Given recent genetic advances, it is not surprising that genetics information is increasingly being used to improve health care. Thousands of conditions caused by single genes (Mendelian diseases) have been identified over the last century. However, Mendelian diseases are rare; thus, few individuals directly benefit from gene identification. In contrast, common complex diseases, such as obesity, breast cancer, and depression, directly affect many more individuals. Common complex diseases are caused by multiple genes, environmental factors, and/or interaction of genetic and environmental factors. This article provides a framework for the successful conduct of gene—environment studies. To accomplish this goal, the basic study designs and procedures of implementation for gene—environment interaction are described. Next, examples of gene—environment interaction in obesity epidemiology are reviewed. Last, the authors review reasons why epidemiological studies that incorporate gene—environment interaction have been unable to demonstrate statistically significant interactions and why conflicting results are reported.
Abecasis, G.R., E. Noguchi, A. Heinzmann, J.A. Traherne, S. Bhattacharyya, N.I. Leaves, et al. 2001. ``Extent and Distribution of Linkage Disequilibrium in Three Genomic Regions.'' American Journal of Human Genetics68:191-97.
2.
Adkins, R.M.2004. ``Comparison of the Accuracy of Methods of Computational Haplotype Inference Using a Large Empirical Dataset.'' BMC Genetics5:22.
3.
Akey, J., L. Jin, and M. Xiong.2001. ``Haplotypes Vs Single Marker Linkage Disequilibrium Tests: What Do We Gain?'' European Journal of Human Genetics9:291-300.
4.
Akey, J.M., H. Wang, M. Xiong, H. Wu, W. Liu, M.D. Shriver, et al. 2001. ``Interaction Between the Melanocortin-1 Receptor and P Genes Contributes to Inter-Individual Variation in Skin Pigmentation Phenotypes in a Tibetan Population.'' Human Genetics108:516-20.
5.
Albert, P.S., D. Ratnasinghe, J. Tangrea, and S. Wacholder.2001. ``Limitations of the Case-Only Design for Identifying Gene-Environment Interactions.'' American Journal of Epidemiology154:687-93.
6.
Almasy, L. and J. Blangero.1998. ``Multipoint Quantitative-Trait Linkage Analysis in General Pedigrees.'' American Journal of Human Genetics62:1198-211.
7.
Anchordoquy, H.C., C. McGeary, L. Liu, K.S. Krauter, and A. Smolen.2003. ``Genotyping of Three Candidate Genes After Whole-Genome Preamplification of DNA Collected From Buccal Cells.'' Behavior Genetics33:73-78.
8.
Anderlik, M.R. and M.A. Rothstein.2001. ``Privacy and Confidentiality of Genetic Information: What Rules for the New Science?'' Annual Review of Genomics and Human Genetics2:401-33.
9.
Andrieu, N. and A.M. Goldstein.1998. ``Epidemiologic and Genetic Approaches in the Study of Gene-Environment Interaction: An Overview of Available Methods .'' Epidemiologic Reviews20:137-47.
10.
Ashford, J.W.2004. ``ApoE Genotype Effects on Alzheimer's Disease Onset and Epidemiology.'' Journal of Molecular Neuroscience23:157-65.
11.
Ashg.1996. `` ASHG Report. Statement on Informed Consent for Genetic Research. The American Society of Human Genetics.'' American Journal of Human Genetics59:471-77.
12.
Barroso, I., M. Gurnell, V.E. Crowley, M. Agostini, J.W. Schwabe, M.A. Soos, et al. 1999. ``Dominant Negative Mutations in Human PPARgamma Associated With Severe Insulin Resistance, Diabetes Mellitus and Hypertension .'' Nature402:880-83.
13.
Benjamini, Y., D. Drai, G. Elmer, N. Kafkafi, and I. Golani.2001. ``Controlling the False Discovery Rate in Behavior Genetics Research.'' Behavioural Brain Research125:279-84.
14.
Beskow, L.M., W. Burke, J.F. Merz, P.A. Barr, S. Terry, V.B. Penchaszadeh, et al. 2001. ``Informed Consent for Population-Based Research Involving Genetics.'' Journal of the American Medical Association286:2315-21.
15.
Bingham, S.A., C. Gill, A. Welch, K. Day, A. Cassidy, K.T. Khaw, et al. 1994. ``Comparison of Dietary Assessment Methods in Nutritional Epidemiology: Weighed Records V. 24 H Recalls, Food-Frequency Questionnaires and Estimated-Diet Records.'' British Journal of Nutrition72:619-43.
