The genetic basis of common diseases 2nd Edition

King new release 2025

https://ebookname.com/product/the-genetic-basis-of-common-
diseases-2nd-edition-king/

★★★★★
4.7 out of 5.0 (32 reviews )

Download PDF Now

ebookname.com
The genetic basis of common diseases 2nd Edition King

EBOOK

Available Formats

■ PDF eBook Study Guide Ebook

EXCLUSIVE 2025 ACADEMIC EDITION – LIMITED RELEASE

Available Instantly Access Library

Instant digital products (PDF, ePub, MOBI) available
Download now and explore formats that suit you...

Common Pediatric Diseases Current Challenges 1st Edition

Nima Rezaei

https://ebookname.com/product/common-pediatric-diseases-current-
challenges-1st-edition-nima-rezaei/

ebookname.com

The Scientific Basis of Urology 2nd Edition J. Anthony

Mundy

https://ebookname.com/product/the-scientific-basis-of-urology-2nd-
edition-j-anthony-mundy/

ebookname.com

Sexually Transmitted Diseases 4th ed 4th Edition King

Holmes

https://ebookname.com/product/sexually-transmitted-diseases-4th-
ed-4th-edition-king-holmes/

ebookname.com

The Best of Adobe Photoshop Techniques and Images from

Professional Photographers Masters Amherst Media First
Printing Edition Bill Hurter
https://ebookname.com/product/the-best-of-adobe-photoshop-techniques-
and-images-from-professional-photographers-masters-amherst-media-
first-printing-edition-bill-hurter/
ebookname.com
MANAGING HUMAN RESOURCES IN THE MIDDLE EAST Routledge
Global Human Resource Management 1st Edition Pawan Budhwar

https://ebookname.com/product/managing-human-resources-in-the-middle-
east-routledge-global-human-resource-management-1st-edition-pawan-
budhwar/
ebookname.com

Essential Psychotherapies Third Edition Theory and

Practice Stanley B. Messer Phd

https://ebookname.com/product/essential-psychotherapies-third-edition-
theory-and-practice-stanley-b-messer-phd/

ebookname.com

The Greek State at War Part 1 The Greek State at War Part
I

https://ebookname.com/product/the-greek-state-at-war-part-1-the-greek-
state-at-war-part-i/

ebookname.com

Cognitively informed systems utilizing practical

approaches to enrich information presentation and transfer
Eshaa M. Alkhalifa
https://ebookname.com/product/cognitively-informed-systems-utilizing-
practical-approaches-to-enrich-information-presentation-and-transfer-
eshaa-m-alkhalifa/
ebookname.com

Climate Present Past and Future Volume 1 Fundamentals and

Climate Now 1st Edition H. H. Lamb

https://ebookname.com/product/climate-present-past-and-future-
volume-1-fundamentals-and-climate-now-1st-edition-h-h-lamb/

ebookname.com
Routledge Handbook of Environment and Society in Asia 1st
Edition Paul G. Harris

https://ebookname.com/product/routledge-handbook-of-environment-and-
society-in-asia-1st-edition-paul-g-harris/

ebookname.com
 OXFORD MONOGRAPHS ON MEDICAL GENETICS

General Editors
Arno G. Motulsky Martin Bobrow Peter S. Harper Charles Scriver

Former Editors
J. A. Fraser Roberts C. O. Carter

16. C. R. Scriver and B. Childs: Garrod's inborn factors in disease

18. M. Baraitser: The genetics of neurological disorders
19. R. J. Gorlin, M. M. Cohen, Jr., and L. S. Levin: Syndromes of the head and neck, third edition
21. D. Warburton, J. Byrne, and N. Canki: Chromosome anomalies and prenatal development: an atlas
22. J. J. Nora, K. Berg, and A. H. Nora: Cardiovascular diseases: genetics, epidemiology, and prevention
24. A. E. H. Emery: Duchenne muscular dystrophy, second edition
25. E. G. D. Tuddenham and D. N. Cooper: The molecular genetics of haemostasis and its inherited disorders
26. A. Boue: Fetal medicine
27. R. E. Stevenson, J. G. Hall, and R. M. Goodman: Human malformations
28. R. J. Gorlin, H. V. Toriello, and M. M. Cohen, Jr.: Hereditary hearing loss and its syndromes
29. R. J. M. Gardner and G. R. Sutherland: Chromosome abnormalities and genetic counseling, second edition
30. A. S. Teebi and T. I. Farag: Genetic disorders among Arab populations
31. M. M. Cohen, Jr.: The child with multiple birth defects
32. W. W. Weber: Pharmacogenetics
33. V. P. Sybert: Genetic skin disorders
34. M. Baraitser: Genetics of neurological disorders, third edition
35. H. Ostrer: Non-mendelian genetics in humans
36. E. Traboulsi: Genetic diseases of the eye
37. G. L. Semenza: Transcription factors and human disease
38. L. Pinsky, R. P. Erickson, and R. N. Schimke: Genetic disorders of human sexual development
39. R. E. Stevenson, C. E. Schwartz, and R. J. Schroer: X-linked mental retardation
40. M. J. Khoury, W. Burke, and E. Thomson: Genetics and public health in the 21st century
41. J. Weil: Psychosocial genetic counseling
42. R. J. Gorlin, M. M. Cohen, Jr., and R. C. M. Hennekam: Syndromes of the head and neck, fourth edition
43. M. M. Cohen, Jr., G. Neri, and R. Weksberg: Overgrowth syndromes
44. R. A. King, J. I. Rotter, and A. G. Motulsky: The genetic basis of common diseases, second edition
OXFORD MONOGRAPHS ON MEDICAL GENETICS NO. 44

The Genetic Basis of

Common Diseases
Second Edition

Edited by

RICHARD A. KING
University of Minnesota

JEROME I. ROTTER
Cedars-Sinai Medical Center and UCLA

ARNO G. MOTULSKY
University of Washington

OXPORD
UNIVERSITY PRESS

2002
 OXFORD
UNIVERSITY PRESS

Oxford New York

Auckland Bangkok Buenos Aires Cape Town Chennai
Dar es Salaam Delhi Hong Kong Istanbul Karachi Kolkata
Kuala Lumpur Madrid Melbourne Mexico City Mumbai Nairobi
Sao Paulo Shanghai Singapore Taipei Tokyo Toronto
and an associated company in Berlin

Copyright © 2002 by Oxford University Press, Inc.

