Genetic Studies of Schizophrenia and Bipolar Disorder

Since the early 20th century, both schizophrenia (SZ) and bipolar disorder (BP) have been observed to run in families. This link was conclusively determined to be at least in part genetic in a number of twin and/or adoption studies. With the introduction of genetic polymorphisms, the identification of these factors accelerated. Dozens of whole-genome linkage studies clearly implicated a few genomic regions in each disorder, such as 13q, 8q, and 6q in BP and 5q, 6p, and 8p in SZ. Even then, debates about their etiological relationship followed findings of shared linkage regions. Since 2002, genes such as DTNBP1, NRG1, and G72/G30 have been identified in schizophrenia samples in regions of linkage and subsequently replicated in independent samples, including some BP samples. Since 2007, whole-genome association studies have been performed in ever larger samples. These have led to some novel and subsequently replicated findings such as ZNF804A markers associated in both disorders, the identification of widespread association in the major histocompatibility complex, and genome-wide correlation in small-effect polygenic variation between them. The identification of numerous copy number variants on a genome-wide scale in independent samples highlighted commonalities between SZ and developmental and learning disorders. Although the overlap in genetic findings between BP and SZ is incontrovertible, it remains to be established whether this is due to the presence of a single underlying genetic signature manifesting as a clinically variable phenotype (i.e., a unitary psychosis model). The impact of psychotic BP in many BP samples on overlap findings has not been fully investigated. A change in nosological conventions based on these data is premature, and careful examination of clinical subtypes in large samples could be informative. At the current time, large-scale sequencing and investigations of epigenetic factors, gene-gene, and gene-environment interactions, and other sources of complexity are in very early stages but are likely to contribute substantially in the future.