16.
Borecki, I.B. and B.K. Suarez.2001. ``Linkage and Association: Basic Concepts .'' Advances in Genetics42:45-66.
17.
Botto, L.D. and M.J. Khoury.2001. ``Commentary: Facing the Challenge of Gene-Environment Interaction: The Two-by-Four Table and Beyond. '' American Journal of Epidemiology153:1016-20.
18.
Bouchard, C. and A. Tremblay.1997. ``Genetic Influences on the Response of Body Fat and Fat Distribution to Positive and Negative Energy Balances in Human Identical Twins.'' Journal of Nutrition127 (5 Suppl.): 943S-47.
19.
Bouchard, C., A. Tremblay, J.P. Despres, A. Nadeau, P.J. Lupien, G. Theriault, et al. 1990. ``The Response to Long-Term Overfeeding in Identical Twins.'' New England Journal of Medicine322:1477-82.
20.
Bourgain, C., E. Genin, and F. Clerget-Darpoux .2002. ``Comparison of Family Based Haplotype Methods Using Intragenic SNPs in Candidate Genes. '' European Journal of Human Genetics10:313-19.
21.
Bourgain, C., E. Genin, P. Holopainen, K. Mustalahti, M. Maki, J. Partanen, et al. 2001. ``Use of Closely Related Affected Individuals for the Genetic Study of Complex Diseases in Founder Populations. '' American Journal of Human Genetics68:154-59.
22.
Bourgain, C., E. Genin, P. Margaritte-Jeannin, and F. Clerget-Darpoux .2001. ``Maximum Identity Length Contrast: A Powerful Method for Susceptibility Gene Detection in Isolated Populations.'' Genetic Epidemiology21 (Suppl. 1): S560-4.
23.
Bourgain, C., E. Genin, H. Quesneville, and F. Clerget-Darpoux .2000. ``Search for Multifactorial Disease Susceptibility Genes in Founder Populations.'' Annals of Human Genetics64 (Pt. 3): 255-65.
24.
Bray, M.S.2000. ``Genomics, Genes, and Environmental Interaction: The Role of Exercise.'' Journal of Applied Physiology88:788-92.
25.
Brennan, P.A., S.A. Mednick, and B. Jacobsen.1996. ``Assessing the Role of Genetics in Crime Using Adoption Cohorts.'' Ciba Foundation Symposium194:115-23; Discussion 123-28.
26.
Breslow, N.E. and N.E. Day.1987. ``Statistical Methods in Cancer Research. Volume II- The Design and Analysis of Cohort Studies.'' IARC Scientific Publications82:1-406.
27.
Brookes, A.J.1999. ``The Essence of SNPs.'' Gene234:177-86.
28.
Buchwald, M.1996. ``Cystic Fibrosis: From the Gene to the Dream. '' Clinical and Investigative Medicine19:304-10.
29.
Byng, M.C., J.C. Whittaker, A.P. Cuthbert, C.G. Mathew, and C.M. Lewis.2003. ``SNP Subset Selection for Genetic Association Studies.'' Annals of Human Genetics67 (Pt. 6): 543-56.
30.
Cadoret, R.J., T.W. O'Gorman, E. Heywood, and E. Troughton.1985. ``Genetic and Environmental Factors in Major Depression.'' Journal of Affective Disorders9:155-64.
31.
Caggana, M., J.M. Conroy, and K.A. Pass.1998. ``Rapid, Efficient Method for Multiplex Amplification From Filter Paper.'' Human Mutation11:404-9.
32.
Chagnon, Y.C., T. Rankinen, E.E. Snyder, S.J. Weisnagel, L. Perusse, and C. Bouchard.2003. ``The Human Obesity Gene Map: The 2002 Update.'' Obesity Research11:313-67.
33.
Clark, A.G.1990. ``Inference of Haplotypes From PCR-Amplified Samples of Diploid Populations.'' Molecular Biology and Evolution7:111-22.
34.
Clayton, D.1999. ``A Generalization of the Transmission/Disequilibrium Test for Uncertain-Haplotype Transmission.'' American Journal of Human Genetics65:1170-77.
35.
Clayton, D. and H. Jones.1999. ``Transmission/Disequilibrium Tests for Extended Marker Haplotypes.'' American Journal of Human Genetics65:1161-69.
36.