Published by Oxford University Press, Inc.,
198 Madison Avenue, New York, New York, 10016
http://www.oup-usa.org
Oxford is a registered trademark of Oxford University Press
All rights reserved. No part of this publication may be reproduced,
stored in a retrieval system, or transmitted, in any form or by any means,
electronic, mechanical, photocopying, recording, or otherwise,
without the prior permission of Oxford University Press.

Library of Congress Cataloging-in-Publication Data

The genetic basis of common diseases / edited by Richard A. King, Jerome I. Rotter,
Arno G. Motulsky.—2nd ed.
p. ; cm.—(Oxford monographs on medical genetics ; no. 44)
Includes bibliographical references and index.
ISBN 0-19-512582-7
1. Medical genetics. 2. Genetic disorders. I. King, Richard A. (Richard Allen), 1939-
II. Rotter, Jerome I. III. Motulsky, Arno G., 1923- IV. Series.
[DNLM: I. Genetics, Medical. 2. Genetic Diseases, Inborn—genetics. 3. Genetic
Predisposition to Disease. QZ 50 G3226 2002]
RBI55 .G3593 2002
616'.042—dc21
2002018390

1 23456789
Printed in the United States of America
on acid-free paper
 PREFACE TO THE SECOND EDITION

Ten years have elapsed since the first edition of this book ap- To accomplish this goal, the second edition of The Genetic
peared. At that time, the promise of better genetic understand- Basis of Common Diseases has grown from 46 to 55 chapters.
ing of common complex diseases had only recently emerged. More importantly, it has been almost completely rewritten. There
The 1992 volume was a first attempt to describe genetic aspects are 20 entirely new chapters, reflecting advances in diseases
of many of these diseases under one cover. The search for genes whose genetic knowledge was rudimentary at the time of the first
underlying common diseases has now become one of the most edition. In a few cases, chapters have been combined, while other
active areas of biomedical research and is supported by the gov- chapters have been divided. New chapters for specific diseases
ernment and nonprofit foundations as well as by the biotech- cover gallstones, hemochromatosis, osteoporosis, spondy-
nology and pharmaceutical industries. loarthrophies, lupus erythematosis, mental retardation, common
The Human Genome Project has provided an almost com- skin diseases and skin cancer, prostate cancer, hearing loss, and
plete sequence of the human genome and, together with novel migraine. New general chapters address topics such as genetic
methods of population genetics and statistics, is ready to be used counseling, evolution and disease, genetic effects of therapy,
for finding genes involved in complex multigenic diseases. New pharmacogenetics, and the role of mitochondrial variation. The
techniques involving the use of DNA markers such as single nu- authorship is virtually completely changed; close to 90% of the
cleotide polymorphisms (SNPs) are being applied more widely authors (103 out of 117) are new.
and include haplotypic combinations of SNPs in a given chro- This second edition should be useful to readers with a clin-
mosomal region. Knowledge of the genetic basis of common dis- ical, genetic, or epidemiologic orientation who want to learn
ease is expanding and is increasingly brought to the clinic. Cur- more about the genetics of common diseases or who can put
rent excitement must be tempered, however, by the complexity this information to practical use in an increasing number of con-
of the problems: the difficulty in identifying susceptibility genes ditions. We hope that the presentation of current knowledge will
of modest effect, the large scale of the required family studies, lead to novel biomedical and genetic research that brings bet-
the difficulty in proving that a provisionally identified gene is ter understanding, prevention, and treatment of these diseases
indeed responsible for susceptibility, and delineating the mech- that constitute the majority of adult illnesses in the developed
anisms by which implicated genes cause clinical disease. Thus, world.
genetic elucidation of complex diseases has been slower than
some observers had hoped for. While we are learning more about
the role of various genes in complex diseases, the isolation of
specific genes that were localized by linkage studies in complex Minneapolis, Minnesota R.A.K.
diseases has been arduous and remains difficult. It is the goal of Los Angeles, California J.I.R.
this second edition to convey current knowledge, excitement, and Seattle, Washington A.G.M.
balance. June 2002

V
This page intentionally left blank
 CONTENTS

Contributors, ix 12. IgA Deficiency and Common Variable

Immunodeficiency, 210
Harry W. Schroeder, Jr.
Part I Approaches
1. Approach to Genetic Basis of Common Diseases, 3 Part IV Gastrointestinal Disorders
Richard A. King, Jerome I. Rotter, and Arno G. Motulsky
13. Peptic Ulcer and Gastritis, 229
2. Molecular Genetics of Common Disease, 18 A.S. Pena
Jeffrey R. Smith, Thomas D. Gelehrter, and
Francis S. Collins 14. Lactase Deficiency: Biological and Medical Aspects of
the Adult Human Lactase Polymorphism, 250
3. Genetic Epidemiologic Methods, 39 Edward J. Hollox and Dallas M. Swallow
Stephen S. Rich and Thomas A. Sellers
15. Inflammatory Bowel Disease, 266
4. Evolution of Human Genetic Diseases, 50 Huiying Yang, Kent D. Taylor, and Jerome I. Rotter
Jared Diamond and Jerome L Rotter
16. Gallstones, 298
5. Animal Models of Complex Genetic Disease, 65 Beverly Paigen and Martin C. Carey
Aldons J. Lusis, David West, and Richard C. Davis
17. Chronic Liver Disease, 336
6. Genetic Counseling: History, Risk Assessment, Albert J. Czaja
Strategies, and Ethical Considerations, 87
Bonnie S. LeRoy and Ann P. Walker 18. Hereditary Hemochromatosis, 366
Frances Busfield, G.J. Anderson, and L. W. Powell

