Familial transmission of schizophrenia in Palau: A 20-year genetic epidemiological study in three generations.

Our genetic epidemiological studies of schizophrenia and other psychotic disorders (SCZ) in the isolated population of Palau have been ongoing for 20 years. Results from the first decade showed that Palau has an elevated prevalence of SCZ and that cases cluster in extended multigenerational pedigrees interconnected via complex genetic relationships after centuries of endogamous, but not consanguineous, marriages. The aim of our second decade of research, which extended data collection into a third generation of young, high-risk (HR) Palauans, was to identify significant predictors of intergenerational transmission of illness. Our findings revealed that degree of familial loading and gender effects on reproductive fitness are important modifiers of risk for transmission of SCZ. Among 45 distinct multiplex families, we identified 10 high-density (HD) Palauan families, each with 7-29 SCZ cases, which contain half of Palau's 260 SCZ cases and 80% of the 113 SCZ cases with one or more affected first-degree relatives, indicating that familial loading is a major risk factor for SCZ in Palau. Cases that belong to multiply affected sibships are more common than cases with an affected parent. Furthermore, only 6/38 multiply affected sibships have an affected parent, strong evidence that many unaffected parents are obligate carriers of susceptibility genes. Although reproductive fitness is dramatically reduced in affected males, the 30% minority who do become fathers are twice as likely as affected mothers to transmit SCZ to an offspring. As they evolve, these HD families can help to elucidate the genetic mechanisms that predict intergenerational transmission of SCZ.

Early signs and symptoms of psychosis among Palauan adolescents.

AIM: This study was designed to identify early symptoms associated with the occurrence of psychosis during adolescence. METHOD: Participants were recruited in the Republic of Palau, an isolated island nation in Micronesia with a prevalence rate for schizophrenia of 1.99%. Diagnostic interviews were used to obtain reports of early and current symptoms from 112 genetically high-risk (GHR) and 208 genetically low-risk (GLR) adolescents (ages 16-23). Based on current psychotic symptoms, participants were sorted into three groups: non-clinical, at-risk/symptomatic risk and clinically symptomatic. RESULTS: Multivariate analysis of variance revealed several between-group differences on rates of early symptoms. Most notably, youth who were in the GHR-clinically symptomatic group reported significantly higher rates of early marijuana use than GLR-clinically symptomatic youth, who were significantly more likely to report early symptoms of depression and behaviour disorders. In addition, several gender based differences in the link between early symptoms and adolescent onset psychosis were noted. CONCLUSIONS: Findings are generally consistent with previous research on early indicators, though several unexpected findings suggest that results from this study may not be fully generalizable beyond this relatively isolated and culturally distinct Micronesian nation.

Adoption, family relations and psychotic symptoms among Palauan adolescents who are genetically at risk for developing schizophrenia.

PURPOSE: This paper focuses on the role of adoption and family relations as moderators of genetic risk for psychotic disorders. METHODS: Participants included 184 adolescents in the Republic of Palau identified to be at genetic risk for schizophrenia and other psychotic disorders. Palau is an island nation in Micronesia with a lifetime prevalence of 1.99% for schizophrenia and 2.67% for psychotic disorders more broadly defined. In Palauan culture, kinship adoption is a common cultural practice; 47 of the 184 participants had been adopted at an early age. The current study was designed to test the hypothesis that adoption would function as a protective factor among Palauan youth at genetic risk for the development of psychotic symptoms. Participants were evaluated for psychotic and other psychiatric symptoms using KSADS-PL. Concurrently, the Youth Self Report was used to assess the perceived quality of family relationships. RESULTS: Results indicated that adopted adolescents were more likely to develop psychotic symptoms than non-adopted adolescents. However, perceived family relations moderated the association between adoption status and psychotic symptoms, such that adopted adolescents with poorer family relations reported disproportionately higher rates of psychotic symptoms. Family relations also moderated the association between level of genetic risk and psychotic symptoms, independently of adoption status. CONCLUSION: Consistent with previous research, adolescents at high genetic risk who reported more positive family relations also reported fewer psychotic symptoms.