Cloninger, C.R., M. Bohman, and S. Sigvardsson.1981. ``Inheritance of Alcohol Abuse: Cross-Fostering Analysis of Adopted Men.'' Archives of General Psychiatry38:861-68.
37.
Colhoun, H.M., P.M. McKeigue, and G. Davey Smith .2003. ``Problems of Reporting Genetic Associations With Complex Outcomes.'' Lancet361:865-72.
38.
Collins, F.S., M. Morgan, and A. Patrinos.2003. ``The Human Genome Project: Lessons From Large-Scale Biology.'' Science300:286-90.
39.
Comuzzie, A.G.2002. ``The Emerging Pattern of the Genetic Contribution to Human Obesity.'' Best Practice & Research: Clinical Endocrinology & Metabolism16:611-21.
40.
Comuzzie, A.G. and D.B. Allison.1998. ``The Search for Human Obesity Genes .'' Science280:1374-77.
41.
Comuzzie, A.G., J.E. Hixson, L. Almasy, B.D. Mitchell, M.C. Mahaney, T.D. Dyer, et al. 1997. ``A Major Quantitative Trait Locus Determining Serum Leptin Levels and Fat Mass Is Located on Human Chromosome 2.'' Nature Genetics15:273-76.
42.
Conti, D.V. and J.S. Witte.2003. ``Hierarchical Modeling of Linkage Disequilibrium: Genetic Structure and Spatial Relations.'' American Journal of Human Genetics72:351-63.
43.
Daniel, H.2002. ``Genomics and Proteomics: Importance for the Future of Nutrition Research.'' British Journal of Nutrition87 (Suppl. 2), S305-11.
44.
Dawson, E., G.R. Abecasis, S. Bumpstead, Y. Chen, S. Hunt, D.M. Beare, et al. 2002. ``A First-Generation Linkage Disequilibrium Map of Human Chromosome 22.'' Nature418:544-48.
45.
Dina, C., D. Meyre, S. Gallina, E. Durand, A. Korner, P. Jacobson, et al. 2007. ``Variation in FTO Contributes to Childhood Obesity and Severe Adult Obesity.'' Nature Genetics39:724-26.
46.
Duerr, R.H., K.D. Taylor, S.R. Brant, J.D. Rioux, M.S. Silverberg, M.J. Daly, et al. 2006. ``A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene.'' Science314:1461-63.
47.
Efron, B. and R. Tibshirani.2002. ``Empirical Bayes Methods and False Discovery Rates for Microarrays.'' Genetic Epidemiology23:70-86.
48.
Eisen, E.J. and J.E. Legates.1966. ``Genotype-Sex Interaction and the Genetic Correlation Between the Sexes for Body Weight in MUS MUSCULUS. '' Genetics54:611-23.
49.
Erichsen, H.C. and S.J. Chanock.2004. ``SNPs in Cancer Research and Treatment .'' British Journal of Cancer90:747-51.
50.
Eriksson, M., W.T. Brown, L.B. Gordon, M.W. Glynn, J. Singer, L. Scott, et al. 2003. ``Recurrent de Novo Point Mutations in Lamin A Cause Hutchinson-Gilford Progeria Syndrome.'' Nature423:293-98.
51.
Excoffier, L. and M. Slatkin.1995. ``Maximum-Likelihood Estimation of Molecular Haplotype Frequencies in a Diploid Population.'' Molecular Biology and Evolution12:921-27.
52.
Fallin, D., A. Cohen, L. Essioux, I. Chumakov, M. Blumenfeld, D. Cohen, et al. 2001. ``Genetic Analysis of Case/Control Data Using Estimated Haplotype Frequencies: Application to ApoE Locus Variation and Alzheimer's Disease.'' Genome Research11:143-51.
53.
Farrer, L.A., L.A. Cupples, J.L. Haines, B. Hyman, W.A. Kukull, R. Mayeux, et al. 1997. ``Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease. A Meta-Analysis. ApoE and Alzheimer Disease Meta Analysis Consortium.'' Journal of the American Medical Association278:1349-56.
54.
Foppa, I. and D. Spiegelman.1997. ``Power and Sample Size Calculations for Case-Control Studies of Gene-Environment Interactions With a Polytomous Exposure Variable.'' American Journal of Epidemiology146:596-604.
55.
Frayling, T.M., N.J. Timpson, M.N. Weedon, E. Zeggini, R.M. Freathy, C.M. Lindgren, et al. 2007. ``A Common Variant in the FTO Gene Is Associated With Body Mass Index and Predisposes to Childhood and Adult Obesity.'' Science316:889-94.