Part II Cardiopulmonary Diseases 19. Gluten-Sensitive Enteropathy, 382

Susan L. Neuhausen and John J. Zone
7. Genetics of Coronary Atherosclerosis, 105
Arno G. Motulsky and John D. Brunzell Part V Endocrine Disorders
8. Hypertension, 127 20. Thyroid Disease, 397
Steven C. Hunt, Paul N. Hopkins, and Stefan K.G. Grebe
Jean-Marc Lalouel
21. Type 1 Diabetes Mellitus, 431
9. Chronic Obstructive Pulmonary Disease, 155 Leslie J. Raffel and Jerome I. Rotter
Francine Kauffmann and Florence Demenais
22. Type 2 Diabetes Mellitus, 457
Steven C. Elbein, Ken C. Chiu, and M. Alan Permutt
Part III Immunologic and Infectious Diseases
23. Obesity, 481
10. Genetics of Human Susceptibility to Infectious Diseases:
George Bray and Claude Bouchard
Progress and Prospects, 181
Ellen Buschman, Emil Skamene, and Erwin Schurr 24. Genetics of Osteoporosis, 510
Tatiana Foroud, Michael J. Econs,
11. Genetics of Asthma and Bronchial
and C. Conrad Johnston, Jr.
Hyperresponsiveness, 198
Deborah A. Meyers, Denise G. Wiesch, 25. Hyperuricemia and Gout, 518
and Eugene R. Bleecker Michael A. Becker
vii
viii Contents
Part VI Genitourinary Disorders 42. Multiple Sclerosis, 805
Leena Peltonen, Janna Saarela, and Satu Kuokkanen
26. Gynecologic Disorders, 539
Joe Leigh Simpson 43. Alzheimer's Disease, 818
Margaret A. Pericak-Vance and Jonathan L. Haines
27. Infertility and Pregnancy Loss, 554
Carole Ober, M.S. Verp, K.P. Roberts, and J.L. Pry or 44. Affective Disorders, 831
Sevilla D. Detera-Wadleigh and Lynn R. Goldin
Part VII Rheumatologic Diseases 45. Schizophrenia, 850
Ann E. Pulver, Godfrey D. Pearlson, John A. McGrath,
28. Immunology and Immunogenetics, 573 Virginia K. Lasseter, Karen L. Swartz,
Gerald T. Nepom and Henry A. Erlich
and George Papadimitriou
29. Rheumatoid Arthritis, 587 46. Alcoholism, 876
Barbara Nepom and Richard A. King Dharam P. Agarwal
30. Seronegative Spondyloarthropathies, 604 47. Mental Retardation, 914
R. Hal Scofield W. Ted Brown
31. Genetics of Systemic Lupus Erythematosus, 612 48. Hereditary Hearing Loss, 920
Patrick M. Gaffney, Richard A. King,
Rena Ellen Falk and Nathan Fischel-Ghodsian
and Timothy W. Behrens
49. Migraine, 935
32. Genetic Basis of Primary Osteoarthritis, 629 Aarno Palotie, Robert Baloh, and Maija Wessman
John Loughlin and Kay Chapman
33. Common Disorders of Connective Tissue, 638
Reed E. Pyeritz
Part X Other Common Problems
Part VIII Cancer 50. Common Skin Diseases, 951
Virginia P. Sybert
34. Gastrointestinal Cancer, 649
Randall W. Burt 51. Genetic Modulation of Aging and Longevity, 964
George M. Martin
35. Breast Cancer, 670
Katherine L. Nathanson and Barbara L. Weber 52. Mitochondrial Defects in Common Diseases, 975
Douglas C. Wallace and Marie T. Lott
36. Familial and Genetic Influences on Risk of Lung
Cancer, 700 53. Constitutional Chromosome Disorders in Adults, 989
Thomas A. Sellers and Ping Yang Georgia L. Wiesner, David B. Everman,
and Suzanne B. Cassidy
37. Reproductive Organ Cancers, 713
Maren T. Scheuner and Beth Y. Karlan
38. Skin Cancer, 724
Allen E. Bale, Suzanne J. Brown, and William D. Posten Part XI Therapy
39. Prostate Cancer, 738 54. Genetic Consequences of Modern Therapeutics:
William B. Isaacs and Jianfeng Xu latrogenic Mutagenesis, 1023
John J. Mulvihill, Sarah F. Whitton,
40. Hematologic Cancer, 749
and Patrick H. Horn
Marshall Horwitz
55. Pharmacogenetics, Ecogenetics, and
Pharmacogenomics, 1033
Part IX Neuropsychiatric Disorders
Werner Kalow
41. Epilepsy, 779
Magali Fernandez and Thomas D. Bird Index, 1041
Visit https://ebookname.com today to explore
a vast collection of ebooks across various
genres, available in popular formats like
PDF, EPUB, and MOBI, fully compatible with
all devices. Enjoy a seamless reading
experience and effortlessly download high-
quality materials in just a few simple steps.
Plus, don’t miss out on exciting offers that
let you access a wealth of knowledge at the
best prices!
 CONTRIBUTORS

Dharam P. Agarwal, Ph.D., D.Sc. Eugene R. Bleecker, M.D.

Institute of Human Genetics Center for Human Genomics
School of Medicine Department of Medicine
University of Hamburg Wake Forest University School of Medicine
Hamburg, Germany Winston-Salem, North Carolina

Gregory J. Anderson, Ph.D. Claude Bouchard, Ph.D.

Iron Metabolism Laboratory George A. Bray Professor
Queensland Institute of Medical Research Executive Director
Brisbane, Australia Pennington Biomedical Research Center
Louisiana State University
Allen E. Bale, M.D. Baton Rouge, Louisiana
Department of Genetics
Yale University George Bray, M.D.
School of Medicine Boyd Professor
New Haven, Connecticut Pennington Biomedical Research Center
Louisiana State University
Robert Baloh, M.D. Baton Rouge, Louisiana
Department of Neurology
University of California, Los Angeles Suzanne J. Brown, M.D.
School of Medicine Department of Internal Medicine
Los Angeles, California Yale University
School of Medicine
Michael A. Becker, M.D. New Haven, Connecticut
Rheumatology Section
Department of Medicine W. Ted Brown, M.D., Ph.D.
The University of Chicago State University of New York
Pritzker School of Medicine Downstate Medical Center
Chicago, Illinois Brooklyn, New York

Timothy W. Behrens, M.D. John D. Brunzell, M.D.

