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Evaluation of the Genetic Architecture of Cystic Fibrosis

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EVALUATION OF THE GENETIC ARCHITECTURE OF CYSTIC FIBROSIS by Melis Atalar Aksit A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March 2020 © 2020 Melis Atalar Aksit All rights reserved Abstract Cystic fibrosis (CF) is an autosomal recessive disease caused by variants in CFTR. Individuals with CF show a high degree of variability in disease severity, complications and survival. This phenotypic variability is influenced by a combination of the allelic heterogeneity in CFTR, genetic modifiers outside of CFTR, environmental factors, and stochastic (random) factors. In this study, I evaluate genetic modifiers that influence the age of onset of diabetes occurring as a complication of CF (cystic fibrosis- related diabetes, or CFRD), and the impact of one of the most common CF-causing mutations in CFTR, W1282X. In Chapter 2, in a genome-wide association study for CFRD, I obtained genome- wide significance for variants at a novel locus (PTMA) and two known CFRD genetic modifiers (TCF7L2 and SLC26A9). Furthermore, I determined CFRD and T2D have more etiologic and mechanistic overlap than previously known, aligning along pathways involving β-cell function rather than insulin sensitivity. In Chapter 3, I identified a variant in a well-studied locus, CDKN2B-AS1, that is associated with markedly earlier onset of cystic fibrosis-related diabetes in females. This finding could partially explain why females with cystic fibrosis develop diabetes at a younger age than males, and provides new information on disease etiology that could affect future risk-assessment strategies. In Chapter 4, I demonstrated how W1282X, one of the most common CF- causing mutations, results in a premature termination codon which induces nonsense- mediated mRNA decay. This finding indicates transcripts with this mutation will not generate any protein, and hence treatment with CFTR modulators (which act on expressed protein) would not be beneficial. ii Taken together, these findings highlight the importance of understanding the genetic etiology of each individual’s disease for appropriate treatment. The nature of the CF-causing mutation in CFTR will inform proper treatment, and genetic risk factors outside of CFTR influences disease severity may be used to adjust disease surveillance strategies such as adjusting the age or frequency of diabetes screening tests. Furthermore, this work provides a better understanding of the genetic architecture of cystic fibrosis- related diabetes, which gives us insight into the mechanism of this disease. iii Thesis Committee Advisor & 1st Reader: Garry R. Cutting, MD Professor of Pediatrics and Medicine McKusick-Nathans Institute of the Department of Genetic Medicine Johns Hopkins School of Medicine Advisor & 2nd Reader: Scott M. Blackman, MD, PhD Associate Professor of Pediatrics McKusick-Nathans Institute of the Department of Genetic Medicine Johns Hopkins School of Medicine Chair & 3rd Reader: Terri H. Beaty, PhD Professor Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Loyal A. Goff, PhD Assistant Professor of Neuroscience McKusick-Nathans Institute of the Department of Genetic Medicine Johns Hopkins School of Medicine Dan E. Arking, PhD Professor of Medicine McKusick-Nathans Institute of the Department of Genetic Medicine Johns Hopkins School of Medicine iv Dedication To my parents, whom I owe this PhD to. Their unconditional support and selfless sacrifices has brought me to where I am today. To my sister, who has been by my side since day one, and has brought so much joy into my life. To my husband, who has brought out the best in me. I would not have been able to get through my thesis without him, and I know I can get through anything because he is by my side. v Acknowledgements My thesis would not have been possible without the support of many people I am so lucky to have in my life. First and foremost, I’d like to thank my thesis advisors, Dr. Garry Cutting and Dr. Scott Blackman. I am very lucky to be mentored by these two amazing physician scientists. Dr. Cutting has provided a great lab environment with a lot of support. He keeps all of us motivated and provides us with all the resources we need to be successful. Dr. Blackman patiently guided me on how to do better analyses, payed attention to the detail, and helped perfect my work. Together, the two of them provided the perfect balance which made my doctoral thesis work very enjoyable. I am very grateful for all of their help and guidance. In addition, I would like to thank my colleagues in the lab, who have made me look forward to coming in to lab every day. Dr. Neeraj Sharma has been an unofficial third mentor to me. He is extremely hard working, very knowledgeable, and always happy to answer all of my questions. I am very grateful for all of the opportunities and support he gave me along the way. In addition, the upper year PhD students, Dr Briana Vecchio-Pagan, Dr. Melissa Lee, Dr. Ted Han, Dr. Allison McCague, and Dr. Anh-Thu Lam have been a great example for me and provided me advice that allowed my thesis work to go much more smoothly. I am especially grateful for Dr. Anh-Thu Lam, my “kitten pair”, who is always on top of things, has patiently listened and helped me prepare for all of my presentations and exams, and most importantly has become a great, lifelong friend. In addition, I am grateful for Karen Raraigh, who has been a great resource for me; she knows all of the details of all of the genetic variants in CFTR by heart, and always helps put things into perspective from a patient stand point. I would also like to thank all of the other past and present lab members; Anya Joynt, Alyssa Bowling, Matthew Pellicore, Taylor Evans, Emily Marcisak, Corey Lu, Yasmin Akhtar, Kathleen Paul and Derek Osorio, for the countless great memories and making my time as a doctoral thesis student so enjoyable. In addition, I am very grateful for Patricia Cornwall, who has made sure that everything goes very smoothly, and has always known how to make me laugh in the process. vi I would also like to thank our collaborators at the Center for Inherited Disease Research (CIDR) of JHMI. Dr. Hua Ling, Dr. Peng Zhang, Dr. Elizabeth Pugh, and Kurt Hetrick have been extremely helpful and undoubtedly significantly improved my thesis work. Lastly, I would like to thank the human genetics program. I am grateful for Dr. Barbara Migeon for founding this PhD program which provided me with so many opportunities. I am also very grateful for Dr. David Valle and Sandy Muscelli for providing an environment filled with so many opportunities and making sure everything goes smoothly in the process. Finally, I would like to thank my fellow doctoral students in the program, for their support and friendship. I owe my thesis to all of these people, whom together provided me with this incredible support system. I am very grateful for all of their support, advice, and encouragement. vii Table of Contents Abstract ii Thesis Committee iv Dedication v Acknowledgements vi Table of Contents viii List of Tables x List of Figures xii Chapter 1: Introduction 1 1.1 Cystic Fibrosis 2 1.2 Phenotypic heterogeneity in CF 2 1.3 Cystic Fibrosis-Related Diabetes 4 1.4 Genetic Modifiers of Cystic Fibrosis-Related Diabetes 6 1.5 Nonsense-mediated mRNA Decay and W1282X 8 Chapter 2: Genetic modifiers of cystic fibrosis-related diabetes 9 have extensive overlap with type 2 diabetes and related traits 2.1 Introduction 10 2.2 Results 12 2.3 Discussion 22 2.4 Methods 28 Chapter 3: Common variants in CDKN2B-AS1 delay onset of 68 CFRD in females 3.1 Introduction 69 viii 3.2 Results 70 3.3 Discussion 74 3.4 Methods 76 Chapter 4: Decreased mRNA and protein stability of W1282X 84 limits response to modulator therapy 4.1 Introduction 85 4.2 Results 87 4.3 Discussion 93 4.4 Materials and Methods 97 Chapter 5: Conclusions 114 Reference 118 Curriculum Vitae 132 ix List of Tables Chapter 2: Table 2.1 Characteristics of patients enrolled by the studies 41 comprising the International Cystic Fibrosis Gene Modifier Consortium. Table 2.2 Association statistics for top variant at each genome-wide 42 significant locus. Table S2.1 Associations of potential covariates with CFRD onset. 50 Table S2.2 Association statistics of variants that exceeded genome-wide 51 significance. Table S2.3 Association statistics for all variants that exceeded suggestive 52 significance. Table S2.4 Association statistics of T2D risk variants previously identified as 54 CFRD modifiers other than TCF7L2. Table S2.5 Associations of variants with T2D and CFRD that were 55 genome-wide significant in either study. Table S2.6 Variants included in each polygenic risk score. 60 Table S2.7 Polygenic Risk Score (PRS) association statistics. 65 Table S2.8 Variants included in the CFRD PRS. 66 Table S2.9 Table S2.11. Association summary statistics for F508del only, non F508del homozygotes, and F508del homozygosity * SNP interaction term analyses in variants that exceeded genome-wide significance. x Chapter 4: Table S4.1 EMGs containing full-length CFTR cDNA and flanking introns 113 faithfully reproduce splicing patterns observed in affected tissues. xi List of Figures Chapter 2: Figure 2.1 Manhattan plot of Phase 1 + 2 combined association analysis. 36 Figure 2.2 LocusZoom and Forest Plots of genome-wide significant loci, 37 TCF7L2 (A-B), PTMA (C-D), and SLC26A9 (E-F). Figure 2.3 Comparison of the genetic risk architectures of CFRD and T2D. 38 Figure 2.4 Cumulative incidence (A-B) and prevalence (C-D) plots by CFRD PRS 40 in test and replication populations.
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  • The Ciliopathy-Associated CPLANE Proteins Direct Basal Body Recruitment of Intraflagellar Transport Machinery

