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Dissertation Docteur De L'université Du Luxembourg PhD-FSTC-2018-36 The Faculty of Sciences, Technology and Communication DISSERTATION Defence held on 26/04/2018 in Luxembourg to obtain the degree of DOCTEUR DE L’UNIVERSITÉ DU LUXEMBOURG EN BIOLOGIE by Dheeraj Reddy BOBBILI Born on 28 July 1988 in Autonagar, (India) UNRAVELING THE COMPLEX GENETICS OF NEUROLOGICAL DISORDERS Dissertation defence committee Dr. Rejko Krüger, dissertation supervisor Professor, Université du Luxembourg Dr. Enrico Glaab, Chairman Senior Research Scientist, Université du Luxembourg Dr. Reinhard Schneider, Vice-Chairman Head of bioinformatics core facility, Université du Luxembourg Dr. Federico Zara Professor, Laboratory of Neurogenetics, Istituto Giannina Gaslini Dr. Jose Antonio López Escámez Hospital Universitario Virgen de las Nieves, Granada Unraveling the complex genetics of neurological disorders A dissertation by Dheeraj Reddy Bobbili Completed in the Bioinformatics Core Group, Luxembourg Centre for Systems Biomedicine To obtain the degree of DOCTEUR DE L’UNIVERSITÉ DU LUXEMBOURG EN BIOLOGIE Dissertation Defence Committee: Supervisor: Prof. Dr. Rejko krüger Committee members: Dr. Enrico Glaab Dr. Reinhard Schneider Dr. Jose Antonio López-Escámez Dr. Federico Zara 2018 To my parents. Declaration I hereby declare that this dissertation has been written only by the undersigned and without any assistance from third parties. Furthermore, I confirm that no sources have been used in the preparation of this thesis other than those indicated herein. Dheeraj Reddy Bobbili Belval, Luxembourg May 2, 2018 ACKNOWLEDGMENTS I am thankful to Prof. Dr. Rejko krüger for being my supervisor. It is an honor to have you as my supervisor. You have been very supportive during my entire PhD. Your guidance and constructive ideas have helped me a lot during my PhD. I would like to thank Dr. Patrick May for his time and patience during the entire process of my PhD, right from hiring me to the end of my PhD. You have been a great inspiration and were always available whenever I needed you. You always believed in me and your enthusiasm towards research has motivated me to push myself harder. This work would not have been possible without you. Dr. Reinhard Schneider, I am very grateful to you for allowing me to be part of bioinformatics core and providing me with best of the facilities to conduct research. You are an inspiration, I have learnt a lot from you and it was a great opportunity to be part of your team. Dr. Federico Zara, Dr. Jose Antonio López-Escámez and Dr. Enrico Glaab, thank you very much for taking time of your busy schedules to be part of my jury committee. I am deeply indebted to you for your efforts. I am extremely grateful to all my collaborators within and outside Luxembourg. Especially, Prof. Dr. Holger Lerche, Dr. Bernd A. Neubauer, Dr. Dennis Lal, Dr. Kamel Jabbari, Dr. Javier Simón-Sánchez and Anamika Giri for allowing me to access and work with the data. Thank you, Prof. Dr. Rudi Balling for being an inspiration not just for me, but to the entire LCSB. You have built a great place to work. I would like to thank all the colleagues from LCSB for your support during my entire period here. A special thanks to the awesome biocore team, you are amazing and great people. During my PhD, each one of you have helped me one way or the other and I really appreciate your support. You guys have made biocore a wonderful place to work and It has been an amazing journey to work with you guys. Many of you are more than colleagues and have become good friends. Your suggestions in professional and personal life are invaluable. A special thanks to Venkata, i Marek, Roland, Wei, Marie, Sarah, Kavita, Anshika, Anya, Joe, Susanne, Peter, Yohan, Noua, Adriano, Marx and Christophe. I would like to thank the High Performance Computing team of University of Luxembourg for their continuous support during the course of my PhD. To all my good friends in Luxembourg, Aravind, Sunil, Aishwarya, Shaman, Maharshi and Serena. I cannot thank you guys enough for always being there for me, you made my life in Luxembourg a lifelong memory to cherish for. There are also many people in Luxembourg who helped me at various times, I owe them a lot. I thank all my friends back in India, each one of you have made a difference in my life and I have no words to express my feelings towards you. You guys never forget me and I am very lucky to have you guys as my friends. To my extended family, especially Raghu anna thank you so much for always believing in me and at times the only person to support me to pursue my dreams. Geeta vadina, you were always welcoming and happy to see me. You guys were the closest relatives that I have here and I am really glad for that. Thanks to all my cousins and other family members who have been an enormous support and took care of amma whenever there is a need. Finally, to my