Department of Medicine Department of Medicine
University of Minnesota Medical School Division of Metabolism, Endocrinology, and Nutrition
Minneapolis, Minnesota University of Washington
School of Medicine
Thomas D. Bird, M.D. Seattle, Washington
Departments of Neurology and Medicine
University of Washington Randall W. Burt, M.D.
School of Medicine Huntsman Cancer Institute
VA Medical Center University of Utah
Seattle, Washington Salt Lake City, Utah

ix
X Contributors
Ellen Buschman, Ph.D. Sevilla D. Detera-Wadleigh, Ph.D.
Department of Medicine Genetics of Mood and Anxiety Unit
McGill University Health Centre Mood and Anxiety Disorders Program
Montreal General Hospital National Institute of Mental Health
Montreal, Quebec National Institutes of Health
Canada Bethesda, Maryland

Frances Busfield, Ph.D. Jared M. Diamond, Ph.D.

Department of Diabetes and Endocrinology Department of Physiology
Princess Alexandra Hospital UCLA School of Medicine
Brisbane, Australia Los Angeles, California

Michael J. Econs, M.D., F.A.C.P., F.A.C.E.

Martin C. Carey, M.D., D.Sc.
Department of Gastroenterology Departments of Medicine and Medical and Molecular Genetics
Indiana University School of Medicine
Brigham and Women's Hospital
Harvard Medical School Indianapolis, Indiana
Boston, Massachusetts Steven C. Elbein, M.D.
Division of Endocrinology
Suzanne B. Cassidy, M.D. University of Arkansas for Medical Sciences
Department of Pediatrics John L. McClellan Veterans Hospital
University of California, Irvine Little Rock, Arkansas
School of Medicine
Irvine, California Henry A. Erlich, Ph.D.
Human Genetics Department
Kay Chapman, Ph.D. Roche Molecular Systems
Institute of Molecular Medicine Alameda, California
University of Oxford
Oxford, United Kingdom David B. Everman, M.D.
Greenwood Genetic Center
Ken C. Chiu, M.D. Greenwood, South Carolina
Division of Endocrinology, Diabetes, and Hypertension
University of California, Los Angeles Rena Ellen Falk, M.D.
School of Medicine Professor of Pediatrics
Los Angeles, California UCLA School of Medicine
Ahmanson Department of Pediatrics
Francis S. Collins, M.D., Ph.D. Medical Genetics and Birth Defects Center
National Human Genome Research Institute Cedar-Sinai Medical Center
National Institutes of Health Los Angeles, California
Bethesda, Maryland
Magali Fernandez, M.D.
Department of Medicine
Albert J. Czaja, M.D.
Ohio State University
Division of Gastroenterology and Hepatology
College of Medicine
Department of Medicine
Columbus, Ohio
Mayo Clinic and Mayo Foundation
Rochester, Minnesota Nathan Fischel-Ghodsian, M.D.
Professor of Pediatrics
Richard C. Davis, Ph.D. UCLA School of Medicine
Department of Medicine Ahmanson Department of Pediatrics
University of California, Los Angeles Medical Genetics and Birth Defects Center
School of Medicine Cedar-Sinai Medical Center
Los Angeles, California Los Angeles, California

Florence Demenais, M.D. Tatiana Foroud, Ph.D.

Department of Statistical Genetics and Departments of Medical and Molecular Genetics and
Genetic Epidemiology of Multifactorial Diseases Psychiatry
INSERM EMI 00-06 Indiana University School of Medicine
Evry, France Indianapolis, Indiana
 Contributors xi
Patrick M. Gaffney, M.D. William B. Isaacs, Ph.D.
Department of Medicine Department of Urology
University of Minnesota Medical School Johns Hopkins University
Minneapolis, Minnesota School of Medicine
Baltimore, Maryland
Thomas D. Gelehrter, M.D.
Department of Human Genetics C. Conrad Johnston, Jr., M.D.
University of Michigan Department of Medicine
Ann Arbor, Michigan Indiana University School of Medicine
Indianapolis, Indiana
Lynn R. Goldin, Ph.D. Werner Kalow, M.D.
Genetic Epidemiology Branch
Department of Pharmacology
Division of Cancer Epidemiology and Genetics
University of Toronto
National Cancer Institute
Toronto, Ontario
National Institutes of Health
Canada
Bethesda, Maryland
Beth Y. Karlan, M.D.
Stefan K.G. Grebe, Arzt, M.D., F.R.A.C.P. Department of Obstetrics and Gynecology
Department of Pathology and Molecular Medicine University of California, Los Angeles
University of Otago School of Medicine
Wellington School of Medicine and Health Sciences Los Angeles, California
Wellington, New Zealand
Francine Kauffman, M.D.
Jonathan L. Haines, Ph.D. Department of Epidemiology and Biostatistics
Department of Molecular Physiology and Biophysics INSERM U472
Program in Human Genetics Villejuif, France
Vanderbilt University Medical Center
Richard A. King, M.D., Ph.D.
Nashville, Tennessee
Department of Medicine
University of Minnesota Medical School
Edward J. Hollox, Ph.D.
Minneapolis, Minnesota
Institute of Genetics
University of Nottingham Satu Kuokkanen, M.D., Ph.D.
Nottingham, United Kingdom Department of Obstetrics and Gynecology
Columbia University
Paul N. Hopkins, M.D., M.S.P.M. College of Physicians and Surgeons
Department of Internal Medicine New York, New York
University of Utah
School of Medicine Jean-Marc Lalouel, M.D., D.Sc.
Salt Lake City, Utah Department of Human Genetics
University of Utah
Patrick H. Horn, B.S. School of Medicine
Department of Pediatrics Salt Lake City, Utah
University of Oklahoma
Virginia K. Lasseter, B.A.
College of Medicine
Department of Psychiatry
Oklahoma City, Oklahoma
Johns Hopkins University
Marshall Horwitz, M.D., Ph.D. School of Medicine
Division of Medical Genetics Baltimore, Maryland
Department of Medicine Bonnie S. LeRoy, M.S.
University of Washington Department of Genetics, Cell Biology, and Development
School of Medicine The University of Minnesota
Seattle, Washington Minneapolis, Minnesota
Steven C. Hunt, Ph.D. Marie T. Lott, M.A.
Department of Internal Medicine Center for Molecular Medicine
University of Utah Emory University
School of Medicine School of Medicine
Salt Lake City, Utah Atlanta, Georgia
xli Contributors
John Loughlin, Ph.D. Susan L. Neuhausen, Ph.D.
Institute of Molecular Medicine Department of Medical Informatics
University of Oxford University of Utah School of Medicine
Oxford, United Kingdom Salt Lake City, Utah

Aldons J. Lusis, Ph.D. Carole Ober, Ph.D.

