Genetic predisposition plays an important role in most common psychiatric disorders. The identification of a specific gene associated with a psychiatric illness can lead to improved management of the gene-associated disorder. Mutations in the wolframin gene are associated with mental illness. Many patients with the Wolfram syndrome (WS), who are homozygous or compound heterozygous for wolframin mutations, have severe psychiatric symptoms. In WS families, close blood relatives, who have a high probability of carrying a single wolframin mutation, had a statistically significant excess, over spouse controls, of psychiatric hospitalizations, attempted and completed suicides, and self-reports of mental illness. Since heterozygous carriers of wolframin mutations are relatively frequent in the population according to the general Hardy-Weinberg principle, such mutations might be responsible for the illnesses of many psychiatric patients. The hypothesis that heterozygous carriers of a wolframin mutation are predisposed to psychiatric illness was tested in subjects from 25 WS families. In all, 11 relatives who had psychiatric hospitalizations could be genotyped through mutation analysis. Eight of these carried the wolframin mutation transmitted in their family, significantly (one-sided P=0.0022) more than the 3.0 expected if there were no association between psychiatric hospitalizations and mutations at this locus. All eight mutation-positive subjects had been hospitalized for a major depression. This confirmation of the association is not influenced by confounders, undetected stratification, or genetic heterogeneity. The relative risk of psychiatric hospitalization for depression was estimated to be 7.1 (95% CI 1.9-26.6) for carriers of a single wolframin mutation compared to noncarriers.