    The Ciliopathy-Associated CPLANE Proteins Direct Basal Body Recruitment of Intraflagellar Transport Machinery

    The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Toriyama, M., C. Lee, S. P. Taylor, I. Duran, D. H. Cohn, A. Bruel, J. M. Tabler, et al. 2016. “The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.” Nature genetics 48 (6): 648-656. doi:10.1038/ng.3558. http:// dx.doi.org/10.1038/ng.3558. Published Version doi:10.1038/ng.3558 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:29626113 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Genet Manuscript Author . Author manuscript; Manuscript Author available in PMC 2016 November 09. Published in final edited form as: Nat Genet. 2016 June ; 48(6): 648–656. doi:10.1038/ng.3558. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery Michinori Toriyama1, Chanjae Lee1, S. Paige Taylor2, Ivan Duran2, Daniel H. Cohn3, Ange- Line Bruel4, Jacqueline M. Tabler1, Kevin Drew1, Marcus R. Kelley5, Sukyoung Kim1, Tae Joo Park1,**, Daniella Braun6, Ghislaine Pierquin7, Armand Biver8, Kerstin Wagner9, Anne Malfroot10, Inusha Panigrahi11, Brunella Franco12,13, Hadeel Adel Al-lami14, Yvonne Yeung14, Yeon Ja Choi15, University of Washington Center for Mendelian Genomics16, Yannis Duffourd4, Laurence Faivre4,17, Jean-Baptiste Rivière4,18, Jiang Chen15, Karen J.