Familial Transmission of Schizophrenia in Palau: A 20-Year Genetic Epidemiological Study in Three Generations

Our genetic epidemiological studies of schizophrenia and otherpsychotic disorders (SCZ) in the isolated population of Palauhave been ongoing for 20 years. Results from the first decadeshowed that Palau has an elevated prevalence of SCZ and thatcases cluster in extended multigenerational pedigrees intercon-nected via complex genetic relationships after centuries of en-dogamous, but not consanguineous, marriages. The aim of ourseconddecadeofresearch,whichextendeddatacollectionintoathird generation of young, high-risk (HR) Palauans, was toidentifysignificantpredictorsofintergenerationaltransmissionof illness. Our findings revealed that degree of familial loadingand gender effects on reproductive fitness are important modi-fiersofriskfortransmissionofSCZ.Among45distinctmultiplexfamilies, we identified 10 high-density (HD) Palauan families,eachwith7–29SCZcases,whichcontainhalfofPalau’s260SCZcases and 80% of the 113 SCZ cases with one or more affectedfirst-degree relatives, indicating that familial loading is a majorrisk factor for SCZ in Palau. Cases that belong to multiplyaffected sibships are more common than cases with an affectedparent. Furthermore, only 6/38 multiply affected sibships haveanaffectedparent,strongevidencethatmanyunaffectedparentsareobligatecarriersofsusceptibilitygenes.Althoughreproduc-tive fitness is dramatically reduced in affected males, the 30%minority who do become fathers are twice as likely as affectedmothers to transmit SCZ to an offspring. As they evolve, theseHD families can help to elucidate the genetic mechanisms thatpredict intergenerational transmission of SCZ.