29 March 2007. In the March 20 Molecular Psychiatry online, researchers in the U.S. reported the first whole-genome association analysis of a schizophrenia case-control data set. The study, of half a million markers, identified only one locus that has a strong effect. But that locus allowed the researchers to zoom in on some rare missense mutations in two genes that have heretofore not been associated with schizophrenia. Because both code for cytokine receptors, the finding may help researchers understand previously described connections between this debilitating psychiatric disorder and diseases of the immune system, such as autoimmune disorders (see SRF related news story), prenatal infection, and familial leukemia.
250,000 SNPs on a Chip
Whole-genome association analysis is one of the latest tools geneticists employ to identify susceptibility genes for complex disorders. The technique uses extremely dense DNA arrays, or chips, to simultaneously detect hundreds of thousands of single nucleotide polymorphisms (SNPs) in DNA extracted from blood samples. It can be used on relatively small sample sets. In this case, Todd Lencz and colleagues at The Zucker Hillside Hospital, Glen Oaks, New York, used two chips to genotype 500,000 SNPs in 178 patients—158 diagnosed with schizophrenia, 13 with schizoaffective disorder, seven with schizophreniform disorder—and 144 controls. The researchers found a single SNP that passes the stringent criteria for statistical significance. That SNP (rs4129148) is located in the vicinity of the gene for colony stimulating factor, receptor 2 alpha (CSF2RA), and lies in the pseudoautosomal region 1 (PAR1) that is present on both chromosomes X and Y. The C allele of the locus was more frequently found in schizophrenia patients (59 percent, versus only 31 percent in controls).
The authors noted that with this type of association study it is imperative to carry out further fine mapping and to validate the finding in additional cohorts. Lencz and colleagues used additional case-control cohorts to perform haplotype analysis of common SNPs near the CSF2RA locus, and they also looked at the frequency of missense mutations in the region. They found two haplotype blocks that significantly associated with schizophrenia, one comprising three common SNPs in intron 8 of CSF2RA and the other containing three SNPs spanning introns 4-6 of an the adjacent gene for interleukin 3 receptor alpha (IL3RA). The authors also found seven novel missense mutations—four in CSF2RA and three in IL3RA—that may be associated with the disease. Only one of these missense mutations was found in 31 controls, while a total of 15 of the mutations were detected among 71 cases.
Together, the whole-genome association data, the haplotype analysis, and the missense mutations that are overrepresented in the schizophrenia samples suggest the presence of a susceptibility locus on the PAR1 region and implicate the two cytokine-receptor genes. However, the authors caution that “as with any genetic association study, additional independent replications from other laboratories will be critical to confirm these novel findings.”
Although they are involved in an ever growing list of physiological processes, cytokines were first described, and are still best known, for mediating inflammation and other immune system responses. The authors note that these findings may help explain epidemiological evidence linking schizophrenia to perturbations of the immune system. Prenatal exposure to pathogens, for example, has been recognized as a risk factor for the disease (see SRF related news story), while HLA antigen mismatching between mother and fetus may also play a role (see SRF related news story). The authors also note that reduced incidence of schizophrenia has been reported in families where there is a history of lymphoma and leukemia, which have both been linked to abnormalities in IL-3, colony stimulating factor, and their receptors. In fact, a commonly identified linkage peak for schizophrenia lies on chromosome 5q, near the gene for IL-3 (see Chen et al., 2007). Further studies may help elucidate any role of these immune regulatory molecules in the disease.—Tom Fagan.
Lencz T, Morgan TV, Athanasiou M, Dain B, Reed CR, Kane JM, Kucherlapati R, Malhotra AK. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psych. 2007. March 20. Abstract