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.

The Palau Early Psychosis Study: distribution of cases by level of genetic risk.

The Palau Early Psychosis Study (PEPS) was designed to examine the pathogenesis of early psychosis in a high-risk population isolate. This paper describes the characteristics of our community-based, non-help seeking sample of 404 Palauan adolescents and quantifies the presence of early psychosis by level of genetic risk. The sample included 53 offspring of a schizophrenic parent designated as "Genetically Highest Risk" (GHR+) and 68 nieces/nephews of sib-pairs/trios, designated as "Genetically High Risk" (GHR). The remaining subjects were recruited through a high school survey that identified 62 "Genetically Moderate Risk" (GMR) adolescents with an affected second or third degree relative and 221 "Genetically Low Risk" (GLR) subjects with no close affected relatives. The GLR adolescents included 117 symptomatic or "Clinically High Risk" (CHR) adolescents and 104 asymptomatic normal controls. Based on a modified K-SADS-PL assessment, we identified 221 adolescents with early psychosis, 62 or 28% of whom had already transitioned to a psychotic disorder. Together, the two highest risk groups contributed 31% of the adolescent-onset psychosis cases and 27% of the prodromals. More than half of the early psychosis cases (53%) were GLR adolescents. The mean age of onset for DSM-IV psychosis was 12.9 years, and males transitioned at an earlier age than females. Our results indicate that Palauan adolescents, even GLR adolescents with no close affected relatives, have elevated rates of early psychosis. These young subjects can contribute valuable information about the familial transmission of schizophrenia, the developmental course of the illness, and rates of transition to frank psychosis.

The Palau Early Psychosis Study: neurocognitive functioning in high-risk adolescents.

OBJECTIVE: The purpose of the present study was to evaluate both the independent and joint effects of genetic risk and clinical status on neurocognitive functioning in adolescents from a population isolate with an elevated risk for schizophrenia and strong familial aggregation of cases. METHOD: The subjects were 310 non-help seeking, drug-naïve adolescents 14-19 years of age from the Republic of Palau. The sample comprised 98 Genetically High Risk (GHR) adolescents, 54 of whom were symptomatic, and 212 Genetically Low Risk (GLR) adolescents, including 113 Clinically High Risk (CHR) subjects who were symptomatic and 99 normal controls who were non-symptomatic. Neurocognitive testing was conducted after the clinical assessment and included Wechsler Memory Scale tests of logical, visual and working memory, the perceptual organization and processing speed subtests of the WISC-III, CPT-IP measures of sustained attention, and tests of fine and gross neuromotor function. RESULTS: GHR adolescents showed impairments in immediate logical memory, verbal working memory, CPT-IP performance, and fine motor skills. The only two cognitive components influenced by the presence of early psychosis symptoms were WISC-III perceptual organization and spatial working memory. Neurocognitive deficits did not increase with increasing levels of psychopathology. We found no significant interactive effects of genetic risk and clinical status on neurocognitive functioning. CONCLUSIONS: Genetic risk and clinical status exert independent effects on neurocognitive function in HR adolescents, and genetic risk has a broader impact than clinical status. Our results suggest that many of the neurocognitive impairments associated with early psychosis are genetically mediated and can occur in genetically vulnerable individuals regardless of their clinical status. However, visuospatial processing appears to be uniquely disrupted by emerging symptomatology.

Comorbid depressive symptoms in the developmental course of adolescent-onset psychosis.

