Linkage and association studies have been conducted to attempt to identify the genetic factors on a molecular level (Figure 1).In association studies there are two complementary approaches. The first approach is based on candidate genes that are either selected because the chromosomal region harboring the gene has been previously identified, e.g. in systematic linkage analyses (positional candidates), or because the selected gene fits into a specific a priori hypothesis regarding the underlying pathophysiology (functional candidates). The second approach does not depend on any pre-existing hypothesis or knowledge of a specific gene or gene region. Instead, the whole genome is investigated systematically for risk variants (genome-wide association study; GWA study). Until recently, a systematic, genome-wide screen was only possible in linkage studies, which search for a correlation between genetic markers and affection status in families with multiple affected members and which require the genotyping of only a few hundred genetic markers. In the past, association studies focused exclusively on candidate genes, but advances in genotyping technology and progress in understanding the genetic variability of the human genome now permit use of the systematic, genome-wide screen.
