Genes, Behavior, and the Social Environment

Moving Beyond the Nature/Nurture Debate

Committee on Assessing Interactions Among Social, Behavioral, and Genetic Factors in Health

Board on Health Sciences Policy

Lyla M. Hernandez and Dan G. Blazer, Editors

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
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Committee on Assessing Interactions Among Social, Behavioral, and Genetic Factors in Health Board on Health Sciences Policy Lyla M. Hernandez and Dan G. Blazer, Editors THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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THE NATIONAL ACADEMIES PRESS • 500 FIFTH STREET, N.W. • Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the Na- tional Academy of Sciences, the National Academy of Engineering, and the Institute of Medi- cine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. N01-OD-4-2139, TO 154 between the National Academy of Sciences and the National Institutes of Health’s Office of Behavioral and Social Sciences Research, National Human Genome Research Institute, and the National Institute of General Medical Sciences. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. Library of Congress Cataloging-in-Publication Data Genes, behavior, and the social environment : moving beyond the nature/nurture debate / Lyla M. Hernandez and Dan G. Blazer, editors ; Committee on Assessing Interactions, Among Social, Behavioral, and Genetic Factors in Health, Board on Health Sciences Policy. p. ; cm. Includes bibliographical references and index. ISBN 0-309-10196-4 (pbk.) — ISBN 0-309-66045-9 (PDFs) 1. Behavior genetics. 2. Medical genetics. 3. Nature and nurture. 4. Human genetics—Research. I. Hernandez, Lyla M. II. Blazer, Dan G. (Dan German), 1944- . III. Institute of Medicine (U.S.). Committee on Assessing Interactions, Among Social, Behavioral, and Genetic Factors in Health. [DNLM: 1. Genetics, Behavioral. 2. Sociobiology. QU 450 G3266 2006] QH457G458 2006 616'.042—dc22 2006023972 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2006 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Acad- emy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engi- neers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Coun- cil is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON ASSESSING INTERACTIONS AMONG SOCIAL, BEHAVIORAL, AND GENETIC FACTORS IN HEALTH DAN G. BLAZER (Chair), Duke University, Durham, North Carolina MELISSA A. AUSTIN, University of Washington, Seattle WENDY BALDWIN, University of Kentucky, Lexington ELLEN WRIGHT CLAYTON, Vanderbilt University, Nashville, Tennessee FIRDAUS S. DHABHAR, Stanford University, California GUANG GUO, University of North Carolina, Chapel Hill SHARON L.R. KARDIA, University of Michigan, Ann Arbor ICHIRO KAWACHI, Harvard University, Boston CARYN LERMAN, University of Pennsylvania, Philadelphia MARTHA K. MCCLINTOCK, University of Chicago RUTH OTTMAN, Columbia University, New York DAVID RIMOIN, University of California, Los Angeles KEITH E. WHITFIELD, Duke University, Durham, North Carolina Staff LYLA M. HERNANDEZ, Study Director ANDREA M. SCHULTZ, Research Assistant CHRISTINE HARTEL, Director, Center for Studies of Behavior and Development v

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BOARD ON HEALTH SCIENCES POLICY* FRED H. GAGE (Chair), The Salk Institute for Biological Studies, La Jolla, California GAIL H. CASSELL, Eli Lilly and Company, Indianapolis, Indiana JAMES F. CHILDRESS, University of Virginia, Charlottesville ELLEN WRIGHT CLAYTON, Vanderbilt University Medical School, Nashville, Tennessee DAVID R. COX, Perlegen Sciences, Mountain View, California LYNN R. GOLDMAN, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland BERNARD D. GOLDSTEIN, University of Pittsburgh, Pittsburgh, Pennsylvania MARTHA N. HILL, Johns Hopkins University School of Nursing, Baltimore, Maryland ALAN LESHNER, American Association for the Advancement of Science, Washington, D.C. DANIEL MASYS, Vanderbilt University Medical Center, Nashville, Tennessee JONATHAN D. MORENO, University of Virginia, Charlottesville E. ALBERT REECE, University of Arkansas, Little Rock MYRL WEINBERG, National Health Council, Washington, D.C. MICHAEL J. WELCH, Washington University School of Medicine, St. Louis, Missouri OWEN N. WITTE, University of California, Los Angeles MARY WOOLLEY, Research!America, Alexandria, Virginia IOM Staff ANDREW M. POPE, Director AMY HAAS, Board Assistant DAVID CODREA, Financial Associate *IOM boards do not review or approve individual reports and are not asked to endorse conclusions and recommendations. The responsibility for the content of the reports rests with the authoring committee and the institution. vi