AIM: Depressive symptoms are common in the early prodromal phase of schizophrenia and other psychotic disorders. The objectives of the present study were to retrospectively examine the severity of depressive symptoms and their relationship to positive symptoms over the developmental course of adolescent-onset psychosis (AO-PSY). METHODS: The subjects were 62 unmedicated adolescents with DSM-IV psychosis and 104 normal controls from a Pacific island isolate with an elevated prevalence of schizophrenia. We used a modified K-SADS-PL to assess adolescents for a full range of Axis I psychopathology and quantified severity of depressive and positive symptoms over the adolescent's lifespan. RESULTS: Among AO-PSY subjects, 84% reported abnormal levels of depressive symptoms with mean onset 1.3 years prior to transition to psychosis. In 60% of the AO-PSY subjects with depressive symptoms, positive symptoms began first. A continuous linear increase in depressive symptom severity over the developmental course of illness mirrored the steady rise in positive symptom severity as psychosis emerged. CONCLUSIONS: We found that it is typically a combination of positive symptoms and depressive symptoms building in parallel that leads from the prodrome to frank psychosis. These results suggest that depressive symptoms represent more of an integral component of disease progression than an independent risk factor that predicts transition to early onset psychosis.

Preventive intervention for early psychosis in adolescents--the Palau Youth at Risk Project.

We have studied a total of 393 adolescents 14 to 19 years from Palau, where the lifetime morbid risk for broadly defined schizophrenia is 2.67% and cases cluster in large extended families. These Palauan adolescents included 52 offspring of a schizophrenic parent designated as "Genetically Highest Risk" or GHR+ and 61 nieces/nephews of affected sib-pairs/trios, designated "Genetically High Risk" or GHR. The remaining 280 subjects were recruited based on the results of a survey of Palauan high school students that was designed to screen for clinically HR and normal control adolescents with no close affected relatives. Among the selected high school students were 60 adolescents with one affected second or third degree relative who were designated as "Genetically Moderate Risk" (GMR). The remaining 220 subjects with no close affected relatives were designated as "Genetically Low Risk" (GLR). Based on a comprehensive clinical assessment using the K-SADS, we identified a total of 230 Palauan adolescents with early psychosis, 48 or 21% of whom had already transitioned to a DSM-IV psychotic disorder, predominantly schizophrenia. Together, the two highest genetic risk groups contributed 35% of the adolescent-onset DSM-IV psychosis cases and 26% of the prodromals. More than half of the early psychosis cases (55%) had no close affected relatives, indicating that genetic liability provides only a partial explanation of elevated risk. Our results support the value of screening for early psychosis in the high schools, conducting a full-scale clinical assessment to identify adolescents with early "prodromal" symptoms, and initiating a family-based intervention program designed to delay or even prevent the onset of florid psychosis. This intervention program comprises regular symptom reassessments so that referrals for treatment can be made as needed plus family psycho-education designed to engage the family in a program of care and support for the early psychosis patient.

P50 sensory gating in adolescents from a pacific island isolate with elevated risk for schizophrenia.

BACKGROUND: Gating or inhibition of the P50 auditory evoked potential is a heritable neurobiological trait that has shown strong potential to serve as an endophenotype for schizophrenia. P50 sensory gating deficits have been found repeatedly in schizophrenic patients and in their unaffected first-degree relatives. P50 sensory gating has not yet been studied in high-risk (HR) offspring nor in prodromal adolescents. METHODS: A paired-stimulus auditory event-related potential paradigm was used to examine P50 sensory gating in 44 genetically HR adolescent offspring and 43 clinically HR prodromal adolescents with the same low genetic liability as a comparison group of 39 normal adolescents. RESULTS: Auditory sensory gating, as measured by the P50 ratio, was impaired in both genetically HR offspring and also in the clinically HR prodromal adolescents with no close affected relatives. In the genetically HR group, abnormal P50 sensory gating was found only in offspring who met criteria for the schizophrenia prodrome. CONCLUSIONS: Our findings suggest that P50 deficits are associated with the presence of prodromal symptoms, regardless of genetic risk. The results are consistent with the hypothesis that genetic liability in HR offspring increases risk for prodromal symptoms, and prodromal symptoms, in turn, increase risk for impaired sensory gating.