56.
Froguel, P. and G. Velho.1999. ``Molecular Genetics of Maturity-Onset Diabetes of the Young.'' Trends in Endocrinology and Metabolism10:142-46.
57.
Gabriel, S.B., S.F. Schaffner, H. Nguyen, J.M. Moore, J. Roy, B. Blumenstiel, et al. 2002. ``The Structure of Haplotype Blocks in the Human Genome.'' Science296:2225-29.
58.
Gambaro, G., F. Anglani, and A. D'Angelo.2000. ``Association Studies of Genetic Polymorphisms and Complex Disease.'' Lancet355:308-11.
59.
Garcia-Closas, M., K.M. Egan, J. Abruzzo, P.A. Newcomb, L. Titus-Ernstoff, T. Franklin, et al. 2001. ``Collection of Genomic DNA From Adults in Epidemiological Studies by Buccal Cytobrush and Mouthwash.'' Cancer Epidemiology, Biomarkers & Prevention10:687-96.
60.
Garcia-Closas, M. and J.H. Lubin.1999. ``Power and Sample Size Calculations in CaseControl Studies of Gene-Environment Interactions: Comments on Different Approaches. American Journal of Epidemiology149:689-92.
61.
Gauderman, W.J.2002. ``Sample Size Requirements for Matched Case-Control Studies of Gene-Environment Interaction.'' Statistics in Medicine21:35-50.
62.
Greenland, S.1983. ``Tests for Interaction in Epidemiologic Studies: A Review and a Study of Power.'' Statistics in Medicine2:243-51.
63.
Guttmacher, A.E. and F.S. Collins.2002. ``Genomic Medicine-A Primer.'' New England Journal of Medicine347:1512-20.
64.
Hasstedt, S.J., Q.F. Ren, K. Teng, and S.C. Elbein.2001. ``Effect of the Peroxisome Proliferator-Activated Receptor-gamma 2 Pro(12)Ala Variant on Obesity, Glucose Homeostasis, and Blood Pressure in Members of Familial Type 2 Diabetic Kindreds. '' Journal of Clinical Endocrinology and Metabolism86:536-41.
65.
Heath, A.C., R. Jardine, and N.G. Martin.1989. ``Interactive Effects of Genotype and Social Environment on Alcohol Consumption in Female Twins. '' Journal of Studies on Alcohol50:38-48.
66.
Heath, E.M., N.W. Morken, K.A. Campbell, D. Tkach, E.A. Boyd, and D.A. Strom.2001. ``Use of Buccal Cells Collected in Mouthwash as a Source of DNA for Clinical Testing.'' Archives of Pathology & Laboratory Medicine125:127-33.
67.
Heitmann, B.L., L. Lissner, T.I. Sorensen, and C. Bengtsson.1995. ``Dietary Fat Intake and Weight Gain in Women Genetically Predisposed for Obesity.'' American Journal of Clinical Nutrition61:1213-17.
68.
Herbert, A., N.P. Gerry, M.B. McQueen, I.M. Heid, A. Pfeufer, T. Illig, et al. 2006. ``A Common Genetic Variant Is Associated With Adult and Childhood Obesity.'' Science312:279-83.
69.
Horvath, S., X. Xu, and N.M. Laird.2001. ``The Family Based Association Test Method: Strategies for Studying General Genotype-Phenotype Associations. '' European Journal of Human Genetics9:301-6.
70.
Horvath, S., X. Xu, S.L. Lake, E.K. Silverman, S.T. Weiss, and N.M. Laird.2004. ``Family-Based Tests for Associating Haplotypes With General Phenotype Data: Application to Asthma Genetics.'' Genetic Epidemiology26:61-69.
71.
Hwang, S.J., T.H. Beaty, K.Y. Liang, J. Coresh, and M.J. Khoury.1994. ``Minimum Sample Size Estimation to Detect Gene-Environment Interaction in Case-Control Designs.'' American Journal of Epidemiology140:1029-37.
72.
Kelada, S.N., D.L. Eaton, S.S. Wang, N.R. Rothman, and M.J. Khoury.2003. ``The Role of Genetic Polymorphisms in Environmental Health.'' Environmental Health Perspectives111:1055-64.
73.
Keselman, H.J., R. Cribbie, and B. Holland.2002. ``Controlling the Rate of Type I Error Over a Large Set of Statistical Tests.'' British Journal of Mathematical and Statistical Psychology55 (Pt. 1): 27-39.
