Second, interactions between genes (GxG) or between genes and environmental variables (GxE) seem necessary to account for observed risks, but we rely heavily on analytic approaches that assess single genes. In a few cases, genes with known molecular interactions with the candidates have also generated replicated association. Environmental risk factors remain largely unknown and are Inhibitors,research,lifescience,medical difficult or very expensive to test in many samples. Third, these phenotypes are common, so the liability alleles seem likely to be common, although increased rates of rare deletions and duplications (structural or copy number

variants) in cases have been observed multiple times and suggest that rare variation may also contribute to risk in a proportion of cases. The common risk variants are expected to occur with relatively high frequency in the general population, reducing contrast between affected Inhibitors,research,lifescience,medical and unaffected individuals and reducing power. The impact of individual rare structural variants in the subset of cases where they are observed is harder to assess currently, but the observation Inhibitors,research,lifescience,medical of an aggregate increase appears robust, further increasing the apparent etiological complexity. Fourth, the expected frequency of risk alleles and the clinical variability in presentation, course, and outcome suggest that the etiology of individual cases may be heterogeneous,

derived from different specific genes or alleles between individuals. Allelic heterogeneity substantially reduces the Inhibitors,research,lifescience,medical power of selleck chemicals association designs. Fifth, diagnostic boundaries are difficult to draw, and the best phenotype to study is a complex choice. It is critically important to consider this last point and the phenotypes that yield the strongest evidence in some detail. An example: schizophrenia gene identification Through 2004, 25 complete or nearly complete genome scans for schizophrenia

(in which about 400 individual genetic markers are genotyped at regular intervals over the entire human genome) were published (for review see refs 40,41). None provided evidence for genes of major effect. Inhibitors,research,lifescience,medical Some linkage regions Thalidomide were replicated in these studies, and a number of promising genes emerged from sequential linkage and association studies and multiple replication reports. We focus here on those regions with the best replication record and with evidence emerging from other contemporary studies: 22q12-q13 8p22-p21, 6p24-p22, and 1q32-42. Two additional regions with little support in the primary literature, 2p11.1-q21.1 and 3p25.3-p22.1, were among the most significant in a meta-analysis of schizophrenia genome scans. A number of other regions (including 5q22-q31 and 15q13-q14) have less strong summary evidence but also overlap with evidence from more recent GWAS and structural variation studies. Chromosome 22q, the VCFS microdeletion, and COMT Chromosome 22q has been widely studied using many different designs.