A compelling genetic hypothesis for a complex disease: PRODH2/DGCR6 variation leads to schizophrenia susceptibility.

Abstract

The human genome sequence is facilitating the task of identifying disease genes, understanding their normal functions and why compromising their function is associated with specific features of a disorder and its inheritance pattern (1). Genetic disorders with simple dominant and recessive (Mendelian) patterns of inheritance are invariably caused by rare single-gene mutations that are both necessary and sufficient for the disease to manifest. However, some single-gene disorders can display a complex pattern of inheritance. The prototype for this class is fragile X syndrome (2), whose non-Mendelian and complex pattern of X-linked inheritance arises from dynamic evolution of the mutation within families (3). Thus, complexity in inheritance patterns is not inconsistent with single-gene defects although geneticists routinely equate the non-Mendelian nature of a trait with inheritance at multiple genes (4). Genetic dissection of multigenic disorders is truly challenging yet possible (5), particularly with the human genome sequence in hand. In an outstanding piece of sleuthing, Maria Karayiorgou and colleagues (6) now show that genetic variation in proline dehydrogenase on human chromosome 22q11 is a likely and significant cause of schizophrenia. The familial nature of schizophrenia does not conform to simple dominant or recessive modes of inheritance.