Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia.

Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition. The interest in COMT as a candidate SZ risk factor has led to numerous case-control and family-based studies, with the majority placing emphasis on examining a functional Val/Met polymorphism within this enzyme. Unfortunately, these studies have continually produced conflicting results. To assess the genetic contribution of other COMT variants to SZ susceptibility, we investigated three single-nucleotide polymorphisms (SNPs) (rs737865, rs4633, rs165599) in addition to the Val/Met variant (rs4680) in a highly selected sample of Australian Caucasian families containing 107 patients with SZ. The Val/Met and rs4633 variants showed nominally significant associations with SZ (P<0.05), although neither of the individual SNPs remained significant after adjusting for multiple testing (most significant P=0.1174). However, haplotype analyses showed strong evidence of an association; the most significant being the three-marker haplotype rs737865-rs4680-rs165599 (global P=0.0022), which spans more than 26 kb. Importantly, conditional analyses indicated the presence of two separate and interacting effects within this haplotype, irrespective of gender. In addition, our results indicate the Val/Met polymorphism is not disease-causing and is simply in strong linkage disequilibrium with a causative effect, which interacts with another as yet unidentified variant approximately 20 kb away. These results may help explain the inconsistent results reported on the Val/Met polymorphism and have important implications for future investigations into the role of COMT in SZ susceptibility.

Multicenter linkage study of schizophrenia loci on chromosome 22q.

The hypothesis of the existence of one or more schizophrenia susceptibility loci on chromosome 22q is supported by reports of genetic linkage and association, meta-analyses of linkage, and the observation of elevated risk for psychosis in people with velocardiofacial syndrome, caused by 22q11 microdeletions. We tested this hypothesis by evaluating 10 microsatellite markers spanning 22q in a multicenter sample of 779 pedigrees. We also incorporated age at onset and sex into the analysis as covariates. No significant evidence for linkage to schizophrenia or for linkage associated with earlier age at onset, gender, or heterogeneity across sites was observed. We interpret these findings to mean that the population-wide effects of putative 22q schizophrenia susceptibility loci are too weak to detect with linkage analysis even in large samples.

Second stage of a genome scan of schizophrenia: study of five positive regions in an expanded sample.

In a previous genome scan of 43 schizophrenia pedigrees, nonparametric linkage (NPL) scores with empirically derived pointwise P-values less than 0.01 were observed in two regions (chromosomes 2q12-13 and 10q23) and less than 0.05 in three regions (4q22-23, 9q22, and 11q21). Markers with a mean spacing of about 5 cM were typed in these regions in an expanded sample of 71 pedigrees, and NPL analyses carried out. No region produced significant genomewide evidence for linkage. On chromosome 10q, the empirical P-value remained at less than 0.01 for the entire sample (D10S168), evidence in the original 43 pedigrees was slightly increased, and a broad peak of positive results was observed. P-values less than 0.05 were observed on chromosomes 2q (D2S436) and 4q (D4S2623), but not on chromosomes 9q or 11q. It is concluded that this sample is most supportive of linkage on chromosome 10q, with less consistent support on chromosomes 2q and 4q. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:864-869, 2000.

Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q.

Evidence for suggestive linkage to schizophrenia with chromosome 6q markers was previously reported from a two-stage approach. Using nonparametric affected sib pairs (ASP) methods, nominal p-values of 0.00018 and 0.00095 were obtained in the screening (81 ASPs; 63 independent) and the replication (109 ASPs; 87 independent) data sets, respectively. Here, we report a follow-up study of this 50cM 6q region using 12 microsatellite markers to test for linkage to schizophrenia. We increased the replication sample size by adding an independent sample of 43 multiplex pedigrees (66 ASPs; 54 independent). Pairwise and multipoint nonparametric linkage analyses conducted in this third data set showed evidence consistent with excess sharing in this 6q region, though the statistical level is weaker (p=0.013). When combining both replication data sets (total of 141 independent ASPs), an overall nominal p-value=0.000014 (LOD=3. 82) was obtained. The sibling recurrence risk (lambdas) attributed to this putative 6q susceptibility locus is estimated to be 1.92. The linkage region could not be narrowed down since LOD score values greater than three were observed within a 13cM region. The length of this region was only slightly reduced (12cM) when using the total sample of independent ASPs (204) obtained from all three data sets. This suggests that very large sample sizes may be needed to narrow down this region by ASP linkage methods. Study of the etiological candidate genes in this region is ongoing.

Genome scan of schizophrenia.

OBJECTIVE: The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. METHOD: A genomewide map of 310 microsatellite DNA markers with average spacing of 11 centimorgans was genotyped in 269 individuals--126 of them with schizophrenia-related psychoses--from 43 pedigrees. Nonparametric linkage analysis was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. RESULTS: Nonparametric linkage scores did not reach a genomewide level of statistical significance for any marker. There were five chromosomal regions in which empirically derived p values reached nominal levels of significance at eight marker locations. There were p values less than 0.01 at chromosomes 2q (with the peak value in this region at D2S410) and 10q (D10S1239), and there were p values less than 0.05 at chromosomes 4q (D4S2623), 9q (D9S257), and 11q (D11S2002). CONCLUSIONS: The results do not support the hypothesis that a single gene causes a large increase in the risk of schizophrenia. The sample (like most others being studied for psychiatric disorders) has limited power to detect genes of small effect or those that are determinants of risk in a small proportion of families. All of the most positive results could be due to chance, or some could reflect weak linkage (genes of small effect). Multicenter studies may be useful in the effort to identify chromosomal regions most likely to contain schizophrenia susceptibility genes.