A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits.

We studied the patterns of linkage disequilibrium (LD) in the human genome among three populations: African Americans, Caucasians and Ashkenazi Jews. These three populations represent admixed, outbred and isolated populations, respectively. The study examined defined chromosomal regions across the whole genome. We found that SNP allele frequencies are highly correlated between Ashkenazi Jews and Caucasians and somewhat distinct in African Americans. In addition, Ashkenazi Jews have a modest increase in LD compared with Caucasians, and both have greater LD than African Americans. The three populations differed more significantly with regard to haplotype heterogeneity. We found, as expected, that Ashkenazi Jews display the greatest extent of homogeneity and African Americans the greatest extent of heterogeneity. We found that most of the variance in LD can be attributed to the difference between regions and markers rather than to that between different population types. The average recombination rates estimated by low-resolution genetic maps can only explain a small fraction of the variance between regions. We found that LD (in terms of r(2)) decreases as a function of distance even within the so-called 'haplotype blocks'. This has significant consequences when using LD mapping for the genetic dissection of complex traits, as higher density SNP maps will be required to scan the genome.

The complex genetic nature of many common diseases makes the identification of the genes that predispose to these ailments a difficult task. In this review we discuss the elements that contribute to the complexity of polygenic diseases and describe an experimental strategy for disease-related gene discovery that attempts to overcome these factors. This strategy involves a population-based case-control paradigm and makes use of a highly informative, homogeneous founder population, many of whose members presently reside in Israel. The properties of single nucleotide polymorphisms, which are presently the markers of choice, are discussed, and the technologies that are currently available for SNP genotyping are briefly presented.

Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of (i) a large sample size-to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well defined homogeneous population; and (iii) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype (P=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.

Sample size required for the TDT and the case-control designs was studied for marker-based genome-wide scans for disease association. The influence of various parameters on sample size required to attain a given level of power was analyzed in detail. Small genotypic relative risks, low levels of linkage disequilibrium, and departure from equal frequencies for the disease allele and associated marker allele, significantly and similarly increase sample size required by either the TDT or case-control design. Under the case-control paradigm, we show that the optimal strategy will often be to collect many more control individuals than disease cases with the optimal ratio depending on the relative cost of acquiring cases as compared to controls. For the TDT, the number of required simplex families is virtually equal to the number of cases required for similar power in case-control studies with an equal number of cases and controls. The case-control approach may therefore prove to be more economical and expeditious than the TDT design for diseases in which the cost and time required to collect simplex families is much greater than that needed to acquire isolated disease cases. Nevertheless, possible population stratification needs to be addressed when the case-control design is applied.

We have compared several genotyping methods to assess their applicability to single nucleotide polymorphism (SNP) allele frequency estimation in DNA pools. The accuracy of these methods (restriction fragment length polymorphism, real-time pyrophosphate DNA sequencing, single base extension with fluorescently labeled ddNTPs, homogeneous 5'-nuclease assay, and MALDI-TOF mass spectrometry) was tested by calculating the standard deviation among heterozygous individuals (which are natural DNA pools with 50% representation of each allele) and by estimating allele frequency in artificial pools. We show that although the methods differ in their accuracy, they can all serve for quantification of allele frequency in DNA pools with reasonable accuracy. We found that the influence of the error variance attributed to pool construction on quantification accuracy is insignificant and is SNP dependent.

The complex genetic nature of many common diseases makes the identification of the genes that predispose to these ailments a difficult task. Consequently, many factors have to be considered in choosing the optimal approach to be taken in gene discovery of susceptibility genes. The elements to be considered include the applicability of a family-based linkage paradigm versus a population-based association design and the effects of linkage disequilibrium (LD) and genotypic relative risk (GRR). In this review we discuss these various points and describe the impact on LD and GRR of studying an isolated (also termed 'founder' or 'homogeneous') population, such as Ashkenazi Jews, as compared to an outbred population, such as Caucasians.