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Language Phenotypes of Autism: Towards an Understanding of the Communication Domain of Autism

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Language Phenotypes of Autism: Towards an Understanding of the Communication Domain of Autism LANGUAGE PHENOTYPES OF AUTISM: TOWARDS AN UNDERSTANDING OF THE COMMUNICATION DOMAIN OF AUTISM by ABBY ELISE HARE A dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey and The Graduate School of Biomedical Sciences University of Medicine and Dentistry of New Jersey In partial fulfillment of the requirements For the degree of Doctor of Philosophy Graduate Program in Microbiology and Molecular Genetics Written under the direction of Dr. Linda Brzustowicz And approved by __________________________________ __________________________________ __________________________________ ___________________________________ __________________________________ New Brunswick, New Jersey October, 2013 i 2013 Abby Elise Hare ALL RIGHTS RESERVED ABSTRACT OF THE DISSERTATION Language Phenotypes of Autism: Towards an Understanding of the Communication Domain of Autism By ABBY ELISE HARE Dissertation Director: Dr. Linda Brzustowicz Autism spectrum disorders (ASD) are complex neurodevelopmental disorders that are characterized by deficits in communication, social impairment, and the presence of restricted and repetitive behaviors. The work presented in this dissertation aims to reduce the genetic heterogeneity of samples ascertained for ASD by developing communication phenotypes for use in two genetics studies. Communication impairments in ASD can include impairments in speech or language and, like all traits in ASD, can range in severity from person to person. The first study involved a genome-wide linkage analysis in a sample of multiplex autism families for two non-verbal motor speech (NVMSD) phenotypes: NVMSD:ALL including nonverbal and minimally verbal subjects and NVMSD:C where there is behavioral evidence that language comprehension is relatively intact. Evidence for linkage was identified on several chromosomes: 1q24.2, 3q25.31, 4q22.3, 5p12, 5q33.1, 17p12, 17q11.2, and 17q22 for NVMSD:ALL and 4p15.2 and 21q22.2 for NVMSD:C. Genome-wide analysis and fine mapping of candidate genes did not produce strong evidence for association. The second study identified language (LI) and reading (RI) impairment phenotypes in a dataset ascertained for autism and specific language ii impairment (SLI) in the same family. These families were extensively phenotyped with a comprehensive testing battery where all language measures were found to be heritable. In addition to LI and RI, social impairment and obsessive-compulsive behavioral phenotypes were identified in these families using well-respected assessments (SRS and Y-BOCS, respectively). Genome-wide linkage analysis yielded evidence for linkage on 13q21.2 (YBOCS), 14q32.31 (SRS), 15q25.1 (LI), 15q26.2 (SRS), and 16p12.3 (RI). Genome-wide analysis and fine mapping of candidate genes did not produce strong evidence for association. The identification of non- overlapping loci for each phenotype supports the hypothesis that these phenotypes successfully identify unique communication and social impairment loci in ASD. Furthermore, as the second study was conducted in families ascertained for autism and for SLI, these results support the hypothesis that some individuals with ASD and those with SLI without ASD may have some shared genetic etiology. The lack strong evidence for association suggests that rare and/or multiple variants may play a role in the etiology of ASD. iii ACKNOWLEDGEMENTS First and foremost, I would like to acknowledge the families that participated in the studies presented in this dissertation. These families have selflessly volunteered in the hopes of contributing to the knowledge of autism etiology. Without these families, genetic studies such as these would not be possible. Thank you to all who have donated their time, patience, and DNA to both the Autism Genetics Resource Exchange and the New Jersey Language and Autism Genetics Study (NJLAGS). Scientific research is a collaborative field where many individuals come together from various fields to contribute their knowledge. I would like to thank the following collaborators for their technical and scientific contributions: Dr. Christopher Bartlett and his laboratory for his major contributions to the NJLAGS analyses and expertise in Specific Language Impairment, Dr. Steven Buyske for conducting factor analysis as well as other statistical analyses, Drs. Barbie Zimmerman-Bier and Charles Cartwright for their medical expertise and contributions to the medical evaluations of NJLAGS families, Dr. Derek Gordon for his consultation on simulation analyses of our genetic data, the many testers who have collected data for NJLAGS, and Dr. Veronica Vieland and her colleagues for developing and supporting the statistical methodologies used for family-based linkage and association analyses. I would also like to acknowledge the Rutgers University Cell and DNA Repository Infinite Biologics for DNA storage and genotyping of the NJLAGS samples. I would like to extend my gratitude to the members of the Brzustowicz laboratory, past and present, who have I had the pleasure of working with: Bill Manley, Ray Zimmerman, Jaime Messenger, Jared Hayter, Carmen Ramirez, Gillian Silver, Zena Fermano, Josh Pennino, Anthony Marcketta, Brenda Patel, Pilar Garavito, Neda Gharani, Mike Moreau, Ariane Seto, and Karen iv Law. I would especially like to thank Drs. Marco Azaro and Judy Flax, not only for their countless hours of guidance and collaboration, but also for their friendship and support. Lastly, I would also like to thank my committee members Drs. Linda Brzustowicz, Jim Millonig, Tara Matise, Bonnie Firestein, and Gerard Costa for their guidance and consultation throughout my graduate school experience. I am deeply grateful to my advisor and mentor, Linda Brzustowicz, for her tremendous support and encouragement. Linda helped me to grow as a scientist by allowing me to pursue my own ideas while keeping me focused. I am eternally grateful to her for the many opportunities I have been given for those that are still to come. Funding for the AGRE work was provided by NIMH R01MH76433 (Veronica Vieland), R01MH086117 (Veronica Vieland), R01MH76435 (Linda Brzustowicz) and R01MH070366 (Linda Brzustowicz). Funding for the NJLAGS work was provided by NIMH R01MH70366 (Linda Brzustowicz), Challenge Grant RC1MH088288-01 (Linda Brzustowicz), and the New Jersey Governor’s Council for Medical Research and Treatment of Autism. v DEDICATION This dissertation is dedicated to the following people: My parents, Jeffrey and Cathryn Hare, who taught me the importance of hard work, courage, and perseverance. My longtime friends, Robin Pierce and Lauren Rees, for their support and comic relief. And to Matthew Harris, my soulmate and partner in life. Thank you to all. vi TABLE OF CONTENTS ABSTRACT OF THE DISSERTATION ................................................................................ ii ACKNOWLEDGEMENTS .............................................................................................. iv DEDICATION .............................................................................................................. vi TABLE OF CONTENTS ................................................................................................. vii LIST OF TABLES ........................................................................................................... x LIST OF FIGURES ........................................................................................................xii Chapter 1: Introduction .............................................................................................. 1 Autism – General Background ..............................................................................................1 Genetics of Autism ..............................................................................................................4 Genetic Studies of Autism ...................................................................................................7 Language and Autism ........................................................................................................ 20 Rationale for Thesis Experiments ....................................................................................... 23 Chapter 2: Combined linkage and linkage disequilibrium analysis of a motor speech phenotype within families ascertained for autism risk loci ........................................ 27 Abstract ........................................................................................................................... 28 Introduction ..................................................................................................................... 29 Methods .......................................................................................................................... 32 Results ............................................................................................................................. 40 Discussion ........................................................................................................................ 46 Conclusion ........................................................................................................................ 52 Chapter 3: Follow-up Linkage and Association Analyses of a Nonverbal Motor Speech Phenotype Identified in the AGRE Data Set ............................................................... 54 Abstract: .......................................................................................................................... 55 Background:
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