The genetics of schizophrenia spectrum disorders have come a long way since the early demonstration of a substantial genetic component by family, twin and adoption studies. After over a decade of intensive molecular genetic studies, initially by linkage scans and candidate gene association studies, and more recently genome-wide association studies, a picture is now emerging that susceptibility to schizophrenia spectrum disorders is determined by many genetic variants of different types, ranging from single nucleotide polymorphisms to copy number variants, including rare and de novo variants, of pleiotropic effects on multiple diagnoses and traits. Further large-scale genome-wide association studies, and the forthcoming availability of affordable whole-genome sequencing technology, will further characterise the genetic variants involved, which in turn will be translated to improved clinical practice.
The hereditary nature of schizophrenia and schizophrenia spectrum disorders has been long recognised. The first systematic family study of schizophrenia dates back to 1916 by Ernst Rudin.1 This was long before the molecular structure of the genetic material was elucidated, and long before DNA sequence could be directly measured. Early studies were therefore mainly concerned with the demonstration and quantification of genetic influences based on the pattern of disease occurrence in families. Converging lines of evidence from family, adoption and twin studies pointed to a genetic basis of schizophrenia. The risk of schizophrenia was shown to be significantly higher in the first degree relatives of affected individuals, with a risk ratio of about 10.2 Elevated risk of schizophrenia was found in the biological families but not the adoptive families of affected adoptees.2 Twin studies demonstrated a higher concordance rate for monozygotic than dizygotic twins. The heritability of schizophrenia was estimated at 81%, according to a meta-analysis of 12 twin studies.3 The meta-analysis also showed a small (11%) but significant contribution of shared environmental effects
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