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A: Background Concepts

John Attia, MD, PhD; John P. A. Ioannidis, MD, PhD; Ammarin Thakkinstian, PhD; Mark McEvoy, MMedSc; Rodney J. Scott, PhD; Cosetta Minelli, PhD; John Thompson, PhD; Claire Infante-Rivard, MD, PhD; Gordon Guyatt, MD, MSc

JAMA. 2009;301(1):74-81.

This is the first in a series of 3 articles serving as an introduction to clinicians wishing to read and critically appraise genetic association studies. We summarize the key concepts in genetics that clinicians must understand to review these studies, including the structure of DNA, transcription and translation, patterns of inheritance, Hardy-Weinberg equilibrium, and linkage disequilibrium. We review the types of DNA variation, including single-nucleotide polymorphisms (SNPs), insertions, and deletions, and how these can affect protein function. We introduce the idea of genetic association for both single-candidate gene and genome-wide association studies, in which thousands of genetic variants are tested for association with disease. We use the APOE polymorphism and its association with dementia as a case study to demonstrate the concepts and introduce the terminology used in this field. The second and third articles will focus on issues of validity and applicability.

Author Affiliations: Centre for Clinical Epidemiology and Biostatistics, University of Newcastle, Hunter Medical Research Institute, and Department of General Medicine, John Hunter Hospital, Newcastle, Australia (Dr Attia and Mr McEvoy); Department of Hygiene and Epidemiology, University of Ioannina, School of Medicine, Ioannina, Greece, and Center for Genetic Epidemiology and Modeling, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts (Dr Ioannidis); Clinical Epidemiology Unit, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (Dr Thakkinstian); Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, New Lambton, Australia, and Centre for Information Based Medicine, Faculty of Health, University of Newcastle, Hunter Medical Research Institute, Newcastle, Australia (Dr Scott); Respiratory Epidemiology and Public Health, National Heart and Lung Institute, Imperial College, London, England (Dr Minelli); Department of Health Sciences, University of Leicester, Leicester, England (Dr Thompson); Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, Montreal, Canada (Dr Infante-Rivard); and Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada (Dr Guyatt).

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