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Pleiotropy in Complex Traits

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Pleiotropy in Complex Traits Pleiotropy in complex traits Sophie Hackinger Wellcome Sanger Institute University of Cambridge Jesus College This dissertation is submitted for the degree of Doctor of Philosophy September 2018 ii Abstract Thesis title: Pleiotropy in complex traits Name: Sophie Hackinger Genome-wide association studies (GWAS) have uncovered thousands of complex trait loci, many of which are associated with multiple phenotypes. The dedicated study of these pleiotropic effects is becoming increasingly common due to the availability of sample collections with high-dimensional phenotype data, such as the UK Biobank, and can yield important insights into the aetiology underlying complex disorders. In my PhD, I performed multi-trait analyses of medically relevant complex phenotypes to identify shared genetic factors. My first project involved a genome-wide overlap analysis of osteoarthritis (OA) and bone- mineral density (BMD), using summary statistics from two large-scale GWAS. OA and BMD are known to be inversely correlated, yet the genetics underlying this link remain poorly understood. I found robust evidence for association with OA at the SMAD3 locus, which is known to play a role in bone remodeling and cartilage maintenance. My second project aimed to elucidate the increased prevalence of type 2 diabetes (T2D) in schizophrenia (SCZ) patients. I used GWAS summary statistics of SCZ and T2D from the PGC and DIAGRAM consortia, respectively, to perform polygenic risk score analyses in three patient groups (SCZ only, T2D only, comorbid SCZ and T2D) and population-based controls. I find that the comorbid patient group have a higher genetic risk for both T2D and SCZ compared to controls, supporting the hypothesis that the epidemiologic link between these disorders is at least in part due to genetic factors. In my third project, I leveraged the correlation structure of over 274 protein biomarkers and 57 quantitative traits to perform multivariate GWAS on correlated trait clusters in a Greek isolated population. This approach uncovered several novel cis-associations not identified in single-trait GWAS, and highlights the power advantage of multivariate analysis. An important consideration for future studies will be the interpretation and follow-up of cross-phenotype associations, and the translation of these insights into clinical use. iii Declaration I hereby declare that the work described in this thesis is the result of my own work and includes nothing which is the outcome of work done in collaboration, except where otherwise stated. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text This thesis does not exceed 60,000 words (excluding Abstract, Table of Contents, Figure and Tables and References) as prescribed Degree Committee for the Faculty of Biology at the University of Cambridge. Sophie Hackinger September 2018 iv “Let’s not try to figure out everything at once.” – Matt Berninger v vi Acknowledgements First and foremost, I owe an immeasurably large “Thank you” to my supervisor, Prof Ele Zeggini, for nearly four years of support, guidance and encouragement. I also owe my gratitude to my thesis committee members Carl Anderson and Angela Wood, whose feedback helped to shape the projects described here. Since this is the only section of a thesis that generally has a realistic chance of attracting a readership > 4, I will try to keep the rest of it light and perhaps even moderately entertaining: A big thank you to past members of Team144, with special shout-outs to Kostas (<3), for being “the normal guy”; Bram, for many meme-rable moments; and Arthur, whose French I will continue to excuse and who always “know what do”. Of course, this list would not be complete without wanna-be-full-time-Team144-member and excellent Mariachi player, Fernando, who sits behind the wall. Casting the net of gratitude past N333, I also have to thank Loukas, for verbal sparring; Dan (de Lion), for many punderful conversations; Alex, for keeping the spice flowing; Joanna, for being a very reliable provider of procrastination material, as well as loyal consumer of my baking experiments; and José, for the daily embodiment of the “Morgan building spirit”. Now moving beyond sunny Hinxton (in random order): Thank you to Bianca and Nita, my oldest friends, who are always in my corner and – somewhat miraculously – still have not gotten bored of me. Nita also deserves a special thank you for being the link to my non-genetic family – Agron, Aferdita, Rron and Vesa. I would not be the person I am today without them (and how many people can say they are lucky enough to have two mums and two dads?). I am of course immensely grateful to my genetic parents for unconditional support and for supplying me with: my DNA (mum & dad), curiosity and vii an appetite for adventure (mum), culinary curiosity and an adventurous appetite (dad), as well as the super-power of irony (also dad). A big thank you to Hannah, for being the best partner in crime and 50% of the Dubious Duo; Sun-Gou, who lives on in the memory of past and present Anderson team members (as well as across the pond, in Boston), for being the signal that drowns out the noise (Tejas); and my late cat Sina, for providing almost 18 years of furry stress-relief. A special paragraph devoid of irony and jokes needs to be dedicated to the people who laid the intellectual foundation this thesis is built on: my former high school teachers. In particular, Peter Pail, whose eight years of English classes not only equipped me with the linguistic skills to undertake this doctorate, but also challenged and helped develop my capacity for critical thinking. I am honoured to have had him as my mentor. Last but not least, I would like to thank Scott and Brian Devendorf, Aaron and Bryce Dessner, and Matt Berninger, for providing the soundtrack to this PhD, and to my life in general. viii Publications From this thesis: Hackinger S, Prins B, Mamakou V, Zengini E, Marouli E, et al. Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia. Transl Psych. 2018 23;8(1):252 Hackinger S, Zeggini E. Statistical methods to detect pleiotropy in human complex traits. Open Biol. 2017; 7(11). Hackinger S, Trajanoska K, Styrkarsdottir U, Zengini E, Steinberg J, Ritchie GRS, et al. Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus. Hum Mol Genet. 2017; 26(19):3850- 3858. Arising elsewhere: Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, [...], Hackinger S, Hattersley AT, Herder C, Ikram MA, Ingelsson M. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet. 2018;50(11):1505-1513 Mahajan A, Wessel J, Willems SM, Zhao W, Robertson NR, Chu AY, […], Hackinger S, Hai Y, Han S, Tybjærg-Hansen A, et al. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nat Genet 2018; 50(4):559-571. Mamakou V, Hackinger S, Zengini E, Tsompanaki E, Marouli E, Serafetinidis I, et al. Combination therapy as a potential risk factor for the development of type 2 diabetes in patients with schizophrenia: the GOMAP study. BMC Psychiatry 2018; 18(1):249. Zengini E, Hatzikotoulas K, Tachmazidou I, Steinberg J, Hartwig FP, Southam L, Hackinger S, et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nature Genetics 2018:1. Casalone E, Tachmazidou I, Zengini E, Hatzikotoulas K, Hackinger S, Suveges D, et al. A novel variant in GLIS3 is associated with osteoarthritis. Ann Rheum Dis 2018; 77(4):620- 623. Marouli E, Kanoni S, Mamakou V, Hackinger S, Southam L, Prins B, et al. Evaluating the glucose raising effect of established loci via a genetic risk score. PLoS One 2017; 12(11):e0186669. ix Hackinger S, Kraaijenbrink T, Xue Y, Mezzavilla M, Asan, van Driem G, et al. Wide distribution and altitude correlation of an archaic high-altitude-adaptive EPAS1 haplotype in the Himalayas. Hum Genet 2016; 135(4):393-402. x Table of Contents Abstract ....................................................................................................................................................................... iii Declaration ............................................................................................................................................................ iviii Acknowledgements ............................................................................................................................................... viii Publications .............................................................................................................................................................. iix Table of Contents ..................................................................................................................................................... xi List of Figures .........................................................................................................................................................
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