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In the last 7 years, we have witnessed the emergence of the first molecular insights into the etiopathogenic mechanisms of psychiatric illness. These have resulted from the first genome-wide association studies (GWASs) with sufficient power to detect small allelic effects. Two major factors have contributed to these advances. First, technological breakthroughs have made it possible to affordably interrogate the human genome in exquisite detail in large numbers. DNA microarrays have made it possible to rapidly genotype millions of single nucleotide polymorphisms (SNPs), providing information on common alleles, with the added benefit of also being used to detect structural copy number variants (CNVs), including deletions, insertions, and duplications. Next-generation sequencing methods have advanced such that the cost of sequencing whole genomes has diminished more than a million-fold. This has allowed the completion of megaprojects such as HapMap1 and the Thousand Genomes Project,2 which have in turn greatly benefitted studies of specific illnesses by allowing them to “fill in the gaps” in their own limited genomic data.  The second major factor has been the convening of large international consortia comprised of individual groups, which together have resulted in samples of tens of thousands of cases and controls.3 This has resulted from the realization that the small effect sizes of most common variants can only be detected using very large Ns, which could never be obtained in any single study. Schizophrenia has been one of the main beneficiaries of these advances. For the first time, numerous genetic markers have been reliably associated with illness across multiple populations. The Psychiatric Genomics Consortium (PGC) Schizophrenia Workgroup has by now amassed most of the existing GWAS samples in the field and continues to grow.4 The most recent “mega-analysis” has resulted in the identification of >100 significantly associated loci, of which 75% included protein coding genes.4 While many of the reported genes have been novel, with no previous suggestions of effect on schizophrenia risk, others have long been suspected. The latter include DRD2 and several genes involved in glutamatergic neurotransmission. At the level of rare variants (<1% minor allele frequency), a number of deleterious CNVs have been identified,5–8 and the accumulation of rare sequence variants has been in genes that have been implicated in GWASs and other genetic studies.9,10 While it is nearly certain that no discovered genetic risk factor will be deterministic, we are in a very different position now than when systems of psychiatric diagnosis and classification could only rely on expert consensus, which was used to generate operationalized criteria. In this article, I will describe recent and ongoing efforts to utilize the wealth of genomic information provided by GWA and other studies to clarify basic issues in the diagnosis and classification of schizophrenia.

Can Genomics Help Usher Schizophrenia Into the Age of RDoC and DSM-6?