Neurogenetics of psychiatric disorders

232 Pages·2007·3.18 MB·English

by  Akira Sawa

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Edited by
Akira Sawa
Johns Hopkins University School of Medicine
Baltimore, Maryland, USA
Melvin G. McInnis
University of Michigan Depression Center
Ann Arbor, Michigan, USA
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Library of Congress Cataloging-in-Publication Data
Neurogenetics of psychiatric disorders/edited by Akira Sawa,Melvin G.
McInnis.
p. ; cm. -- (Medical psychiatry ; 36)
Includes bibliographical references and index.
ISBN-13:978-0-8493-3610-2 (Hardcover :alk. paper)
ISBN-10:0-8493-3610-4 (Hardcover :alk. paper)
1. Mental illness--Genetic aspects. 2. Mental illness--Physiological aspects.
3. Neurogenetics. I. Sawa,Akira. II. McInnis, Melvin G. III. Series.
[DNLM:1. Mental Disorders--genetics. 2. Genetics,Medical.
W1 ME421SM v.36 2007/WM 140 N4948 2007]
RC455.4.G4N46 2007
616.89’042--dc22 2006103467
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Preface
Neurogenetics forms the bridge between biology and neuroscience on one hand
and genetics on the other. Clinical applications of neurogenetics are evolving,and
it is anticipated that within a few years they will expand well beyond the current
genetic testing for the few simple “one gene”forms of illness (such as is the case
for Huntington’s disease and some forms of Alzheimer’s disease).
There is a growing expectation that clinicians will soon be able to exploit
and utilize pharmacogenetics in the care of their patients. It is further anticipated
that knowledge of genetic subtypes of neuropsychiatric disorders will result in a
rethinking of the disease concept as it is currently known in the Diagnostic and
Statistical Manual of Mental Disorders IV structure of American (and worldwide)
psychiatry. Finally,the National Institutes of Health has made restructuring of the
clinical research engine a priority, and it has a stated focus on translating the
research from bench to bedside.
The focus of this publication is the translation of bench-based research to
the clinical bedside, with the aim of ushering in the enthusiasm and practicality
of these results at the clinical level. For the most part, textbooks on psychiatric
disorders lack updated information on the biology of disease genes. We believe
that these disease genes will become the essential platform upon which neuro-
science will build a productive application of science in the clinical setting. This
book offers the most current overview of how basic neuroscience contributes to
the clinical practice of psychiatry.
The book begins with an introduction to the current state of genetics in
major mental illnesses,including an overview of the relevant history and findings
of genetics from the past century. We use Alzheimer’s disease as the prototype for
the pathways heading to integration of genetics, biology, and clinical studies in
the cognitive and behavioral realm and illustrate the points elaborated above. We
follow with a discussion of major mental illnesses,such as schizophrenia,as well
as the rare single-gene neuropsychiatric diseases. What we have learned from
iii
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iv Preface
these disease states will serve as an example for how we can approach the more
common psychiatric disorders in both the adult and child.
Next, we focus on the disease models involving candidate genes in model
organisms. This section is highly significant since such models will ultimately
bridge basic science or genes to their clinical applications. It is the translation of
such knowledge that has been absent for the clinician. We begin this section with
chapters that organize candidate gene products classified by their functions. In
particular, we discuss the gene products either as neurotransmission or neuro-
development associated in the pathophysiology of schizophrenia. Following these
chapters, we provide an overview of genetics-based models, including rodents
and lower vertebrates. For the final chapter, we develop and present a unified
model that includes concepts of genetic and environmental cross-talks for the
disorders. We intend to show that this research will soon become the basis for
treatment of these disorders. New drugs will no longer be “me too” drugs
developed on the basis of similarities to existing medications, but will be the
result of specific inquiry of the biological and genetic mechanisms discovered in
the wake of the genome project.
It is imperative for the clinician to appreciate how a gene is causally asso-
ciated with disease. At the same time, we must pay close attention to the ethics
and implications of such work,and a chapter summarizing the current discussions
in the field is included.
Finally,we conclude with what is on the horizon for translational research.
It is our hope that this publication will serve as a reference source for clinicians,
researchers, and other health care professionals seeking answers to the many
questions related to the understanding of the neurobiology and the relevant treat-
ment implications of neurogenetics of psychiatric disorders. It is our hope that
the clinician,upon reading this book,will be able to “translate”the research and
its applicability to their patients.
Akira Sawa
Melvin G. McInnis
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Contents
Preface .... iii
Contributors ....vii
Part I: GENETICS
1. Alzheimer’s Disease:A Complex Paradigm . . . . . . . . . . . . . . . . . 1
Dimitrios Avramopoulos
2. Gene-Mapping Studies for Schizophrenia:How Useful Are
They forthe Clinician? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Konasale M. Prasad and Vishwajit L. Nimgaonkar
3. Rare Genes of Major Effect in Neuropsychiatric
Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Ben Pickard,David Porteous,Douglas Blackwood,and Walter Muir
Part II: CANDIDATE GENES AND MODELS
4. Neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Kenji Hashimoto and Eiji Hattori
5. Molecular Genetic Study ofSchizophrenia Based on
Neurodevelopmental Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Masashi Ikeda,Shinichiro Taya,Kozo Kaibuchi,
Nakao Iwata,and Norio Ozaki
6. Model Organisms and Neurogenetics . . . . . . . . . . . . . . . . . . . . . . 117
David E. Krantz and George R. Jackson
v