Genomic Architecture of Schizophrenia Across Diverse

Kazima Bulayeva · Oleg Bulayev Stephen Glatt Genomic Architecture of Schizophrenia Across Diverse Genetic Isolates A Study of Dagestan Populations Genomic Architecture of Schizophrenia Across Diverse Genetic Isolates [email protected] Kazima Bulayeva • Oleg Bulayev • Stephen Glatt Genomic Architecture of Schizophrenia Across Diverse Genetic Isolates A Study of Dagestan Populations [email protected] Kazima Bulayeva Oleg Bulayev Russian Academy of Sciences Russian Academy of Sciences Moscow, Russia Moscow, Russia Stephen Glatt Department of Psychiatry and Behavioral Sciences SUNY Upstate Medical University Syracuse, New York USA ISBN 978-3-319-31962-9 ISBN 978-3-319-31964-3 (eBook) DOI 10.1007/978-3-319-31964-3 Library of Congress Control Number: 2016939944 © Springer International Publishing Switzerland 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG Switzerland [email protected] One of remote highland genetic isolate where we had our study [email protected] Foreword Psychiatric disorders are among the world’s most complex and least understood ailments; yet, relative to other medical disorders, they cause a disproportionate share of suffering. The authors of this volume, Dr. Kazima Bulayeva and her son, Dr. Oleg Bulayev, have dedicated not just their scientific careers, but their lives, to combatting these disorders by increasing our understanding of their causes. Their work is the true embodiment of genetic epidemiology, defined by Newton Morton as “a science which deals with the etiology, distribution, and control of disease in groups of relatives and with inherited causes of disease in populations.”1 This volume represents a fitting compilation of decades of labor, a true labor of love that has persevered despite many obstacles, from the financial to the political, to the physical challenges of navigating the mountainous terrain of the Caucasus, to the social and cultural difficulties of developing and nurturing deep interpersonal relationships with the indigenous people in the highlands of Dagestan. Through this effort, Drs. Bulayeva and Bulayev have been able to develop a truly unique relationship with their subjects and a matchless, singular research program. In this monograph, you, the reader, will be immersed into the scientific workflow of Drs. Bulayeva and Bulayev, and you will feel the intensity of their painstaking effort to dissect the genetic underpinnings of mental disorders that aggregate in distinct ethnic isolates. Although technical advances in the field have ushered in an era of personal and precision medicine, Drs. Bulayeva and Bulayev show us the power and the promise of careful ascertainment, rich clinical characterization, and traditional family-based genetic analysis methods for discovering genomic loci that may harbor risk-conferring genes for mental disorders. This work is a testimonial, a 1 Morton, N. E. (1982). Outline of genetic epidemiology. New York: Karger. ISBN 3-8055-2269-X. vii [email protected] viii Foreword tutorial even, on the rewards to be reaped through the careful application of fundamental methods of genetic epidemiology and of sound science. Syracuse, NY, USA Stephen J. Glatt February 10, 2016 [email protected] Preface The study of genetics of complex diseases is one of the main priorities of modern genetics, as these diseases are the leading cause of premature death and disability. Mental diseases—sсhizophrenia, depression, bipolar disorders, and so on—are among the most severe complex diseases for both patients and society. Currently, the rate of affectation by these mental diseases is increasing in most countries. Thousands of scientists from around the world study the genetic and environmental factors influencing the development of the disease, however, and so far, this area of medical genetics is full of conflicting results obtained by different researchers from different countries. We have proposed a cross-isolated population approach, implemented in ethnically and demographically subdivided genetic isolates with the aggregation of specific complex diseases. Unique genetic isolates with the aggregation of certain complex diseases, including schizophrenia, were ascertained in our long-term population-genetic studies of small indigenous ethnics of Dagestan (Northern Caucasus, Russia). Such cross-isolate approach allows us to identify common for all observed isolates and specific for every of them genomic regions containing candidate genes for diseases and genomic structural variants (CNV and ROH) linked with schizophrenia. The study of the same complex phenotype in diverse genetic isolates with different ancestors and high rate of endogamy and inbreeding enables the determination of the entire spectrum of genes and structural genomic variants involved in the pathogenesis of schizophrenia or any other complex disease. Genetic homogeneity and ancestor effect in such isolates helps identify the genomic mechanisms of the disease etiopathogenesis with substantial savings of cost and time, compared with genetically and ethnically heterogeneous large populations. Authors keep cherished memory of prominent geneticists, whose support of our pioneering genetic studies among indigenous peoples of Dagestan had a fundamental importance for the development of the works presented—Timofeev-Resovskii, Dubinin, and Gindilis. We also express our sincere gratitude to the staff of our research group of human genetic adaptation at the NI Vavilov Institute of General Genetics of RAS (VIGG RAS), and members of the regular expeditions in ix [email protected] x Preface Dagestan— Pavlova, Gurgenova, Kurbanov, Guseynova, and Omarova. We are grateful to Politov, Kurbatova, and all the researchers of the Department of Popu- lation Genetics of VIGG RAS for review and recommendation to publish our long- term study results in this book. We are also grateful to the reviewer of the book manuscript—to Professor Golimbet, whose valuable comments in the manuscript helped to improve the presentation of our study in this book. Endless gratitude to our foreign colleagues, whose appreciation and support of our Dagestan Genetic Heritage research program was of fundamental importance for the preservation and development of this study, in spite of the numerous difficulties in the Russian science. They are outstanding scientists from the United States—Erving Gottesman, Paul Thompson and the International Scientific Corpo- ration ENIGMA, Ming Tsuang, Hilary Coon, Henry Harpending, Lynn Jorde, Michael Hammer, and Tatiana Karafet; from Italia—Giorgio Paoli and Sergio Tofanelli; from Germany Klaus-Peter Lesch; and from Japan Toru Takumi and Hideshi Kawakami. Our internships and joint work in their laboratories helped the authors of this book to master the most advanced methods of molecular genetics and bioinformatics technologies and apply them in our studies in Dagestan genetic isolates. Endless thanks to our coauthor in genetic studies of schizophrenia in Dagestan isolates and scientific editor of the book—Prof. Stephen Glatt. His participation in this study assisted in overcoming the differences in clinical and genetic methodol- ogies between Russian and US researches and certainly made available the results of our research in this book to a wide range of English-speaking colleagues and readers. Endless thanks to all Dagestan highlanders from diverse ethnic groups for their volunteer participation in our long-term study. The authors are grateful for the help in preparing the manuscript for publication to Gurgenova and for English translations to Marisa Peryer. Moscow, Russia Kazima Bulayeva Moscow, Russia Oleg Bulayev Syracuse, NY, USA Stephen Glatt [email protected] Contents 1 Current Problems of Complex Disease Genes Mapping .......... 1 1.1 General Problems of Complex Disease Genes Mapping . 1 1.2 Current Approaches of Schizophrenia Spectrum Disease Gene Mapping ........................................... 2 1.3 The Current State of Gene Mapping of Schizophrenia Spectrum Disorders .......................................... 6 References . .......................................... 11 2 Descriptions and Methods of Study in Selected Genetic Isolates of Dagestan .............................................. 21 2.1 History and Ethno-linguistic Diversity of Dagestan . ......... 21 2.2 Genetic and Demographic Structure of the Selected Isolates . 22 2.3 Methods of Clinical Studies

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