74.
Khoury, M.J., T.H. Beaty, and B. Cohen.1993. Fundamentals of Genetic Epidemiology . New York: Oxford University Press .
75.
Khoury, M.J. and W.D. Flanders.1996. ``Nontraditional Epidemiologic Approaches in the Analysis of Gene-Environment Interaction: Case-Control Studies With No Controls!'' American Journal of Epidemiology144:207-13.
76.
Khoury, M.J. and L.M. James.1993. ``Population and Familial Relative Risks of Disease Associated With Environmental Factors in the Presence of Gene-Environment Interaction.'' American Journal of Epidemiology137:1241-50.
77.
Klein, R.J., C. Zeiss, E.Y. Chew, J.Y. Tsai, R.S. Sackler, C. Haynes, et al. 2005. ``Complement Factor H Polymorphism in Age-Related Macular Degeneration.'' Science308:385-89.
78.
Lander, E.S., L.M. Linton, B. Birren, C. Nusbaum, M.C. Zody, J. Baldwin, et al. 2001. ``Initial Sequencing and Analysis of the Human Genome.'' Nature409:860-921.
79.
Lawrence, C. and P. Greenwald.1977. ``Epidemiologic Screening: A Method to Add Efficiency to Epidemiologic Research.'' American Journal of Epidemiology105:575-81.
80.
Lewis, C.E., K.E. North, D. Arnett, I.B. Borecki, H. Coon, R.C. Ellison, et al. 2005. ``Sex-Specific Findings From a Genome-Wide Linkage Analysis of Human Fatness in Non-Hispanic Whites and African Americans: The HyperGEN Study.'' International Journal of Obesity29:639-49.
81.
Li, R., E. Boerwinkle, A.F. Olshan, L.E. Chambless, J.S. Pankow, H.A. Tyroler, et al. 2000. ``Glutathione S-Transferase Genotype as a Susceptibility Factor in Smoking-Related Coronary Heart Disease.'' Atherosclerosis149:451-62.
82.
Lin, S., D.J. Cutler, M.E. Zwick, and A. Chakravarti.2002. ``Haplotype Inference in Random Population Samples.'' American Journal of Human Genetics71:1129-37.
83.
Longmate, J.A.2001. ``Complexity and Power in Case-Control Association Studies .'' American Journal of Human Genetics68:1229-37.
84.
Lowe, C.E., J.D. Cooper, J.M. Chapman, B.J. Barratt, R.C. Twells, E.A. Green, et al. 2004. ``Cost-Effective Analysis of Candidate Genes Using htSNPs: A Staged Approach.'' Genes and Immunity5:301-5.
85.
Luan, J., P.O. Browne, A.H. Harding, D.J. Halsall, S. O'Rahilly, V.K. Chatterjee, et al. 2001. ``Evidence for Gene-Nutrient Interaction at the PPARgamma Locus.'' Diabetes50:686-89.
86.
Lubin, J.H. and M.H. Gail1990. ``On Power and Sample Size for Studying Features of the Relative Odds of Disease.'' American Journal of Epidemiology131:552-66.
87.
Lynch, H.T. and T.C. Smyrk.1999. ``Hereditary Colorectal Cancer. '' Seminars in Oncology26:478-84.
88.
Manson, J.E. and S.S. Bassuk.2003. ``Obesity in the United States: A Fresh Look at Its High Toll.'' Journal of the American Medical Association289:229-30.
89.
Martin, E.R., E.H. Lai, J.R. Gilbert, A.R. Rogala, A.J. Afshari, J. Riley, et al. 2000. ``SNPing Away at Complex Diseases: Analysis of Single-Nucleotide Polymorphisms Around ApoE in Alzheimer Disease.'' American Journal of Human Genetics67:383-94.
90.
Martin, L.J., M.C. Mahaney, L. Almasy, J.E. Hixson, S.A. Cole, J.W. Maccluer, et al. 2002. ``A Quantitative Trait Locus on Chromosome 22 for Serum Leptin Levels Adjusted for Serum Testosterone.'' Obesity Research10:602-7.
91.
Millikan, R.2002. ``The Changing Face of Epidemiology in the Genomics Era .'' Epidemiology13:472-80.
92.
Morris, R.W. and N.L. Kaplan.2002. ``On the Advantage of Haplotype Analysis in the Presence of Multiple Disease Susceptibility Alleles. '' Genetic Epidemiology23:221-33.
