DOCSLIB.ORG

UNIVERSITY of CALIFORNIA Los Angeles Investigation of Sex

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
UNIVERSITY of CALIFORNIA Los Angeles Investigation of Sex UNIVERSITY OF CALIFORNIA Los Angeles Investigation of sex-differential genetic risk factors for autism spectrum disorders A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Neuroscience by Donna Marie Werling 2014 © Copyright by Donna Marie Werling 2014 ABSTRACT OF THE DISSERTATION Investigation of sex-differential genetic risk factors for autism spectrum disorders by Donna Marie Werling Doctor of Philosophy in Neuroscience University of California, Los Angeles, 2014 Professor Daniel H. Geschwind, Chair Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders that affect more males than females, and the mechanisms responsible for increasing males’ risk or protecting females are not understood. This sex biased prevalence is consistent across time and populations, suggesting that an understanding of the processes driving sex-differential risk would likely be informative of fundamental pathophysiology in ASD. One known component of ASD risk is genetic variation. Thus, here I apply several approaches that leverage current knowledge of ASD genetics to investigate the role and mechanisms of sex-differential biology in ASD risk. First, I evaluate a cohort of families with more than one autistic child for evidence of sex- differential, familial risk variation. Second, I use genetic linkage analysis to identify sex- differential risk loci in families from the same multiplex cohort. Third, I characterize gene expression patterns in typical human neocortex to identify points of interaction between typical sexual dimorphism and genes known to carry risk variants for ASD. ii I find that recurrence rates for ASD diagnoses in multiplex families are consistent with a female protective model, in which females require more deleterious genetic variation to be affected with ASD and this greater genetic load is shared with females’ siblings. I also identify several chromosomal loci with evidence of genetic linkage in families either with (chromosome 8p21.2 and 8p12), or without (chromosome 1p31.3), an autistic female. No significant common variants are found in either region that can account for this linkage; these loci will be further investigated by targeted sequencing to identify rare risk variants. Gene expression analyses show that known ASD risk genes are not differentially expressed in males or females in the prenatal or adult human neocortex. However, astrocyte markers and gene sets implicated in immune function and inflammatory processes are expressed at higher levels in males. This suggests that sex-differential factors may operate downstream from, or interact with, ASD risk genes, as opposed to directly regulating the expression of these genes. Overall, findings from these multiple approaches provide valuable context for the function of sex-differential biology in ASD etiology, and suggest promising directions for future research. iii The dissertation of Donna Marie Werling is approved. Arthur P. Arnold Rita M. Cantor Nelson B. Freimer Daniel H. Geschwind, Committee Chair University of California, Los Angeles 2014 iv TABLE OF CONTENTS Chapter 1: Sex differences in autism spectrum disorders......................................................... 1 1.1: Introduction.................................................................................................................. 2 1.2: ASD prevalence in males and females........................................................................ 3 1.3: Presentation of ASD symptoms and related phenotypes in males and females.......... 5 1.4: Sex differences in genetic contributions to ASD risk.................................................. 7 1.5: Sex hormonal contributors to ASD risk....................................................................... 12 1.6: Conclusions.................................................................................................................. 16 Chapter 2: Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins...................................................... 18 2.1: Abstract........................................................................................................................ 19 2.2: Background.................................................................................................................. 20 2.3: Materials and methods................................................................................................. 24 2.3.a: Subjects............................................................................................................... 24 2.3.b: Sex ratios and recurrence risk............................................................................. 26 2.3.c: Quantitative phenotypes..................................................................................... 28 2.3.d: Concordance in twin pairs.................................................................................. 29 2.4: Results.......................................................................................................................... 30 2.5: Discussion.................................................................................................................... 39 2.6: Conclusions.................................................................................................................. 47 Chapter 3: Identification of suggestive sex-differential risk loci and replication of linkage at chromosome 20p13 for autism spectrum disorder.................................................................... 49 3.1: Abstract........................................................................................................................ 50 3.2: Background.................................................................................................................. 51 3.3: Materials and methods................................................................................................. 55 3.3.a: Subjects and genotyping..................................................................................... 55 3.3.b: Linkage analyses using all families.................................................................... 58 3.3.c: Sex-stratified linkage.......................................................................................... 59 3.3.d: Imputation........................................................................................................... 61 v 3.3.e: Linkage-directed association testing................................................................... 