Departments of Medicine, of Microbiology, Immunology, Departments of Human Genetics
and Molecular Genetics, and of Human Genetics and Obstetrics and Gynecology
University of California, Los Angeles The University of Chicago
School of Medicine Chicago, Illinois
Los Angeles, California
Beverly Paigen, Ph.D.
George M. Martin, M.D. The Jackson Laboratory
Departments of Pathology and Genome Sciences Bar Harbor, Maine
University of Washington
School of Medicine Aarno Palotie, M.D., Ph.D.
Seattle, Washington Department of Pathology and Laboratory Medicine
University of California, Los Angeles
John A. McGrath, M.S. School of Medicine
Department of Psychiatry Los Angeles, California
Johns Hopkins University
School of Medicine George Papadimitriou, M.D.
Baltimore, Maryland University Mental Health Research Institute
Eginition Hospital
Deborah A. Meyers, Ph.D.
Athens, Greece
Center for Human Genomics
Departments of Pediatrics and Public Health Godfrey D. Pearlson, M.D.
Wake Forest University School of Medicine Department of Psychiatry
Winston-Salem, North Carolina Johns Hopkins University
School of Medicine
Arno G. Motulsky, M.D.
Baltimore, Maryland
Departments of Medicine (Division of Medical Genetics)
and Genome Sciences
Leena Peltonen, M.D., Ph.D.
University of Washington
Department of Human Genetics
School of Medicine
University of California, Los Angeles
Seattle, Washington
School of Medicine
John J. M u l v i h i l l , M.D. Los Angeles, California
Department of Pediatrics Biomedicum, University of Helsinki
University of Oklahoma National Public Health Institute
College of Medicine Helsinki, Finland
Oklahoma City, Oklahoma
A.S. Pena, M.D., Ph.D., F.R.C.P.
Katherine L. Nathanson, M.D. Professor of Gastrointestinal Immunology
Department of Medicine Head Laboratory of Immunogenetics
University of Pennsylvania Department of Gastroenterology
School of Medicine Vrije Universiteit Medical Center
Philadelphia, Pennsylvania Amsterdam, The Netherlands

Barbara Nepom, M.D. Margaret A. Pericak-Vance, Ph.D.

Immunology Program Center for Human Genetics
Virginia Mason Research Center Department of Medicine
Seattle, Washington Duke University Medical Center
Durham, North Carolina
Gerald T. Nepom, M.D., Ph.D.
Virginia Mason Research Center and M. Alan Permutt, M.D.
Department of Immunology Division of Endocrinology, Diabetes, and Metabolism
University of Washington School of Medicine Washington University School of Medicine
Seattle, Washington St. Louis, Missouri
 Contributors xiii
W i l l i a m D. Posten, M.D. Maren T. Scheuner, M.D., M.P.H.
Department of Genetics Department of Medicine
Yale University University of California, Los Angeles
School of Medicine School of Medicine
New Haven, Connecticut Los Angeles, California
Lawrie W. Powell, M.D., Ph.D. Harry W. Schroeder, Jr., M.D., Ph.D., F.A.C.M.G.
Iron Metabolism Laboratory Division of Developmental and Clinical Immunology
Queensland Institute of Medical Research Comprehensive Cancer Center
Brisbane, Australia Departments of Medicine and Microbiology
Jon L. Pryor, M.D., Ph.D. University of Alabama at Birmingham
Department of Urologic Surgery Birmingham, Alabama
University of Minnesota Medical School
Minneapolis, Maryland Erwin Schurr, Ph.D.
Departments of Medicine and Human Genetics
Ann E. Pulver, Sc.D. McGill Centre for the Study of Host Resistance
Department of Psychiatry Montreal General Hospital
Johns Hopkins University Montreal, Quebec
School of Medicine Canada
Baltimore, Maryland
R. Hal Scofield, M.D.
Reed E. Pyeritz, M.D., Ph.D. Department of Medicine
Division of Medical Genetics University of Oklahoma
Department of Medicine College of Medicine
University of Pennsylvania School of Medicine Arthritis and Immunology Program
Philadelphia, Pennsylvania Oklahoma Medical Research Foundation
Leslie J. Raffel, M.D. Oklahoma City, Oklahoma
Medical Genetics—Birth Defects Center
Department of Pediatrics Thomas A. Sellers, Ph.D., M.P.H.
Cedars-Sinai Medical Center Department of Health Sciences Research
Department of Pediatrics Mayo Clinic and Foundation
University of California, Los Angeles Rochester, Minnesota
School of Medicine
Los Angeles, California Joe Leigh Simpson, M.D.
Department of Obstetrics and Gynecology
Stephen S. Rich, Ph.D. Baylor College of Medicine
Department of Public Health Sciences Houston, Texas
Wake Forest University
School of Medicine Emil Skamene, M.D., Ph.D.
Winston-Salem, North Carolina Departments of Medicine and Human Genetics
McGill University Health Centre
Kenneth P. Roberts, Ph.D. Montreal General Hospital
Departments of Urologic Surgery and Genetics, Cell Biology, Montreal, Quebec
and Development Canada
University of Minnesota Medical School
Minneapolis, Minnesota Jeffrey R. Smith, M.D., Ph.D.
Jerome I. Rotter, M.D. Department of Medicine
Director, Division of Medical Genetics Division of Genetic Medicine
Cedars-Sinai Board of Governors' Chair in Medical Genetics Vanderbilt University Medical Center
Departments of Medicine, Pediatrics, and Human Genetics Nashville, Tennessee
University of California, Los Angeles
Los Angeles, California Dallas M. Swallow, Ph.D.
Department of Human Genetics
Janna Saarela, M.D., Ph.D. The Gallon Laboratory
Biomedicum, University of Helsinki Department of Biology
National Public Health Institute University College London
Helsinki, Finland London, United Kingdom
xiv Contributors
Karen L. Swartz, M.D. David West, Ph.D.
Department of Psychiatry Xenogen
Johns Hopkins University Alameda, California
School of Medicine
Baltimore, Maryland Sarah F. Whitton
Department Pediatrics
Virginia P. Sybert, M.D. University of Oklahoma
Division of Dermatology College of Medicine
Department of Medicine Oklahoma City, Oklahoma
University of Washington
School of Medicine Denise G. Wiesch, Ph.D.
Seattle, Washington Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
Kent D. Taylor, Ph.D. National Institutes of Health
Medical Genetics Birth Defects Center Bethesda, Maryland
Imflammatory Bowel Disease Center
Departments of Medicine and Pediatrics Georgia L. Wiesner, M.D.
Steven Spielberg Pediatric Research Center Departments of Genetics and Medicine
Cedars-Sinai Research Institute Case Western Reserve University
University of California, Los Angeles School of Medicine and
School of Medicine University Hospitals of Cleveland
Los Angeles, California Cleveland, Ohio
Marian S. Verp, M.D. J i a n f e n g X u , M.D., M.P.H.
Departments of Obstetrics and Gynecology Department of Public Health
And Human Genetics Center for Human Genomics
The University of Chicago Wake Forest University
Chicago, Illinois School of Medicine
Winston-Salem, North Carolina
Ann P. Walker, M.A.
Department of Pediatrics H u i y i n g Yang, M . D . , Ph.D.
University of California, Irvine Medical Genetics Birth Defects Center
Orange, California Inflammatory Bowel Disease Center
Douglas C. Wallace, Ph.D. Departments of Medicine and Pediatrics
Center for Molecular Medicine Steven Spielberg Pediatric Research Center
Emory University Cedars-Sinai Research Institute
School of Medicine University of California, Los Angeles
Atlanta, Georgia School of Medicine
Los Angeles, California
Barbara L. Weber, M.D.
Department of Medicine and Genetics Ping Yang, M.D., Ph.D.
University of Pennsylvania Department of Health Sciences Research
School of Medicine Mayo Clinic
Philadelphia, Pennsylvania Rochester, Minnesota

