The two major strategies employed prior to 2007 to localize genetic variation for schizophrenia were candidate gene association studies and genomewide linkage studies.
The conceptual basis of a candidate gene study is straightforward and entails the comparison of the genotype frequencies for a particular genetic marker in cases with schizophrenia to appropriately matched controls. An example is given in which shows how a test for association is created from genotype data. Candidate gene selection is usually based on knowledge of etiology and, for schizophrenia, most association studies have focused on the genes encoding proteins involved in some way with dopamine.
Figure 1 Shows an example of an association study for one genetic marker. The genetic marker is the “famous” COMT val158met polymorphism located on chromosome 22 at base pair position 18,325,825. A “G” at this position codes for (more ...)
There have been at least 1,240 studies of 649 candidate genes in schizophrenia†
the most intensively studied (70 reports). Despite the tremendous amount of work that has gone into these studies, the candidate gene approach has not yielded replicable associations with schizophrenia that meet a high standard of proof. The performance of the candidate gene approach in schizophrenia research is not dissimilar to results from other complex traits of biomedical importance4, 5
The conceptual basis of genomewide linkage studies is more complex, and is based on the correlations between genotypes and schizophrenia in families. These studies are based on families usually containing multiple affected individuals. Genetic markers for genomewide linkage studies (around 300 in the past but now totaling 10,000 or more) are selected to be relatively evenly spaced across the genome. These studies are not based on prior pathophysiological knowledge but rather can discover new knowledge about the locations of genes that might predispose or protect against the development of schizophrenia.
There have been genomewide linkage studies of 31 samples including 6,769 affected individuals. The results of these studies can be searched and investigated on the web‡
. As discussed and depicted elsewhere2
, these results do not appear to converge – no genomic region was identified by more than a few studies and an improbably large fraction of the genome (about half) was implicated by at least one study. Moreover, a meta-analysis of schizophrenia genomewide linkage studies6
was recently updated – genomic regions that previously met genomewide significance were considerably less impressive and no longer exceeded genomewide significance.
Comprehensive evaluation of the accumulated work to date is consistent with the following impressions. First, despite considerable effort, genetic variation that predisposes or protects against has not yet been identified with compelling replication. Second, evidence for several highly plausible candidate genes – e.g., NRG17, 8
, DTNBP19, 10
, or DISC111
– is suggestive but inconclusive and is dissimilar to the pattern of highly consistent and compelling replications found for other complex traits. For example, associations of genetic markers in FTO
with body mass index were precisely replicated in 13 cohorts of over 38,000 individuals12
. Finally, hindsight is the only perfect scientific tool and it is clear sample size requirements for adequate statistical power have almost always been underestimated in prior studies.