Refining Genetic Approaches for Identifying Behavioral Loci

Two decades of linkage and association studies with candidate genes have attempted to decipher the genetic contributions of complex behavioral disorders such as Schizophrenia and Substance Use Disorders with only limited success. We suggest refining these efforts by: 1) using association studies on epidemiologically sound, general population samples with large sample sizes (2000 - 5000) to detect small effect loci, 2) developing continuous behavioral measures that “cut at nature's joint”, 3) capitalizing on DNA haplotypes showing evidence of positive selection as “candidate gene” regions and 4) integrating the results with translational biological methodologies. We review our studies of a large, conserved Xq13 haplotype and discuss directions for future studies in genetic dissection integrating across complementary linkage, association, and microarray strategies.