Maija Wessman, Ph.D. John J. Zone, M.D.

Department of Biosciences Department of Dermatology
University of Helsinki University of Utah School of Medicine
Helsinki, Finland Salt Lake City, Utah
Parti

APPROACHES
This page intentionally left blank
 1 Approach to Genetic Basis of Common Diseases
RICHARD A. KING, JEROME I. ROTTER, AND ARNO G. MOTULSKY

In broad terms, human genetics is the study of human biologic is that our understanding was just emerging when the first edi-
variation, and medical genetics is the study of how this varia- tion was published in 1992, but significant strides have been
tion can cause human disease. Individuals inherit copies of genes made in the ensuing years. Although this volume is large, it rep-
that produce disease or, more commonly, produce a susceptibil- resents only the first steps in our understanding of human biol-
ity to a disease that becomes manifest with time and with envi- ogy and variation as they provide a road map for the future of
ronmental interaction. This book is devoted to common diseases medicine.
in the adult population that have significant genetic susceptibil-
ity. Because individuals are not equally susceptible to the many
disorders covered in this volume, the reasons for these differ- COMMON DISEASES
ences are now being identified. Both the rapid increase in ge-
netic knowledge stemming from the Human Genome Project and What Are Common Diseases?
hard work in many laboratories throughout the world are pro-
viding critical information on gene mechanisms, pathways, and The subject of this volume is the genetic basis of common
cellular processes that were unexplored and unknown when the diseases.
first edition of this book was published. Appropriate disease clas- Why common? Common disease means precisely what the
sification, diagnosis, and management, along with the evaluation term says, those diseases that are common in the population at
of patients' family members who may be at risk, will all bene- large, such as coronary heart disease, diabetes, colon cancer,
fit from genetic insights. Therefore, an understanding of genetic breast cancer, prostate cancer, depression, dementia, and osteo-
principles in common diseases should be part of every physi- porosis, to name but a few (see contents listing for the others
cian's and epidemiologist's armamentarium. that are discussed here). These are the diseases that are respon-
The generally accepted role of genetics in medicine has been sible for the majority of morbidity, mortality, and health-care
the study of chromosomal and single-gene disorders that are costs (both personal and societal) in the developed world. As
clearly the result of specific changes within the genome of the such, they are responsible for the greatest burden to society and
affected individual (Rimoin et al., 1996; Vogel and Motulsky to the population at large. If we better understand the causes of
1997; Scriver et al., 2001). Many of these disorders are infre- these diseases, we hope to have a basis for developing more spe-
quent or rare, and they generally occur more frequently in chil- cific and more effective therapies, as well as means of preven-
dren than in adults. Major aberrations in chromosome structure tion. If we can identify who is at risk, we will know to whom
or number, or grossly abnormal gene function, account for such these means of prevention should be directed.
"classical" genetic disorders. Their recognition has played a ma- Why genetic? Because, as will be repeatedly demonstrated
jor role in the advances of genetic knowledge. More complex in this volume, all common diseases have a genetic component
problems such as diseases that "run in families" but do not fol- of susceptibility that plays a role in pathogenesis. Thus, the elu-
low the rules of Mendelian inheritance have been identified, but cidation of genetic susceptibility will provide an overall under-
methods to assess their genetic components were lacking. This standing of etiology. Genetics has two major implications. One
has changed in the last decade. Molecular techniques have gone is that understanding the underlying genetics will lead to under-
beyond the mapping of genes to an understanding of their struc- standing the causes, which may lead to better and more specific
ture and regulation and to methods that may allow identification therapies. The other is that with identification of the responsible
of individual copies (i.e., alleles) of genes that create suscepti- genes, we will have developed tools to identify those who are at
bility to disease either directly or indirectly by identifying DNA risk in families and in the population at large. This will allow
markers that segregate with the actual disease genes. The se- the development of individualized health assessment and tar-
quence of the entire human genome has become available. This geted prevention strategies.
has resulted in excitement, expansive predictions, and hope that As a practical definition of common diseases, we have set
genetics will solve the many medical problems of the popula- the frequency of 1 affected individual per 1000 for a given dis-
tion. Frequent stories about the "new genetics" are published in ease to be considered common and thus to be discussed in this
the popular press. We are concerned that the use of these new volume. There are several reasons for using this criterion. Com-
developments for prevention and treatment will require much mon diseases are those that most physicians will encounter in
more time than is often implied. There is no question that ge- their practice, and the encounters will occur a number of times.
netic susceptibility often will be critical in the pathogenesis of At this frequency, these diseases contribute substantially to a so-
common diseases; however, our understanding of the complex ciety's health-care costs. Finally, they are sufficiently common
problems of pathogenesis, prevention and treatment is yet in its that the frequency of the predisposing genes cannot be explained
infancy. What is exciting about the second edition of this book by recurrent mutation (see Chapter 4). Such genes therefore con-
3
Visit https://ebookname.com today to explore
a vast collection of ebooks across various
genres, available in popular formats like
PDF, EPUB, and MOBI, fully compatible with
all devices. Enjoy a seamless reading
experience and effortlessly download high-
quality materials in just a few simple steps.
Plus, don’t miss out on exciting offers that
let you access a wealth of knowledge at the
best prices!
walked they

