The F1 approach is depicted on the figure as proceeding from right to left in an attempt to capitalize on current knowledge of the pathophysiology of the illness. The comprehensiveness of the previously described positional cloning approach contrasts with the directness of the candidate gene approach. Neurotransmitter-related genes are often considered the leading candidate genes to be examined for evidence of linkage or linkage disequilibrium with psychiatric disorders. Genes for neurotransmitter receptors and proteins involved in transmitter biosynthesis, storage, release, transduction of message, transport, metabolism, termination of action, and breakdown may all be candidates. When selecting a marker to assay for evidence of association with illness, it is preferable to select a marker within the etiological candidate gene, optimally a marker whose alternative forms (alleles) have a demonstrable pathophysiological difference, e.g., amount of activity or binding affinity.

One of the problems of the candidate gene approach is that, on the basis of the current knowledge of the pathophysiology of psychiatric illness, there is limited justification for considering one gene expressed in the adult brain (or during its development) to be a better candidate than the next such gene. Since it is estimated that more than half of the 50,000 to 100,000 human genes are brain-expressed, the obvious question of multiple testing arises. Analysis of the mathematics of a genome-wide search for linkage disequilibrium has begun, because this may become technically feasible within a few years. However, most current association studies ignore the issue of genome-wide multiple testing and limit candidate genes tested to ones with arguably stronger previous hypotheses based on the limited current understanding of pathophysiology. Additional evidence implicating an etiological candidate gene, such as demonstration of linkage disequilibrium, aids in selecting which gene to investigate further. Mutation scanning may then potentially lead to identification of a disease susceptibility mutation. As with the positional cloning approach, the candidate gene approach culminates the discovery of a disease mutation in an affected individual.

Address reprint requests to Dr. Tamminga, Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, MD 21228. Figure adapted from G.D. Schuler, M.S. Boguski, E.A. Stewart, et al.: A Gene Map of the Human Genome. Science 1996; 274:540–546, and F.S. Collins: Positional Cloning Moves From Perditional to Traditional. Nature Genetics 1995; 9:347–350.