62 3.4: Results.......................................................................................................................... 63 3.4.a: Linkage in all families........................................................................................ 63 3.4.b: Sex-stratified linkage.......................................................................................... 66 3.4.c: Linkage-directed association.............................................................................. 72 3.5: Discussion.................................................................................................................... 73 3.6: Conclusions.................................................................................................................. 78 Chapter 4: Strategies for the identification of functional autism risk variants in linkage regions . .............................................................................................................................. 79 4.1: Linkage signals in autism spectrum disorders............................................................. 80 4.2: Common variant association........................................................................................ 82 4.3: Rare variant association............................................................................................... 84 4.4: Potential implications.................................................................................................. 89 Chapter 5: Gene expression implicates pathways at the interface between sexual dimorphisms and genetic risk variants for autism spectrum disorders........................................................... 90 5.1: Abstract........................................................................................................................ 91 5.2: Background.................................................................................................................. 91 5.3: Materials and methods................................................................................................. 96 5.3.a: Gene expression data from human brain tissue.................................................. 96 5.3.a.i: Adult BrainSpan sample............................................................................ 96 5.3.a.ii: Adult replication sample............................................................................ 97 5.3.a.iii: Prenatal BrainSpan sample....................................................................... 99 5.3.b: Differential expression analysis.......................................................................... 101 5.3.c: Annotation gene sets........................................................................................... 101 5.3.c.i: Autism spectrum disorder risk genes......................................................... 102 5.3.c.ii: Gene expression
Load more

Recommended publications
  • Genomic Modelling of Bipolar Disorders: Comparison of Multifactor Dimension Reduction and Classification-Based Data Mining Methods
    GENOMIC MODELLING OF BIPOLAR DISORDERS: COMPARISON OF MULTIFACTOR DIMENSION REDUCTION AND CLASSIFICATION-BASED DATA MINING METHODS A THESIS SUBMITTED TO THE GRADUATE SCHOOL OF INFORMATICS OF THE MIDDLE EAST TECHNICAL UNIVERSITY BY CENGİZHAN AÇIKEL IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN THE DEPARTMENT OF MEDICAL INFORMATICS MARCH 2017 GENOMIC MODELLING OF BIPOLAR DISORDERS: COMPARISON OF MULTIFACTOR DIMENSION REDUCTION AND CLASSIFICATION-BASED DATA MINING METHODS Submitted by CENGİZHAN AÇIKEL in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Medical Informatics, Middle East Technical University by, Prof. Dr. Deniz Zeyrek Bozşahin ______________ Director, Graduate School of Informatics Assoc. Prof. Dr. Yeşim Aydın Son ______________ Head of Department, Health Informatics Assoc. Prof. Dr. Yeşim Aydın Son ______________ Supervisor, Health Informatics, METU Examining Committee Members: Assoc.Prof.Dr. Cem İyigün ______________ Industrial Engineering, METU Assoc. Prof. Dr. Yeşim Aydin Son ______________ Supervisor, Health Informatics, METU Assist. Prof. Dr. Aybar Can Acar ______________ Health Informatics, METU Assoc.Prof.Dr. Güvem Gümüş Akay ______________ Brain Research Center, Ankara University Assist.Prof.Dr. Ercüment Çiçek ______________ Computer Engineering, Bilkent University Date: ____/____/______ iii I hereby declare that all information in this document has been obtained and presented in accordance with academic rules and ethical conduct. I also declare that, as required by these rules and conduct, I have fully cited and referenced all material and results that are not original to this work. Name, Last Name : Cengizhan AÇIKEL Signature : __________________ iii ABSTRACT GENOMIC MODELLING OF BIPOLAR DISORDERS: COMPARISON OF MULTIFACTOR DIMENSION REDUCTION AND CLASSIFICATION-BASED DATA MINING METHODS Açıkel, Cengizhan Ph.D.
    [Show full text]
  • Downloaded from the Gene Expression Omnibus (GSE25219) Were Used for the Assessment of Prenatal Gene Expression
    UCLA UCLA Electronic Theses and Dissertations Title Investigation of sex-differential genetic risk factors for autism spectrum disorders Permalink https://escholarship.org/uc/item/4cf1h61b Author Werling, Donna Marie Publication Date 2014 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA Los Angeles Investigation of sex-differential genetic risk factors for autism spectrum disorders A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Neuroscience by Donna Marie Werling 2014 © Copyright by Donna Marie Werling 2014 ABSTRACT OF THE DISSERTATION Investigation of sex-differential genetic risk factors for autism spectrum disorders by Donna Marie Werling Doctor of Philosophy in Neuroscience University of California, Los Angeles, 2014 Professor Daniel H. Geschwind, Chair Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders that affect more males than females, and the mechanisms responsible for increasing males’ risk or protecting females are not understood. This sex biased prevalence is consistent across time and populations, suggesting that an understanding of the processes driving sex-differential risk would likely be informative of fundamental pathophysiology in ASD. One known component of ASD risk is genetic variation. Thus, here I apply several approaches that leverage current knowledge of ASD genetics to investigate the role and mechanisms of sex-differential biology in ASD risk. First, I evaluate a cohort of families with more than one autistic child for evidence of sex- differential, familial risk variation. Second, I use genetic linkage analysis to identify sex- differential risk loci in families from the same multiplex cohort.