93.
Nathanson, K.L., R. Wooster, B.L. Weber, and K.N. Nathanson.2001. ``Breast Cancer Genetics: What We Know and What We Need.'' Nature Medicine7:552-56.
94.
Neale, B.M. and P.C. Sham.2004. ``The Future of Association Studies: Gene-Based Analysis and Replication.'' American Journal of Human Genetics75:353-62.
95.
Nichols, T.E. and A.P. Holmes.2002. ``Nonparametric Permutation Tests for Functional Neuroimaging: A Primer With Examples.'' Human Brain Mapping15:1-25.
96.
Niu, T.2004. ``Algorithms for Inferring Haplotypes. '' Genetic Epidemiology27:334-37.
97.
Niu, T., Z.S. Qin, X. Xu, and J.S. Liu.2002. ``Bayesian Haplotype Inference for Multiple Linked Single-Nucleotide Polymorphisms.'' American Journal of Human Genetics70:157-69.
---. 1995. ``Gene-Environment Interaction and Public Health. '' American Journal of Human Genetics56:821-23.
100.
Papassotiropoulos, A., D.A. Stephan, M.J. Huentelman, F.J. Hoerndli, D.W. Craig, J.V. Pearson, et al. 2006. ``Common Kibra Alleles Are Associated With Human Memory Performance.'' Science314:475-78.
101.
Piegorsch, W.W., C.R. Weinberg, and J.A. Taylor.1994. ``Non-Hierarchical Logistic Models and Case-Only Designs for Assessing Susceptibility in Population-Based CaseControl Studies.'' Statistics in Medicine13:153-62.
102.
Poehlman, E.T., A. Tremblay, J.P. Despres, E. Fontaine, L. Perusse, G. Theriault, et al. 1986. ``Genotype-Controlled Changes in Body Composition and Fat Morphology Following Overfeeding in Twins.'' American Journal of Clinical Nutrition43:723-31.
103.
Poehlman, E.T., A. Tremblay, M. Marcotte, L. Perusse, G. Theriault, and C. Bouchard.1987. ``Heredity and Changes in Body Composition and Adipose Tissue Metabolism After Short-Term Exercise-Training. '' European Journal of Applied Physiology and Occupational Physiology56:398-402.
104.
Popkin, B.M. and C.M. Doak.1998. ``The Obesity Epidemic Is a Worldwide Phenomenon.'' Nutrition Reviews56 (4 Pt. 1): 106-14.
105.
Poyser, K.H., H.A. Wyatt, and S.M. Chambers.1998. ``Multiplex Genotyping for Cystic Fibrosis From Filter Paper Blood Spots.'' Annals of Clinical Biochemistry35 (Pt. 5): 611-15.
106.
Prentice, R.L.1995. ``Design Issues in Cohort Studies.'' Statistical Methods in Medical Research4:273-92.
107.
Priori, S.G., P.J. Schwartz, C. Napolitano, R. Bloise, E. Ronchetti, M. Grillo, et al. 2003. ``Risk Stratification in the Long-QT Syndrome .'' New England Journal of Medicine348:1866-74.
108.
Province, M.A.2000. ``A Single, Sequential, Genome-Wide Test to Identify Simultaneously All Promising Areas in a Linkage Scan.'' Genetic Epidemiology19:301-22.
109.
---. 2001. ``Sequential Methods of Analysis for Genome Scans. '' Advances in Genetics42:499-514.
110.
Province, M.A., T.K. Rice, I.B. Borecki, C. Gu, A. Kraja, and D.C. Rao.2003. ``Multivariate and Multilocus Variance Components Method, Based on Structural Relationships to Assess Quantitative Trait Linkage via SEGPATH.'' Genetic Epidemiology24:128-38.
111.
Purcell, S.2002. ``Variance Components Models for Gene-Environment Interaction in Twin Analysis.'' Twin Research5:554-71.
112.
Purcell, S. and P. Sham.2002. ``Variance Components Models for Gene-Environment Interaction in Quantitative Trait Locus Linkage Analysis. '' Twin Research5:572-76.
113.
Qin, Z.S., T. Niu, and J.S. Liu.2002. ``Partition-Ligation-Expectation-Maximization Algorithm for Haplotype Inference With Single-Nucleotide Polymorphisms. '' American Journal of Human Genetics71:1242-47.
114.
