Genome Tools and Methods: Rare Genetic Variation

Abstract Rare genetic variation is increasingly being recognized as contributory to complex neuropsychiatric disorders. This chapter explains the genomic methodologies associated with identifying and interrogating rare variants for causality in these diseases. Modern technologies for identifying variation in individuals and across populations include microarrays and high-throughput sequencing, both of which are discussed in depth. Because of low frequency inherent in rare variation, special study design strategies are required. In family-based trio designs, searching for and analyzing de novo variants has proven effective for identifying genes and pathways that confer significant risk. Similarly, case–control studies can detect variation that is significantly enriched in patient cohorts. We review the application of current genome technologies in psychiatry and discuss new challenges that lie ahead in understanding the genetic mechanisms of psychiatric disorders and demonstrating the clinical translational potential of genetic findings.