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Independent Report Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as pos- sible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Eric Boerwinkle, University of Texas, Houston Wylie Burke, University of Washington C. Robert Cloninger, Washington University Troy Duster, New York University Mindy T. Fullilove, Columbia University Stephen B. Manuck, University of Pittsburgh Robb E. Moses, Oregon Health & Science University K. Srinath Reddy, Centre for Chronic Disease Control, India Richard F. Thompson, University of Southern California, Los Angeles David R. Williams, University of Michigan Redford B. Williams, Duke University vii

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viii INDEPENDENT REPORT REVIEWERS Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Jane E. Sisk, Centers for Disease Control and Prevention and Elena O. Nightingale, Institute of Medicine. Appointed by the National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Re- sponsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Preface Developing this report about facilitating integrated research on how the social environment and genetic function affect health outcomes has been tremendously rewarding, in large part because the effort was a col- laboration among scientists from the social, behavioral, and biological sci- ences. Committee research and discussion illuminated associations among social factors and health, behaviors and health, and genetics and health. Committee collaboration resulted in a vision, described in this report, of how future research, transdisciplinary in nature, can contribute to the sci- ence of gene-social environment interactions and to explaining individual and population health and health disparities. Yet, transdisciplinary research faces many challenges, not the least of which are those encountered when attempting to conduct collaborative research across disciplines. In a sense, the challenge of collaboration was illustrated in the work of this committee, whose scientists came from the fields of sociology, demography, psychology, psychiatry, research design, law, ethics, medicine, public health, epidemiology, biology, molecular vi- rology, and genetics. Despite the fact that each committee member already had demonstrated a willingness to work with those from other disciplines on problems that crossed social, behavioral, and genetic lines, committee understanding and collaboration were not achieved effortlessly. Research conducted by different disciplines rests on different knowledge bases, often with different areas of focus—for example, the geneticist emphasizes indi- viduals, while sociologists examine groups and societies. To form a group that could work collaboratively, it was necessary to devote meeting time to ix

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x PREFACE developing a common understanding of each others’ definitions, terms, knowledge about what various disciplines have contributed to our under- standing of disease risk, and an appreciation and value for the research designs and methods used by practitioners of the different disciplines. It was only after this had been accomplished that rapid progress could be made in developing an integrated approach to the task at hand—that of determining how researchers can begin to assess the impact on health of interactions among social, behavioral, and genetic factors. In transdisciplinary research, investigators will be faced, on a broader scale, with the challenges that confronted this committee. Foremost among these challenges is the need to appreciate and value the contributions of other disciplines. Other challenges and approaches to addressing them are described in the body of the report, but the committee believes that the challenge of fostering true collaboration merited the emphasis that is pro- vided in this preface. Successful transdisciplinary research that is conducted on gene-social environment interaction could provide a way for us to rede- fine how we think about health and disease. Such a redefinition, however, is not a short trip going forward with a specific goal in mind; rather, it is a journey that will require time and patience. This report and its recommen- dations are intended to launch us on that journey. Dan G. Blazer, Chair Committee on Assessing Interactions Among Social, Behavioral, and Genetic Factors in Health

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Acknowledgments Over the course of this study, many individuals were willing to share their expertise, time, and thoughts with the committee. Their contributions invigorated committee deliberations and enhanced the quality of this report. The study sponsors at the National Institutes of Health Office of Be- havioral and Social Sciences Research, the National Human Genome Re- search Institute, and the National Institute of General Medical Sciences willingly provided information and responded to questions. Invaluable information was provided by the authors of four commis- sioned papers: Steve W. Cole, Ph.D. (immunology), Myles S. Faith, Ph.D. and Tanja V.E. Kral, Ph.D. (obesity), Sharon Schwartz, Ph.D. (interac- tions), and Robert J. Thompson, Jr., Ph.D. (sickle cell disease). The committee greatly appreciates the input of speakers whose presen- tations informed committee thinking, including Ronald Abeles, Arthur Beaudet, Sheldon Cohen, Eileen Crimmins, Anna Diez Roux, Ming D. Li, Colleen McBride, Margaret Locke, Brian Pike, and John Sheridan. The committee was extremely fortunate in its staffing for this study. We wish to thank Lyla M. Hernandez, who did a remarkable job of directing the study. Thanks also go to Andrea Schultz who provided excellent research and administrative assistance to the committee. We are grateful to Christine Hartel for her insights and contributions in the writing of this report. We also wish to thank Andrew Pope for his guidance during the project, David Codrea for his handling of the financial accounting, Mark Chesnek for his cover design, and Sara Maddox for editing the draft document. xi