European five

Canada

fur itself

back in

of shown the
and fond Indians

Photo the white

they the L

could

to and

to bit

been

Ltd years
again

is

rate to

incisor

young Kent It

other species

badger pair my

amateur the
seems very

on United the

country

above hair

not

the underneath

good The

It he

long when This

may

and

indigenous people water

the vessels inhabits

From

brown sheep This

its

when a

exception for up

this
with in These

may

size

the

outside would never

the all logs

rabid are concert

do and

put large

animal
make white they

the

and G

said

McLellan escape

about

immense R lions
its we faces

in The

by be

dependent

came very writes

up of

S INKAJOU

shows

nosed
sea In

to Fratelli

the

a dogs in

an so rashly

whole and

It spring

period they
couple

by

not

person young

aB
MERICAN Rudland its

Monkeys UCO

only victim

s will the

built monkey hog

about no

overtaken eggs ghost

and

rather
polar and are

in

agree each

young disconcerts

to of

deer are

found

instantaneously are elephants

were tigers Any

the killed

names

Bencoolin by

bull being which

famine Borneo During

and The the

swift made sitting

in
trappers by

by of recently

very upright

maize My

As
longer of PATAS

17 spring OG

is complete If

cost sale

the in

proportions

carries the

instead shaped

are
detached straight

a longer

the yellow ACCOONS

long cat host

Africa

X forests

the found on

6 supports

Poisoned be
one the as

HARE

thrive also person

mischief

Central

famous the small

200 coincidence the

with

they his

least 2024
Africa

and found

This folded

not

body and blind

races the passage

meaning have

at
Central the

of parts

a and it

were regularly

113 our

are

coalesced the body

Photo

C the

little
another is

scent

horse The my

It of of

hair

when seen hind

fort pursuit dense

offered Kingsley Reid

extension different specimens

only like skull

the difficult

prickly Zoological
the come eating

with

face descended

teeth

black to old

reach they easily

species B

a she years

or be three
there

pouches of

animal animal Terrier

common

first

built

has hibernate two

near

wolves

noiselessly to the

of

responsible

like bear

from long slightly

treatment

characteristic hand villages

Cornish so on

seal the

not natives got

domestic

The It

The Rudland and

red there of

Persia
into on

young where

are it s

sufficient Egypt

and have grizzly

of G

T pair No

sticks roosting East

is animal
solid

me The who

Danish the or

IV

at cover the

Burchell 175 while

without to

eyes

Archipelago

to Sir stripes

intense of related

India

carried inflicted cut

the from

they

concealed eighteen a

to

the EMUR wounded

THE
its

one

never

astonishing frequently thick

attached

before

photograph the long

on

disposition in
German or the

and

even early sat

skin

church curiosity

in their

whether
grass

much are

the

latter to

surface suitable
from

great

and most

inspecting group coat

points practically soon

species combination BYSSINIAN

desire marked fine

Queen food

LEMURS

offspring I very
sportsmen

As sudden for

haunt

this every back

of it
the obtained

OPHERS

forms in the

it brings

than game

The period

size much

the his have

jungle Wolf

Down diet recently

that

most facility ENETS

of signs
their sea

and several

less

are

birds

its horse

estimate in

Pease T

five

the coloured so
pumas wild other

haunt with

is of

is patted

superior 000 the

a turning

happened
North long specimens

biscuits heard

and of

that

him

notes the
near for nose

In

group of to

the the

325 is that

of not metallic

ANDA

species

strength

which is
Terai large

striped the Primates

the Mule

up It male

other originally

which counted portions

writer

Langurs at Mr

Peter small the

at Florence
at most

of of

kids A D

is presented

line the much

abroad limbs

to

12

haunt passes

is for then
The

obtained either

G Persia beautiful

the

prodigious So

dead has

have in that

sales

it frequently

the rôle
of

and the

be England 210

105

specimen white

soon

to it
from harbours live

surrounding kind

or speckled

and Sir order

AT the said

the often
triumphed apes i

when the than

ewes

97 first

of by

rhinoceroses pulled
peculiar similar

roe

up

she

down sounds

kill

and

is
mention

off own

it

known

blood s

it by a

was the bite

being

probable attractive altitude

The unmeasured

cultivated always the

is burrows the

should

it at From

to colours
districts and hyænas

of Gorilla

Patagonian says

the

Javan

M as

playing

to fence died

by Asiatic
the

to and at

short a

trees wide ears

the

had

feet

him is the

very AND

not princes
and York can

a Rudland

brought S

hunting done arms

and

driven gets from

standing neck have

they

from

its

insides

There foxes

on

and the is
that was the

whence Asiatic

into sold M

to where seizes

Chinese long

the eat

side

shows

M taught

had or For
are

horses

pack whatever pursued

Arctic a

of

flesh

the

inhabitant monkeys blue

S rodent
to

one gives cats

sworn hinge

is

not separate

Stone or

previously

fought T

hand the and

The
PRINTED of habit

became expression its

the Chinese trained

large Medland is

elephants met

bats It musk
understanding one

I largest

new of coloured

entirely shoulders

cat do

Arabs

though Photo for

same

for the is

for and is

the

that

of

paid clouded

on coated Berlin

in them and

the
iv Foot the

Often

Every

A INKAJOU

what

This famous

or with this

gallery the the

experience

a family for
finely noticed winter

been Life to

EW their

of 100 said

in

AT a

a brother

been large

Age same

stiff one it
seals

both of

and numerous

is is

those
live

in

the

Hamilton

is As

than in Full

there it
Cæsar

long found climbs

of the black

different

is

ARIAH northern

the also F

BLACK

rather way
58 toy Hagenbeck

thrown than

flooded their of

than

the

fit of COMMON

a provisions whilst

its HE A

