The development of psychiatric illnesses, like most illnesses, is multifaceted and is at least in part due to genetics. Recent research reveals that genetic mutations and genomic disruptions contribute to the development of psychiatric disorders. In the September issue of Science, Daniel H Geschwind and Jonathan Flint discuss various advancements that have been made to tackle the challenges of drawing such conclusions due to the complexity of the conditions. Furthermore, the recent advancements appear promising in terms of understanding the illnesses at a neurobiological level, in hopes of ultimately developing more specific treatment methods. The authors discuss the associated risk of single-nucleotide polymorphisms (SNPs), copy number variations (CNVs), and rare mutations in protein coding domains with psychiatric disorders. Recent research reveals that genetic mutations and genomic disruptions contribute to the development of psychiatric disorders. Although Geschwind and Flint do not discuss the identification of one specific mutated gene that has been identified as causing psychiatric illness, they suggest that there is an association between genetic variants and increased risk of schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. SNPs are single mutations in the DNA sequence at an individual location. Although SNPs are not considered to cause disease, they have been linked to an association with increased risk of illness. Using SNPs and genome-wide association studies, individuals without the illness are compared to affected individuals in an attempt to detect association between the disease status and SNP variation. Recent genome-wide association studies have identified SNP containing locations in regulatory regions of the genome, rather than a specific gene, that may be related to increased risk of psychiatric illness. Along with identification of SNP containing regulatory sequences associated with risk, SNP and genome-wide association studies have yielded insight on the heritability of psychiatric disease. Along with identification of SNP containing regulatory sequences associated with risk, SNP and genome-wide association studies have yielded insight on the heritability of psychiatric disease. The amount of SNP sharing between an affected individual and the parent estimates the inherited portion of the trait. Using this approach, variations at a large number of loci (location of a gene) have been associated with increased risk, although each individual variant has only a small effect. The small effect of mutation at an individual loci indicates that it is the accumulation of variants that has an effect on genetic predisposition. This discovery signifies that due to the small effects of individual loci and the rarity of loci with a large effect, large samples must be used to gain further insight. Researchers have also used microarray analysis, which detects expression of many genes at the same time, to identify rare structural chromosomal variants that may contribute to risk of psychiatric disorders, especially autism spectrum disorder and schizophrenia. These structural chromosomal variants are referred to as copy number variations (CNVs) and they denote the presence of an abnormal number of copies of one or more segments of DNA due to duplication or deletion of a DNA sequence. Recent studies reveal an association between rare CNVs arising in gametes and autism spectrum disorder. Furthermore, studies found that large CNVs located in gene coding regions that arose in gametes (not hereditary) occur in 5-7% of individuals with nonsyndromatic autism spectrum disorder. A similar association between loci containing CNVs that were inherited or arose in gametes has been observed in schizophrenia. The contribution of CNVs is mostly attributed to sporadic accumulation in gametes, rather than familial cases. The third method of genetic analysis that Geschwind and Flint explain is complete sequencing of protein coding regions, in order to detect mutations in protein coding domains (the DNA sequence that is used to encode a protein). Rare protein disrupting variations have been associated with risk of autism spectrum disorder and schizophrenia. Recent studies have demonstrated that recurrent protein disrupting mutations in 33 genes are likely to have an effect on the risk of autism spectrum disorder risk. In families in which there is only one affected individual, it is estimated that 30% of the cases contain coding mutations that arose in gametes. These tools have provided insight into the overlap of psychiatric disorders, in terms of shared genetic contributions. These tools have provided insight into the overlap of psychiatric disorders, in terms of shared genetic contributions. The correlation between bipolar disorder and schizophrenia is 0.68, meaning 68% of the genetic risk factors for the diseases are believed to be shared. SNPs for both bipolar disorder and schizophrenia were genome-wide significant in three locations, while separately they were significant at various other loci. This discovery indicates that while each illness has specific loci disruptions associated with risk, there is also overlap in affected loci that could contribute to risk of both disorders. Similarly, a CNV type mutation in the form of a deletion of a specific sequence, the 22q11-13 deletion, has shown to predispose both autism spectrum disorder and schizophrenia. The observation of overlap between disorders and mixed phenotypic expression strengthens the theory that mutations which disrupt highly conserved genes do not lead to a specific disorder but rather increase the risk associated with a range of developmental disorders. Beyond overlap, studies have found that risk of bipolar disorder and schizophrenia disorder can be expressed below threshold. In other words, unaffected individuals can share some of the same genetic risk factors, without showing the phenotype of illness; instead these individuals demonstrate an increased state of creativity. The increased state of creativity could be considered an evolutionary advantage leading to maintenance of genetic risk factors associated with the development of bipolar disorder and schizophrenia. Individuals with sub-threshold expression are considered to have an intermediate phenotype, meaning they have traits that are shared with individuals that have the disorder but are below the threshold for diagnosis. Geschwind and Flint propose that in general, genetic advancements in understanding psychiatric disorders reveal a collection of rare genetic conditions that contribute to risk and development of psychiatric disorders. Furthermore, they propose that the key to moving forward with these discoveries is to understand if the complex and rare genetic conditions converge by means of biochemical pathways, the specific pathway varying with disease. Geschwind and Flint are in favor of a systems genetics approach, which considers the influence and function of genes at a network level. Recent studies reveal that the genetic risks do converge in biochemical pathways. For example, the genetic risks associated with autism spectrum disorder converge on pathways involving regulation of transcription and chromatic structure during neurogenesis, as well as the subsequent process of synaptic development and function. The network approach to schizophrenia reveals a similar convergence in the pathway responsible for the development of the prefrontal cortex. However, Geschwind and Flint recognize that these insights are limited by the broad basis of the pathways, and that the effects should be examined at the protein function and signaling level. Geschwind and Flint highlight that the direction of the study of genetic variation and the effect on psychiatric illness should be towards integrating emerging knowledge of cell types and circuits with mechanisms of genetic regulation during neurodevelopmental stages. Although the described genetic mechanisms and their implications are convoluted and complex, these discoveries provide a basis for expanding neurobiological understanding of psychiatric illnesses. Geschwind and Flint highlight that the direction of the study of genetic variation and the effect on psychiatric illness should be towards integrating emerging knowledge of cell types and circuits with mechanisms of genetic regulation during neurodevelopmental stages. The discoveries of genetic influence on psychiatric disorders brings us one step closer to a more complete neurobiological approach to treatment. However, over the next few years it is likely that our understanding of the genetic origins of psychiatric disorders will increase to a greater extent. References Geschwind, D., & Flint, J. (2015). Genetics and genomics of psychiatric disease. Science, 1489-1494.