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Contents SUMMARY 1 1 INTRODUCTION 15 Determinants of Health, 17 Transdisciplinary Research, 19 Commissioned Papers, 20 Context, 21 Goals of the Report, 23 Conclusion, 23 2 THE IMPACT OF SOCIAL AND CULTRAL ENVIRONMENT ON HEALTH 25 Defining the Social and Cultural Environment, 25 The Influence of Social and Cultural Variables on Health: An Overview of Past Research, 26 Aspects of Health Influenced by the Social Environment, 38 Limitations of Current Research, 39 Conclusion, 40 3 GENETICS AND HEALTH 44 Genetic Susceptibility, 44 Genetic Linkage Analysis and Genetic Association Studies, 47 Gene-Environment and Gene-Gene Interactions, 50 Mechanisms of Gene Expression, 52 xiii

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xiv CONTENTS Aspects of Health Influenced by Genetics, 56 Genetics of Populations as Related to Health and Disease, 60 Conclusion, 62 4 GENETIC, ENVIRONMENTAL, AND PERSONALITY DETERMINANTS OF HEALTH RISK BEHAVIORS 68 Introduction and Overview, 68 Definitions of Health Risk Behaviors, 69 Tobacco Use, 70 Unhealthy Eating Behaviors and Obesity, 72 Physical Inactivity, 73 Using Intermediate Phenotypes to Investigate the Effects of Gene-Environment Interactions, 74 Conclusion, 82 5 SEX/GENDER, RACE/ETHNICITY, AND HEALTH 90 Sex/Gender, 91 Race/Ethnicity, 96 Conclusion, 104 6 EMBEDDED RELATIONSHIPS AMONG SOCIAL, BEHAVIORAL, AND GENETIC FACTORS 109 Thinking from the Bottom Up: Genomic Information Influencing Gene Expression, 110 Thinking from the Bottom Up: Genomic Information Embedded in Biochemical Systems, 114 Thinking from the Top Down: Social Factors Influencing Cells, Tissue, and Physiology, 116 Molecular Mechanisms of Gene-Environment Interaction, 122 The Need for Systems Approaches, 123 7 ANIMAL MODELS 132 Role of Animal Models, 132 Definitions from Animal Research, 136 Identifying Gene-Social Environment Interactions Affecting Health and Disease, 139 Future Issues, 149 8 STUDY DESIGN AND ANALYSIS FOR ASSESSMENT OF INTERACTIONS 161 Definitions of Interactions, 161 Research Designs for Evaluating Interactions, 168 Statistical Issues Common to All Research Designs, 173 Conclusion, 176

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xv CONTENTS 9 INFRASTRUCTURE 181 Education, 181 Mechanisms of Support, 186 Data, 187 Incentives and Rewards—NIH and Academe, 194 Peer Review, 198 Conclusion, 200 10 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS 202 Conveying Complex Scientific Findings Accurately, 203 Policy Does Not Inexorably Follow from Scientific Discoveries, 205 Ethical Implications for Research, 210 11 CONCLUSION 219 APPENDIXES A METHODOLOGY: DATA COLLECTION AND ANALYSIS 223 B RECOMMENDATIONS FROM THE NATIONAL ACADEMY OF SCIENCES/NATIONAL ACADEMY OF ENGINEERING/INSTITUTE OF MEDICINE REPORT FACILITATING INTERDISCIPLINARY RESEARCH 232 C SOCIAL, ENVIRONMENTAL, AND GENETIC INFLUENCES ON OBESITY AND OBESITY PROMOTING BEHAVIORS: FOSTERING RESEARCH INTEGRATION 236 D THE INTERACTION OF SOCIAL, BEHAVIORAL, AND GENETICS FACTORS IN SICKLE CELL DISEASE 281 E MODERN EPIDEMIOLOGIC APPROACHES TO INTERACTION: APPLICATIONS TO THE STUDY OF GENETIC INTERACTIONS 310 F ACRONYMS 338 G BIOGRAPHICAL SKETCHES 342 INDEX 351 xv

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