Linkage studies of schizophrenia.

The study of schizophrenia genetics has revealed much about the disease but none of the essential secrets of its etiology, so far, for numerous reasons. First, schizophrenia is a complex trait, influenced by both genes and environment. Second, it appears to be a highly heterogeneous disease, with locus and allelic heterogeneity both between and within families likely. Third, since it is common, it is likely that the genetic liability variants are common, and so are found with relatively high frequency in the general population. Fourth, linkage methods, which deliver rapid coverage of the genome, have great power to identify single genes causing Mendelian disorders but are poorly suited to the genetic architecture of complex traits. Although association methods are undeniably more powerful in such situations, affordable technologies to deliver the much higher density whole genome coverage required are not yet available and candidate gene studies of schizophrenia have not produced robust and replicable results. In spite of these limitations, there are now sufficient data to support several conclusions. Numerous regions of the human genome give consistent, though by no means unanimous, support for linkage. The precise nature of these signals is not yet understood, and power to position the effects is poor, but metanalyses show the co-occurrence is unlikely to be due to chance. Combined approaches utilizing linkage for rapid genome coverage and association for fine-scale follow-up have identified several promising candidate genes. Although the definition of replication in a complex trait is itself complex, a number of these candidates have been supported by numerous studies. These converging lines of evidence suggest that the genetics of schizophrenia, long considered a most intractable problem, are at last beginning to be unraveled. Copyright 2004 FP Graham Publishing Co.