SNPs and neuropsychiatric disorders: Discovery and genotyping

Family and twin studies have demonstrated a strong genetic basis for several psychiatric diseases. Classical genetic linkage analyses have yet to conclusively define the relevant loci indicating that many genes with modest relative risk may underlie susceptibility to these disorders. Large-scale association studies focusing on functional polymorphisms are a promising approach to identifying risk alleles. In contrast to linkage analysis, association studies have the power to detect common alleles of modest impact. They have been used successfully to identify genes contributing to numerous complex genetic diseases including hypertension, Alzheimer's disease and thrombosis. The success of large-scale association studies is dependent on the following three factors: (i.) the availability of SNPs in the coding regions of a large number of candidate genes, (ii.) the development of high-through-put technologies for genotyping SNPs and (iii) collection of DNA from well-phenotyped patients. We have identified SNPs in the coding regions (cSNPs) of over 300 candidate genes for neuropsychiatric diseases from biochemical, pharmacological and historical candidates as well as candidate genes underlying areas of the genome implicated in genome scans. We have developed a method for genotyping hundreds of SNPs simultaneously using a fully generic tagged microarray. Using this method, SBE-TAGS, we gonotyped over 100 SNPs (totaling over 5,000 genotypes) with 98-99% accuracy. SBE-TAGS has several attractive features: 30 or more genotyping reactions can be performed in a single microtiter well using unlabelled primers, highly multiplexed PCR reactions can be used as templates, the generic spotted tag array is easily generated, all reagents are commercially available, and determination of genotypes can be automated. Thus, SBE-TAGS brings the highly parallel capabilities of microarrays to bear on SNP genotyping in a way that is readily accessible to a wide range of research laboratories. Association analyses have been beset by several difficulties, ethnic stratification, population specific linkage disequilibrium between markers and causal variants, and inadequate statistical power to detect modest genetic effects. In order to address these problems we have preformed our association analyses in a large sample of bipolar parent-offspring trios using the transmission-disequilibrium test. Alleles showing nominal association in the initial sample were then tested for replication in an additional trio sample. The results of the first 50 SNPs studied will be presented.