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This chapter is a guide for clinicians using genetic association studies to inform their clinical practice. In this chapter, which is restricted to genetic association studies and does not deal with other types of designs, such as genetic linkage studies, we begin by summarizing the key concepts in genetics that are the necessary basis for understanding genetic association studies. We then introduce the idea of genetic association for both single-candidate gene and genome-wide association studies (GWASs). We use the APOE gene polymorphism and its association with Alzheimer disease as a case study to demonstrate the concepts and introduce the terms used in this field.


We then enumerate the major issues in judging the validity of these studies, including disease phenotype definition and potential differences between diseased and nondiseased groups, with a focus on ethnicity and the potential for population stratification. We discuss methods for evaluating the trustworthiness of genetic marker data, including assessment of Hardy-Weinberg equilibrium. We also discuss issues related to multiple comparisons.


Finally, we review issues related to applicability of the results to clinical practice. We provide guidance for evaluating the size and precision of genetic associations and whether the knowledge of genetic associations improves predictive power beyond easily measured clinical variables. We discuss absolute vs relative effects because even a strong genetic risk in relative terms may correspond with a very low absolute risk. We also discuss approaches to evaluating whether a particular genetic risk allele is likely to be present in a given patient. Finally, we provide guidelines for deciding whether a patient is likely better off in knowing the genetic information. Given that genes cannot be modified, one must weigh whether the genetic information is likely to be helpful in planning other health interventions or initiating behavior change.


The Human Genome Project has stimulated interest in genetic determinants of disease. The determinants of common mendelian diseases that involve a single gene (eg, cystic fibrosis, Huntington disease) are well established. More recent research addresses the role of genetics in major causes of human morbidity and mortality through chronic diseases that result from the concomitant effect of environmental, behavioral, and genetic factors. Since 2007, investigators have tested millions of genetic variations (polymorphisms) in GWASs, trying to establish the genetic determinants of chronic diseases, such as coronary artery disease,1-3 type 2 diabetes,4-6 stroke,7-9 multiple sclerosis,10-12 breast cancer,13,14 schizophrenia,15 bipolar disorder,16,17 rheumatoid arthritis,18,19 Crohn disease,16,20 and Alzheimer disease.21-26 Published GWASs are catalogued in the National Institutes of Health's Catalog of Published Genome-Wide Association Studies.27 In March 2014, the catalog listed 1844 published GWASs, with 40 that addressed Alzheimer disease.


The basic construct of a gene-disease association study is relatively simple. In the same way that variation in an exposure (eg, cholesterol) is linked to a health outcome (eg, ...

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