Anuj Goel, Denis Rybin, Eva Albrecht, Anne U Jackson, Heather M Stringham, Ivan R., Jr Correa, Eric Farber-Eger, Valgerdur Steinthorsdottir, Andre G. Uitterlinden, Patricia B. Munroe, Morris J. Brown, Julian Schmidberger, Oddgeir Holmen, Barbara Thorand, Kristian Hveem, Tom Wilsgaard, Karen L Mohlke, Zhe Wang, Aleksey Shmeliov, Marcel den Hoed, Ruth J F Loos, Wolfgang Kratzer, Mark Haenle, Wolfgang Koenig, Bernhard O. Boehm, Tricia M. Tan, Alejandra Tomas, Victoria Salem, Inês Barroso, Jaakko Tuomilehto, Michael Boehnke, Jose C. Florez, Anders Hamsten, Hugh Watkins, Inger Njolstad, H-Erich Wichmann, Mark J Caulfield, Kay-Tee Khaw, Cornelia van Duijn, Albert Hofman, Nicholas J. Wareham, Claudia Langenberg, John B. Whitfield, Nicholas G. Martin, Grant Montgomery, Chiara Scapoli, Ioanna Tzoulaki, Paul Elliott, Unnur Thorsteinsdottir, Kari Stefansson, Evan L. Brittain, MI McCarthy, Philippe Froguel, Patrick M. Sexton, Denise Wootten, Leif Groop, Josée Dupuis, James B Meigs, Giuseppe Deganutti, Tune H. Pers, Christopher A. Reynolds, Yurii S. Aulchenko, Ben Jones (2023)GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification, In: Nature Genetics55(9)pp. 1448-1461 Nature Research

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. Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

James Dooley, V Lagou, Jermaine Goveia, ANNA ULRICH, Katerina Rohlenova, Nathalie Heirman, Tobias Karakach, Yulia Lampi, Shawez Khan, Jun Wang, Tom Dresselaers, Uwe Himmelreich, Marc J Gunter, INGA PROKOPENKO, P Carmeliet, AJ Liston (2020)Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility, In: Cell Reports32(2)107880 Cell Press

Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. Known risk factors include obesity, diet, and type 2 diabetes; however, the low incidence rate and interconnection of these factors confound the isolation of individual effects. Here, we use epidemiological analysis of prospective human cohorts and parallel tracking of pancreatic cancer in mice to dissect the effects of obesity, diet, and diabetes on pancreatic cancer. Through longitudinal monitoring and multi-omics analysis in mice, we found distinct effects of protein, sugar, and fat dietary components, with dietary sugars increasing Mad2l1 expression and tumor proliferation. Using epidemiological approaches in humans, we find that dietary sugars give a MAD2L1 genotype-dependent increased susceptibility to pancreatic cancer. The translation of these results to a clinical setting could aid in the identification of the at-risk population for screening and potentially harness dietary modification as a therapeutic measure. [Display omitted] •Distinct roles for dietary fat, protein, and sugar on murine pancreatic cancer•Dietary glucose triggers Mad2l1 upregulation and tumor cell proliferation in mice•Gene-diet interaction identifies sugar-MAD2L1 link in human pancreatic cancer•Dietary plant fats were protective in human pancreatic cancer susceptibility Dooley et al. used parallel analysis of a murine pancreatic cancer model and a human prospective cohort to study the interaction of diet and pancreatic cancer. Both systems identify complex effects with different dietary components, converging on a link between dietary sugar and the cell-cycle checkpoint gene MAD2L1.

Justiina Ronkainen, Rozenn Nedelec, Angelica Atehortua, ZHANNA BALKHIIAROVA, Anna Cascarano, Vien Ngoc Dang, Ahmed Elhakeem, Esther van Enckevort, Ana Goncalves Soares, Sido Haakma, Miia Halonen, Katharina F Heil, Anni Heiskala, Eleanor Hyde, B Jacquemin, Elina Keikkala, Jules Kerckhoffs, Anton Klåvus, Joanna A Kopinska, Irina Motoc, Johanna Lepeule, Francesca Marazzi, Mari Näätänen, Anton Ribbenstedt, Amanda Rundblad, Otto Savolainen, Valentina Simonetti, Nina de Toro Eadie, Evangelia Tzala, ANNA ULRICH, Thomas Wright, Iman Zarei, Enrico d’Amico, Federico Belotti, Carl Brunius, Christopher Castleton, Marie-Aline Charles, Romy Gaillard, Kati Hanhineva, Gerard Hoek, Kirsten B Holven, Vincent W.V Jaddoe, MARIKA KAAKINEN, Eero Kajantie, M Kavousi, Timo A. Lakka, Jason Matthews, Andrea Piano Mortari, Marja Vääräsmäki, Trudy Voortman, C Webster, Marie Zins, Vincenzo Atella, Maria Bulgheroni, M Chadeau-Hyam, Gabriella Conti, Jayne Evans, Janine F. Felix, Barbara Heude, Marjo-Riitta Jarvelin, Marjukka Kolehmainen, Rikard Landberg, Karim Lekadir, Stefano Parusso, INGA PROKOPENKO, Susanne R de Rooij, Tessa Roseboom, Morris Swertz, Nicholas J. Timpson, Stine M Ulven, Roel Vermeulen, Teija Juola, Sylvain Sebert (2022)LongITools: Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases, In: Environmental epidemiology6(1)e184

The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our “modern” postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases.