Reich, D.E., M. Cargill, S. Bolk, J. Ireland, P.C. Sabeti, D.J. Richter, et al. 2001. ``Linkage Disequilibrium in the Human Genome .'' Nature411:199-204.
115.
Risch, N.J.2000. ``Searching for Genetic Determinants in the New Millennium .'' Nature405:847-56.
116.
Robertson, A.1959. ``The Sampling Variance of the Genetic Correlation Coefficient .'' Biometrics15:469-85.
117.
Rothman, K.J.2002. Epidemiology: An Introduction. New York: Oxford University Press.
118.
Rothman, N., M. Garcia-Closas, W.T. Stewart, and J. Lubin.1999. ``The Impact of Misclassification in Case-Control Studies of Gene-Environment Interactions.'' IARC Scientific Publications148:89-96.
119.
Rothman, N. and R.B. Hayes.1995. ``Using Biomarkers of Genetic Susceptibility to Enhance the Study of Cancer Etiology.'' Environmental Health Perspectives103 (Suppl. 8): 291-95.
120.
Rothman, N., S. Wacholder, N.E. Caporaso, M. Garcia-Closas, K. Buetow, and J.F. Fraumeni Jr.2001. ``The Use of Common Genetic Polymorphisms to Enhance the Epidemiologic Study of Environmental Carcinogens.'' Biochimica et Biophysica Acta1471 (2): C1-10.
121.
Sabatti, C., S. Service, and N. Freimer.2003. ``False Discovery Rate in Linkage and Association Genome Screens for Complex Disorders.'' Genetics164:829-33.
122.
Schaid, D.J. and S.S. Sommer.1993. ``Genotype Relative Risks: Methods for Design and Analysis of Candidate-Gene Association Studies. '' American Journal of Human Genetics53:1114-26.
123.
Schork, N.J., D. Fallin, and J.S. Lanchbury.2000. ``Single Nucleotide Polymorphisms and the Future of Genetic Epidemiology.'' Clinical Genetics58:250-64.
124.
Scott, L.J., K.L. Mohlke, L.L. Bonnycastle, C.J. Willer, Y. Li, W.L. Duren, et al. 2007. ``A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants.'' Science316:1341-45.
125.
Scuteri, A., S. Sanna, W.M. Chen, M. Uda, G. Albai, J. Strait, et al. 2007. ``Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated With Obesity-Related Traits.'' PLoS Genetics3 (7): E115.
126.
Shastry, B.S.2001. ``Molecular and Cell Biological Aspects of Alzheimer Disease .'' Journal of Human Genetics46:609-18.
127.
---. 2002. ``SNP Alleles in Human Disease and Evolution. '' Journal of Human Genetics47:561-66.
128.
Shostak, S.2003. ``Locating Gene-Environment Interaction: At the Intersections of Genetics and Public Health.'' Social Science & Medicine56:2327-42.
129.
Smyth, D.J., J.D. Cooper, R. Bailey, S. Field, O. Burren, L.J. Smink, et al. 2006. ``A GenomeWide Association Study of Nonsynonymous SNPs Identifies a Type 1 Diabetes Locus in the Interferon-Induced Helicase (IFIH1) Region.'' Nature Genetics38:617-19.
130.
Snyder, E.E., B. Walts, L. Perusse, Y.C. Chagnon, S.J. Weisnagel, T. Rankinen, et al. 2004. ``The Human Obesity Gene Map: The 2003 Update .'' Obesity Research12:369-439.
131.
Spence, M.A., D.A. Greenberg, S.E. Hodge, and V.J. Vieland.2003. ``The Emperor's New Methods.'' American Journal of Human Genetics72:1084-87.
132.
Spielman, R.S. and W.J. Ewens.1996. ``The TDT and Other Family-Based Tests for Linkage Disequilibrium and Association.'' American Journal of Human Genetics59:983-89.
133.
Stephens, M., N.J. Smith, and P. Donnelly.2001. ``A New Statistical Method for Haplotype Reconstruction From Population Data.'' American Journal of Human Genetics68:978-89.
134.
Storey, J.D. and R. Tibshirani.2003. ``Statistical Significance for Genomewide Studies.'' Proceedings of the National Academy of Sciences of the United States of America100:9440-45.
Thomas, D.C. and J.S. Witte.2002. ``Point: Population Stratification: A Problem for CaseControl Studies of Candidate-Gene Associations?'' Cancer Epidemiology, Biomarkers & Prevention11:505-12.