    [Show full text]
  • Pectinate Ligament Dysplasia and Primary Glaucoma in Dogs: Investigating Prevalence And
    Pectinate ligament dysplasia and primary glaucoma in dogs: investigating prevalence and identifying genetic risk factors James Andrew Clive Oliver A thesis submitted for the degree of Doctor of Philosophy Animal Health Trust and UCL Institute of Ophthalmology 2018 1 Declaration I, James Oliver, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. James Oliver 2 Acknowledgments Acknowledgements The inception of this project sprung from my experience in treating canine primary glaucoma. The inability to save both the sight and the eyes of affected dogs and provide hope to their owners is a source of continued frustration. My quest, therefore, was to seek help in investigating the genetics of this devastating disease because, as they say, “prevention is better than cure”. At the culmination of this frustration, I was lucky to be practising at the Animal Health Trust (AHT), where Cathryn Mellersh, my primary PhD supervisor, and her world renowned Canine Genetics Research team reside. Without Cathryn’s encouragement, support and devotion to collaborative research to enhance animal welfare, none of this research would have been possible. Thank you Cathryn. I must also thank my UCL supervisor Alison Hardcastle who has always been there in the background to offer support and encouragement. I am also indebted to Paul Foster and David Sargan for performing my first year viva and providing their constructive criticisms which helped shape the direction of the project. My heartfelt thanks extend to Sally Ricketts, Louise Burmeister, Louise Pettitt and Rebekkah Hitti at the AHT for their patience and help in instructing a simple vet in the laboratory and statistical methodology required to perform this work which was an incredibly enjoyable, although at times steep, learning curve.
    [Show full text]
  • Bases Genéticas De La Respuesta Radioadaptativa En Timocitos De Ratón
    UNIVERSIDAD AUTÓNOMA DE MADRID Departamento de Biología Molecular Bases genéticas de la respuesta radioadaptativa en timocitos de ratón Manuel Malavé Galiana Manuel Malavé Galiana Madrid, 2014 Departamento de Biología Molecular Facultad de Ciencias UNIVERSIDAD AUTÓNOMA DE MADRID Bases genéticas de la respuesta radioadaptativa en timocitos de ratón Manuel Malavé Galiana, Biotecnología Javier Santos Hernández, Pablo Fernández-Navarro, José Fernández-Piqueras Centro de Biología Molecular 1 Manuel Malavé Galiana D. José Fernández-Piqueras, Catedrático de Genética del Centro de Biología Molecular Severo Ochoa/Universidad Autónoma de Madrid D. Javier Santos Hernández, Profesor Titular de Genética de la Universidad Autónoma de Madrid D. Pablo Fernández Navarro, Investigador Post-doc del Área de Epidemiología Ambiental y Cáncer del Centro Nacional de Epidemiología CERTIFICAN: Que Don Manuel Malavé Galiana ha realizado el trabajo de tesis doctoral que lleva por título “Bases Genéticas de la respuesta radioadaptativa en timocitos de ratón” bajo nuestra dirección y supervisión. Que, una vez revisado el trabajo, consideramos que éste tiene la debida calidad para su presentación y defensa. Y para que así conste a los efectos oportunos firmamos la presente en Madrid a 13 de noviembre de 2014. José Fernández-Piqueras Javier Santos Hernández Catedrático de Genética Profesor titular de Genética Dpto.Biología, UAM Dpto. Biología, UAM Centro de Biología Molecular Centro de Biología Molecular Severo Ochoa, UAM-CSIC Severo Ochoa, UAM-CSIC Pablo Fernández Navarro Investigador Pos-Doc Miguel Servet Área de Epidemiología Ambiental y Cáncer, Centro Nacional de Epidemiología Instituto de Salud Carlos III, Madrid 2 Manuel Malavé Galiana INDICE I. AGRADECIMIENTOS. …..………………………………………………………… 6 II. RESUMEN. ………………………………………………………………………… 8 III.
    [Show full text]