linkage signal was found in several genome scans in 15q, a region containing the gene for the α– ₇ -nicotine receptor (CHRNA7; Raux et al., 2002). This gene has been associated with an intermediate phenotype related to schizophrenia, the abnormal P50 EEG evoked response. Preliminary evidence has been reported that variants in CHRNA7 are associated with schizophrenia as well. DISC-1 is a gene in 1q43, which was a positive linkage peak in a genome linkage scan from Finland. A chromosomal translocation originating in this gene has been found to be very strongly associated with psychosis in Scottish families having this translocation (Millar et al., 2000). Finally, in a study of gene expression profiling from schizophrenic brain tissue, a gene called RGS4 was found to have much lower expression in schizophrenic brains than in normal brains. This gene is found in another 1q region that was positive in a linkage scan from Canada, and SNPs identified in RGS4 have now been shown to be associated with schizophrenia in at least three population samples (Chowdari et al., 2002). This convergent evidence from linkage and association studies implicates at least seven specific genes as potentially contributing risk for schizophrenia.

Genetic association identifies genes but it does not identify disease mechanisms. Most of the genes implicated thus far are based on associations with variations that are not clearly functional, in the sense that they do not appear to change the integrity of the gene. Most are SNPs in intronic regions of genes, which do not have an impact on traditional aspects of gene function, such as the amino acid sequence or regulation of transcription. So, the associations put a flag on the gene but they do not indicate how inheritance of a variation in the gene affects the function of the gene or the function of the brain. More work is needed in searching for variations that may have obvious functional implications and in basic cell biology to understand how gene function affects cell function.

In two of the genes implicated to date, there is evidence of a potential mechanism of increased risk. Preliminary evidence suggests that SNPs in the promotor region of the CHRNA7 gene that are associated with schizophrenia affect factors that turn on transcription of the CHRNA7 gene, presumably accounting for lower abundance of CHRNA7 receptors, which has been reported in schizophrenic brain tissue (Leonard et al., 2002). This receptor is important in many aspects of hippocampal function and in regulation of the response of dopamine neurons to environmental rewards. Both hippocampal function and dopaminergic responsivity have been prominently implicated in the biology of schizophrenia. The COMT valine allele, which has been associated with schizophrenia in the COMT studies, translates into a more active enzyme, which appears to diminish dopamine in the prefrontal cortex. This leads to various aspects of poorer prefrontal function, in terms of cognition and physiology, which are prominent clinical aspects of schizophrenia, and to intermediate phenotypes associated with risk for schizophrenia (Weinberger et al., 2001). The COMT valine allele also is associated with abnormal control of dopamine activity in the parts of the brain where it appears to be overactive in schizophrenia (Akil et al., 2003). Thus, inheritance of the COMT valine allele appears to increase risk for schizophrenia because it biases toward biological effects implicated in both the negative and positive symptoms of the illness.

It is not obvious how the genes described would specifically relate to adolescence and the emergence of schizophrenia during this time of life. The evidence so far suggests that each of the candidate susceptibility genes has an impact on fundamental aspects of how a brain grows and how it adapts to experience. Each gene may affect the excitability of glutamate neurons—directly or through GABA neuron intermediates, and indirectly through the regulation of dopamine neurons by the cortex. These are fundamental pro

cesses related to the biology of schizophrenia. These are also processes that may be especially crucial to adolescence because cortical development and plasticity are changing dramatically during this period. Thus, it is conceivable that the variations in the functions of these genes associated with schizophrenia lead to compromises and bottlenecks in these processes.

Despite encouraging results from recent linkage and association studies, the literature also contains prominent failures and inconsistencies. Failures to replicate linkage and association signals for schizophrenia suggest that genomic strategies may benefit from a redirection based on our current understanding of the pathophysiology of schizophrenia. For example, the power of genetic studies may increase by examining linkage with quantitative traits that relate to schizophrenia rather than with a formal diagnosis itself. The concept of using intermediate phenotypes, or endophenotypes, is not new (Gottesman & Gould, 2003), but has only recently started to enjoy widespread popularity among those seeking genes for schizophrenia. Gottesman and Shields suggested over 30 years ago that features such as subclinical personality traits, measures of attention and information processing, or the number of dopamine receptors in specific brain regions might lie “intermediate to the phenotype and genotype of schizophrenia” (Gottesman & Shields, 1973). Today, other traits, such as eye-movement dysfunctions, altered brain-wave patterns, and neuropsychological and neuroimaging abnormalities, are under consideration as potentially useful endophenotypes of schizophrenia, because all of these are more common or more severe in schizophrenic patients and their family members than in the general population or among control subjects (Faraone et al., 1995). These deficits may relate more directly than the diagnosis of schizophrenia to the aberrant genes. At the biological level, this is a logical assumption, as genes do not encode for hallucinations or delusions; they encode primarily for proteins that have an impact on molecular processes within and between cells. Thus, endophenotypes may serve as proxies for schizophrenia that are closer to the biology of the underlying risk genes.

With increasing attention in the media to issues relating to genetics and particularly the role of genetic factors in mental illness, an increasing number of individuals will likely be seeking genetic counseling for issues related to schizophrenia. In our experience, by far the most common situation is a married couple who are contemplating having children and the husband or wife has a family history of schizophrenia. They typically ask any combination of three questions: First, is there a genetic test that can be performed on us to determine whether we have the gene for schizophrenia and whether we might pass it on to our children? Second, is there an in utero test that can be given that would determine the risk of the fetus to develop schizophrenia later in life? Third, what is the risk for schizophrenia to our children?

Unfortunately, given the current state of our knowledge, answers to the first two questions are no, we are not yet in the position of having a genetic test that can usefully predict risk for schizophrenia. We would also often add a statement to the effect that this is a very active area of research and there is hope that in the next few years, some breakthrough might occur that would allow us to develop such a test. But, right now we really do not know when or even if that will be possible.

By contrast, useful information can be provided for the third question. Most typically, the husband or wife has a parent or sibling with schizophrenia and they themselves have been mentally healthy. Therefore, the empirical question is what is known about the risk of schizophrenia to the grandchild or niece or nephew of an individual with schizophrenia. Interestingly, this is a subject that has not been systematically studied since the early days of psychiatric genetics in the first decades of the 20th century. The results of these early studies have been summarized in several places, most notably by Gottesman (Gottesman & Shields, 1982), with aggregate risk estimates for schizophrenia of 3.7% and 3.0%, respectively, in grandchildren or nieces and nephews of an individual with schizophrenia. However, this is a considerable overestimate if the parent with the positive family history remains unaffected. That is, the risk to a grandchild or niece or nephew of an individual with schizophrenia when the intervening parent never develops the illness is probably under 2%. Most individuals find this information helpful and broadly reassuring.