Zhanna Balkhiyarova, Rosa Luciano, Marika Kaakinen, Anna Ulrich, Aleksey Shmeliov, Marzia Bianchi, Laura Chioma, Bruno Dallapiccola, Inga Prokopenko, Melania Manco (2021)Relationship between glucose homeostasis and obesity in early life - A study of Italian children and adolescents, In: Human Molecular Geneticsddab287 Oxford University Press

Epidemic obesity is the most important risk factor for prediabetes and type 2 diabetes (T2D) in youth as it is in adults. Obesity shares pathophysiological mechanisms with T2D and is likely to share part of the genetic background. We aimed to test if weighted genetic risk scores (GRSs) for T2D, fasting glucose (FG) and fasting insulin (FI) predict glycaemic traits and if there is a causal relationship between obesity and impaired glucose metabolism in children and adolescents. Genotyping of 42 SNPs established by genome-wide association studies for T2D, FG and FI was performed in 1660 Italian youths aged between 2 and 19 years. We defined GRS for T2D, FG and FI and tested their effects on glycaemic traits, including FG, FI, indices of insulin resistance/beta cell function and body mass index (BMI). We evaluated causal relationships between obesity and FG/FI using one-sample Mendelian randomization analyses in both directions. GRS-FG was associated with FG (beta = 0.075 mmol/l, SE = 0.011, P = 1.58 × 10 −11) and beta cell function (beta = −0.041, SE = 0.0090 P = 5.13 × 10 −6). GRS-T2D also demonstrated an association with beta cell function (beta = −0.020, SE = 0.021 P = 0.030). We detected a causal effect of increased BMI on levels of FI in Italian youths (beta = 0.31 ln (pmol/l), 95%CI [0.078, 0.54], P = 0.0085), while there was no effect of FG/FI levels on BMI. Our results demonstrate that the glycaemic and T2D risk genetic variants contribute to higher FG and FI levels and decreased beta cell function in children and adolescents. The causal effects of adiposity on increased insulin resistance are detectable from childhood age.

V Lagou, Reedik Magi, JJ Hottenga, Harald Grallert, John R. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, R Jansen, JL Min, AS Dimas, ANNA ULRICH, LIUDMILA ZUDINA, Jesper R Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G Stathopoulou, Aaron Isaacs, SM Willems, Pau Navarro, T Tanaka, Anne U Jackson, May E Montasser, Jeff R O'Connell, Lawrence F Bielak, R. Webster, Richa Saxena, Jeanette M Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, SY Shin, Najaf Amin, Albert V Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C D Johnson, T Johnson, Karen Kapur, G Thorleifsson, RJ Strawbridge, Laura J Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, T Fall, Ross M Fraser, A Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, ME Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, J Luan, Momoko Horikoshi, Ping An, S Sanna, Yvonne Boettcher, NW Rayner, Ilja M Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D Hastie, SH Wild, Stela McLachlan, SS Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, G Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, A Hicks, Rainer Rauramaa, S Bandinelli, B Thorand, Yongmei Liu, Iva Miljkovic, L Lind, Alex Doney, M Perola, AD Hingorani, M Kivimäki, Meena Kumari, Amanda J Bennett, C Groves, C Herder, Heikki A Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J L Bakker, Matti Uusitupa, Colin N. A Palmer, J Wouter Jukema, N Sattar, A Pouta, H Snieder, E Boerwinkle, James S Pankow, PK Magnusson, Ulrika Krus, Chiara Scapoli, Eco J C N de Geus, Matthias Blüher, Bruce H R Wolffenbuttel, Michael A Province, G Abecasis, James B Meigs, G Kees Hovingh, Jaana Lindström, James F Wilson, Alan F Wright, GV Dedoussis, Stefan R Bornstein, Peter E H Schwarz, Anke Tönjes, BR Winkelmann, B Boehm, W März, Andres Metspalu, Jackie F Price, P Deloukas, Antje Körner, Timo A. Lakka, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Richard N Bergman, J Tuomilehto, N Wareham, Claudia Langenberg, S Männistö, Paul Franks, C Hayward, Veronique Vitart, J Kaprio, Sophie Visvikis-Siest, Beverley Balkau, D Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia van Duijn, C Gieger, T Illig, L Ferrucci, NL Pedersen, Peter P Pramstaller, Michael Boehnke, Timothy M. Frayling, AR Shuldiner, Patricia A Peyser, Sharon L R Kardia, Lyle J. Palmer, BW Penninx, Pierre Meneton, T Harris, G Navis, Pim van der Harst, George Davey Smith, NG Forouhi, Ruth J F Loos, V Salomaa, N Soranzo, D Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, V Gudnason, DS Siscovick, H Watkins, Cecile Lecoeur, P Vollenweider, A Franco-Cereceda, P Eriksson, Marjo-Riitta Jarvelin, K Stefansson, A Hamsten, G Nicholson, Fredrik Karpe, ET Dermitzakis, C Lindgren, MI McCarthy, P Froguel, MARIKA KAAKINEN, VG Lyssenko, R Watanabe, E Ingelsson, Jose C Florez, J Dupuis, I Barroso, AP Morris, INGA PROKOPENKO (2021)Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability, In: Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability (Nature Communications, (2021), 12, 1, (24), 10.1038/s41467-020-19366-9) Nature Research