137.
Thomson, G.1995. ``Mapping Disease Genes: Family-Based Association Studies .'' American Journal of Human Genetics57:487-98.
138.
Tontonoz, P., E. Hu, J. Devine, E.G. Beale, and B.M. Spiegelman .1995. ``PPAR gamma 2 Regulates Adipose Expression of the Phosphoenolpyruvate Carboxykinase Gene.'' Molecular and Cellular Biology15:351-57.
139.
Tontonoz, P., E. Hu, and B.M. Spiegelman .1994. ``Stimulation of Adipogenesis in Fibroblasts by PPAR gamma 2, a Lipid-Activated Transcription Factor. '' Cell79:1147-56.
140.
---. 1995. ``Regulation of Adipocyte Gene Expression and Differentiation by Peroxisome Proliferator Activated Receptor gamma.'' Current Opinion in Genetics & Development5:571-76.
141.
Towne, B., J. Blangero, and R.M. Siervogel.1993. ``Genotype by Sex Interaction in Measures of Lipids, Lipoproteins, and Apolipoproteins.'' Genetic Epidemiology10:611-16.
142.
Trayhurn, P.2000. ``Proteomics and Nutrition-A Science for the First Decade of the New Millennium.'' British Journal of Nutrition83:1-2.
143.
Tzeng, J.Y., B. Devlin, L. Wasserman, and K. Roeder.2003. ``On the Identification of Disease Mutations by the Analysis of Haplotype Similarity and Goodness of Fit. '' American Journal of Human Genetics72:891-902.
144.
Udry, J.R., J. Kovenock, and N.M. Morris.1996. ``Early Predictors of Nonmarital First Pregnancy and Abortion.'' Family Planning Perspectives28:113-16.
145.
Van Dellen, A. and A.J. Hannan.2004. ``Genetic and Environmental Factors in the Pathogenesis of Huntington's Disease.'' Neurogenetics5:9-17.
146.
Van Den Oord, E.J. and B.M. Neale.2004. ``Will Haplotype Maps Be Useful for Finding Genes?'' Molecular Psychiatry9:227-36.
147.
Venter, J.C., M.D. Adams, E.W. Myers, P.W. Li, R.J. Mural, G.G. Sutton, et al. 2001. ``The Sequence of the Human Genome.'' Science291:1304-51.
148.
Wacholder, S., N. Rothman, and N. Caporaso.2002. ``Counterpoint: Bias From Population Stratification Is Not a Major Threat to the Validity of Conclusions From Epidemiological Studies of Common Polymorphisms and Cancer.'' Cancer Epidemiology, Biomarkers & Prevention11:513-20.
149.
Walker, A.H., D. Najarian, D.L. White, J.F. Jaffe, P.A. Kanetsky, and T.R. Rebbeck.1999. ``Collection of Genomic DNA by Buccal Swabs for Polymerase Chain Reaction-Based Biomarker Assays.'' Environmental Health Perspectives107:517-20.
150.
Xu, C.F., K. Lewis, K.L. Cantone, P. Khan, C. Donnelly, N. White, et al. 2002. ``Effectiveness of Computational Methods in Haplotype Prediction.'' Human Genetics110:148-56.
151.
Yamada, Y., H. Izawa, S. Ichihara, F. Takatsu, H. Ishihara, H. Hirayama, et al. 2002. ``Prediction of the Risk of Myocardial Infarction From Polymorphisms in Candidate Genes.'' New England Journal of Medicine347:1916-23.
152.
Yang, Q. and M.J. Khoury.1997. ``Evolving Methods in Genetic Epidemiology. III. Gene-Environment Interaction in Epidemiologic Research. '' Epidemiologic Reviews19:33-43.
153.
Yang, Z., N.J. Camp, H. Sun, Z. Tong, D. Gibbs, D.J. Cameron, et al. 2006. ``A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration.'' Science314:992-93.
154.
Zhang, K., Z.S. Qin, J.S. Liu, T. Chen, M.S. Waterman, and F. Sun.2004. ``Haplotype Block Partitioning and Tag SNP Selection Using Genotype Data and Their Applications to Association Studies .'' Genome Research14:908-16.
155.
Zhang, S., A.J. Pakstis, K.K. Kidd, and H. Zhao.2001. ``Comparisons of Two Methods for Haplotype Reconstruction and Haplotype Frequency Estimation From Population Data.'' American Journal of Human Genetics69:906-14.