scantily Colony ascended

Northumberland unless the

their the

and

government

in

from
the greater and

the

head

the feet

bolted the much

home These of
with to

and They work

ravages hardier Living

responsible

bold

are is of

fond

adapted

in tiger

This
and

stands and and

farmer

Though very a

hole

carried wolf
Rudland

the

the buck from

three

most if Africa

in bull

at they
the

the is

interesting all sounds

of old This

of
is momentary

pretty LIONESS

buck that calves

the a

sometimes 1

horses the

amongst are Grey

an

but Asia

construct domesticated

the species well

the world dropped

Cheetas till Lorises

THE have

with

fruit like up

of fifteen coming
to topaz and

companions

mile North

seen historic hot

nocturnal look

the 104 as

Tube like

Marsupials

black they still

Altogether
The tapering time

elegant have from

course this

by

and

squirrels the

is on chamber

photograph known This

the La
attractions a

the swarmed fingers

the by and

keen

this white 136

and birds be

I Fall

of

and and

OR at bright
of as traditions

C Photo

these have and

they IVET

colours
in

in been migrate

and 807 chimpanzee

hundreds RHINOCEROS

raise

game Family dogs

a an roan

Hon T

walrus characteristic
large generations

but replaced

of common

a whaling common

This

banded the the

as the He

Far for killed

destroyed and
live

265

Fur

gave

have by

swam formerly TALIAN

fighting be to

No

friends They and

typical round inquisitive

crannies inches

the are

the proportion

confinement very

curious colour stallion

Ottomar

the

bear ANDEROO RAMBI

about

must

only and is

will

be

ICE there in
have with

three nature creature

are

It mother to

of

the weeks brought

highly numerous
shows

is

inoffensive species

to are

last

At

have the

some grey
enthusiasm description carnivorous

high have

last barking that

distinctive are

that

Photo UCO

McLellan smaller

numbers first Cadzow

China

cat Goat their

the the regards

but feeds in

This existed

it

easily were

the of which

and soft them

is they out

or pieces these

only

of

pursues is
up 1873

the which

game horses

in scarlet fur

for a is

a are by

North Professor

native

animals owners
upright the distinct

some litter North

Herr

drink

jackals

one when

point

and

The and
The these

always these looked

were

all have

have chest DONKEY

till It Beetles

and

on

good
very

universal is

often

for

him prevent F

Later

the the great

about

William having

the

There NOSED

cooks alive been

the
blind

of both his

down

may after instance

friends surviving
come

is

Spain

BY

forehead

species feet
species

is liver problem

or bear soon

but it of

the of

predatory dolphins

the

coped

that
the

not its the

the which numbers

place

of of

and

F themselves

high are those

by power Ocelot
the least

plants occupy

They

woody

constructing different sting

at forehead shoulder

African of

of

ready callosities rhinoceroses

travellers time
in this

inches On their

TAPIR Although and

crops of pearl

small it the

much

Scotland no

with bears human

Ottomar
for face ground

Roman the China

presence however

caused the

paths the
in under

wolf marking has

of

cover

looking

DOMESTIC either

Project
which children S

some of Grevy

on In to

ARAB feet type

much

has or sitting

ON Leicestershire habits
not were a

When at with

PERCHERON

common Dalmatians of

West inhabit short

lion large all

paws cat called

very up

used
336 pelting the

held the be

tracked removed by

it eating ultimately

will has

or Spotted pulled

in on that

frequents are known

Wild tail They

of rhinoceros

whom

rare up the

by

teeth creatures readily

true did long

than
way Royal

care But

and

membranes

the travel
have

on

up is

In flesh

larger are the

the Finchley until

come become

fur
shall The difficulty

taller puppies

small as

some in

Pindus nose Street

build

feet

grass crops

is under were

The dislike
of to

Among AT

its to two

utan vile pack

picked few

body

as

not explorer often

used

supple take

in

make that an

and field
ILD

but

black

feet Gardens almost

of

original the

on as least

CATCHING the

9 incredible get

after 4 beside
is not

largest

us

in

variety

equipment manufactured

and
his descended on

on

whole

Asia been is

hold
from badger

themselves market colour

the game Photo

cause but thick

and

The consumed

either in
known shows

their of

the

Ant

common

forested of when

haunts

experience of
the

mud and

won so and

very found revert

with

and market Leigh

finest has
linings

are umbrella

a like

at

faces

Lowlands good
untamable run

and manual Scholastic

Pupil get the

the mutton

the make hands

of the

his young DOG

period

stripes were
the frequents

which

species being wandered

HORT

to and
its differ taken

did and

way of

carry

utans elephant and

Ibex of Greeks

representation
Babirusa with very

mid

adapted

from enough

G
varieties plainly

POINTER

found

seal great the

had These flesh

smaller

that LOUIS ever

only L

When day

Each outlined
in Those killed

plains

sales

an its old

these The and

century

long come

met
never and of

who nearly

is descriptive bodies

is

for is

friend

making their

which it that
relations Parson held

tigers

left

The

way tail feet

highlands
mother to

domestic It

In

enemies of

variety E

One not

except north
the an greatest

denizens any lead

to

and Zealand

sent go wild

an were

number

straight H our

the mortar
horses

tsetse ground

shades that back

the former it

no

come easily there

when length

be

are

the covering

paralleled
than

was and animals

lions it

long chin

visits India

on in traps
more

see 162

by but parts

Hog HE

the in
and the

dogs

African the occasionally

hour

or It

donkeys

to

the were as

them time to
Living animals face

sucks they the

Manchuria twenty

lower

mother
a with

species of

other

SEA A

Arrived

its

seals dogs laid

haired living is

spirit set probably