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

Jared G. Maina, Vincent Pascat, Liudmila Zudina, Anna Ulrich, Igor Pupko, Amelie Bonnefond, Zhanna Balkhiyarova, Marika Kaakinen, Philippe Froguel, Inga Prokopenko (2023)Abdominal obesity is a more important causal risk factor for pancreatic cancer than overall obesity, In: European journal of human genetics : EJHG31(8)pp. 962-966 Springer Nature

Obesity and type 2 diabetes (T2D) are associated with increased risk of pancreatic cancer. Here we assessed the relationship between pancreatic cancer and two distinct measures of obesity, namely total adiposity, using BMI, versus abdominal adiposity, using BMI adjusted waist-to-hip ratio (WHRadjBMI) by utilising polygenic scores (PGS) and Mendelian randomisation (MR) analyses. We constructed z-score weighted PGS for BMI and WHRadjBMI using publicly available data and tested for their association with pancreatic cancer defined in UK biobank (UKBB). Using publicly available summary statistics, we then performed bi-directional MR analyses between the two obesity traits and pancreatic cancer. PGS(BMI) was significantly (multiple testing-corrected) associated with pancreatic cancer (OR[95%CI] = 1.0804[1.025-1.14], P = 0.0037). The significance of association declined after T2D adjustment (OR[95%CI] = 1.073[1.018-1.13], P = 0.00904). PGS(WHRadjBMI) association with pancreatic cancer was at the margin of statistical significance (OR[95%CI] = 1.047[0.99-1.104], P = 0.086). T2D adjustment effectively lost any suggestive association of PGS(WHRadjBMI) with pancreatic cancer (OR[95%CI] = 1.039[0.99-1.097], P = 0.14). MR analyses showed a nominally significant causal effect of WHRadjBMI on pancreatic cancer (OR[95%CI] = 1.00095[1.00011-1.0018], P = 0.027) but not for BMI on pancreatic cancer. Overall, we show that abdominal adiposity measured using WHRadjBMI, may be a more important causal risk factor for pancreatic cancer compared to total adiposity, with T2D being a potential driver of this relationship.

ANNA ULRICH, Pablo Otero-Núñez, John Wharton, Emilia M Swietlik, Stefan Gräf, N Morrell, D Wang, Allan Lawrie, Martin R Wilkins, INGA PROKOPENKO, Christopher J Rhodes (2020)Expression Quantitative Trait Locus Mapping in Pulmonary Arterial Hypertension, In: Genes11(11)1247 MDPI

Expression quantitative trait loci (eQTL) can provide a link between disease susceptibility variants discovered by genetic association studies and biology. To date, eQTL mapping studies have been primarily conducted in healthy individuals from population-based cohorts. Genetic effects have been known to be context-specific and vary with changing environmental stimuli. We conducted a transcriptome- and genome-wide eQTL mapping study in a cohort of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) using RNA sequencing (RNAseq) data from whole blood. We sought confirmation from three published population-based eQTL studies, including the GTEx Project, and followed up potentially novel eQTL not observed in the general population. In total, we identified 2314 eQTL of which 90% were cis-acting and 75% were confirmed by at least one of the published studies. While we observed a higher GWAS trait colocalization rate among confirmed eQTL, colocalisation rate of novel eQTL reported for lung-related phenotypes was twice as high as that of confirmed eQTL. Functional enrichment analysis of genes with novel eQTL in PAH highlighted immune-related processes, a suspected contributor to PAH. These potentially novel eQTL specific to or active in PAH could be useful in understanding genetic risk factors for other diseases that share common mechanisms with PAH.