The Genetics of Schizophrenia
The heritability of schizophrenia has been estimated to be approximately 80%, but years of linkage and association studies have turned up few robust or overlapping results. However, improvements in genetic methods and increased sample sizes may yet account for the apparent “missing heritability”. The longstanding polygenetic hypothesis states that many common variants of low effect size contribute to the disorder. As sample sizes increase, these variants become detectable amidst the sea of noise. Rare, higher risk variants are also becoming detectable with improvements in genetic testing. With rare, high risk, but incompletely penetrant structural variations, and common, low risk variants highly subject to epistasis and environment, the true intricacy of the genetic architecture of schizophrenia is becoming clear. The manner in which genes conspire with the environment to generate psychiatric symptoms is complex and pleiotropic. Truly understanding the genetic underpinnings of schizophrenia may require rethinking the concept of schizophrenia as a unified syndrome. Instead, the genetic origin of variation in endophenotypes, or in particular symptom domains, may be more easily discovered. Genetic testing may never be useful as a diagnostic tool for schizophrenia, but genetics is important for directing our efforts into understanding the biology of this complex disorder.