Recurrence risk to offspring in extended multiplex schizophrenia pedigrees from a Pacific Island isolate

Genetic transmission plays a major role in the pathogenesis of schizophrenia. Family, twin, and adoption studies have consistently shown that risks in relatives are many times greater than the general population risk of approximately 1%. McGue, Gottesman, and Rao (1983; Am J Hum Genet 35:1161-1178) calculated risk estimates of 12.8% for offspring and 3.5% for nieces/nephews of schizophrenia patients based on a large data set of Western European families. The present study evaluated corresponding risk levels in Palau, an isolated population in Micronesia where the prevalence of narrowly (broadly) defined schizophrenia is 1.99% (2.67%) and cases cluster in extended pedigrees, 20 of which contain 80% of affected individuals. We hypothesized that offspring in these extended families would have a higher risk for schizophrenia than offspring in smaller schizophrenia pedigrees from more genetically heterogeneous populations. RDC diagnostic data based on complete ascertainment of cases and their families covering the past two generations were used to quantify empirical recurrence risks in the offspring and nieces/nephews of Palauan schizophrenia patients. Risks to 1st- and 2nd-degree offspring were approximately double the rates found in the smaller Western European families: 23.4% in the offspring of an affected parent, 6.4% in offspring with one affected aunt/uncle, and 15.0% in offspring with two or more affected aunts/uncles. Recurrence rates in offspring of an affected parent were 1.6 times higher in males (27.9%) than in females (17.7%). The high risk levels we found in Palauan offspring reflect the elevated population prevalence, strong familial aggregation, and multi-lineal transmission pattern of schizophrenia in Palau.