loving sister Chinni and her two beautiful kids ammu and duggu. You are the best sister, always positive and supportive even in difficult times. I am lucky to have you asmy sister. Amma and Nanna, I have no words to thank you enough. It is only because of you, I am what I am today. Nanna, I miss you everyday of my life. You were a great inspiration and I always wish that you were with us today to see your kids achieving new heights in their lives. Amma, you are the strongest person that I ever met in my life and I feel blessed to be your son. Love you both. ii ABSTRACT Neurological disorders comprise a group of diseases that affect brain, spine and the nerves that connect them. Many people worldwide are affected by neurological disorders irrespective of their ethnicity, age or gender. Currently, >800 neurological disorders have been identified and the list is still growing. Parkinson’s disease (PD) and epilepsy are two of the most common neurological disorders that cause a significant burden globally. It has been well established that in bothPD and epilepsy, genetics play a significant role in the generation and progression of the disease, while both the diseases have a monogenic or polygenic origin. A review of literature shows that both PD and epilepsy are caused due to the symphony of common, rare and ultra-rare variants. However, there is a high degree of heterogeneity with regard to genetics, which is evident from the lack of confirmation from various studies and the minute overlap between linkage and genome wide association studies (GWAS). Hence, in order to understand the underlying mechanisms of disease generation and progress, there is a need for unification of results obtained from multiple studies and a multifaceted approach studying variants occurring with different allele frequencies. Advances in the field of next generation sequencing (NGS) provided us an opportunity to identify and characterize the genetic variants associated to a disease more efficiently. Two of such useful techniques are whole genome sequencing (WGS) and whole-exome sequencing (WES) where the DNA of an individual is sequenced to identify disease-causing variants. In this thesis, we aimed to uncover the role of rare/ultra-rare variants in PD and epilepsy, using WGS/WES data. To achieve the aforementioned goal, state-of-the-art bioinformatic tools and statistical methods were used on various datasets generated by different studies. The work on epilepsy was divided into three parts. First, the burden analysis of rare variants in typical rolandic epilepsy (RE) and atypical rolandic epilepsy (ARE) was conducted, where we observed an increased burden of rare loss of function (LoF) variants across several disease genesets iii in RE/ARE cases. Whereas, in the second part, burden analyses of rare variants in several genesets were conducted in genetic generalized epilepsy (GGE). A significant burden was observed for rare nonsynonymous variants in GABAA receptors in the discovery cohort. Furthermore, the observed burden was replicated in two independent datasets, of which one was a WES study while the other was a targeted panel sequencing of GABAA receptor genes. From the identified variants in GABAA receptors in the discovery cohort, selected variants were functionally validated. Third, in RE/ARE and GGE, analysis of rare copy number deletions showed a significant burden and several novel candidate genes were identified. In PD, firstly private variants in the Parkinson’s Progression Markers Initiative (PPMI) dataset were studied, where we observed a genome-wide burden of private LoF variants and prediction models were constructed based on the burden score. Second, the genome-wide burden of U1 splice variants was observed in the PPMI dataset and the observation was confirmed in the Parkinson Disease Genetic Sequencing Consortium (PDGSC) dataset. Finally, we discovered several rare, novel variants (coding, non-coding and CNVs) belonging to multiple families from two familial PD studies (>50 families) that were segregating with PD. Altogether, this work demonstrates the utility of NGS in discovering novel genes and genesets found to be implicated in PD and epilepsy and show their heterogeneous contribution to the disease aetiology. These discoveries could improve the diagnostics of both PD and epilepsy by expanding the knowledge of molecular mechanisms underlying the disease and potentially help in establishing modern therapeutic applications. iv SCIENTIFIC OUTPUT Majority of this thesis has been adapted from the work that has either been published, is currently under peer-review and/or ready for submission with the candidate as the first/co-first author. All the projects in the thesis have been performed along with several collaborators and part of consortia and hence only the manuscripts with a major contributions have been incorporated as part of this thesis.
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