A typological model of schizophrenia based on age at onset,sex and familial morbidity

We investigated the age at onset distributions of schizophrenia in men and women and the relationship of age at onset and sex to the familial rates of schizophrenia and manic-depression in data from a Swedish family study of 270 schizophrenic probands. On the logarithmic scale, the age at onset distribution of schizophrenia in both male and female relatives was bimodal, suggesting that broadly defined schizophrenia may be a mixture of 2 (probably related) disorders. The risk of schizophrenia in relatives decreased as a function of the age at onset of the proband, irrespective of the sex of the proband or relative. In contrast, the risk of manic-depression was significantly higher in relatives of female probands with an age at onset in the twenties than in relatives of female probands with earlier or later onset, or in relatives of male probands. This suggests a third disorder related to affective psychosis, with an intermediate age at onset and female preponderance.     

Schizophrenia: age at onset, gender and familial risk

In a family history study of 366 schizophrenic probands and their 1851 first-degree relatives, we found a relationship between age at onset of psychosis in the male probands and the risk for schizophrenia in their relatives. The relatives of male schizophrenic probands whose onset of psychosis occurred when they were younger than 17 years of age had an increased risk of schizophrenia when compared with the relatives of male probands with an age at onset greater than 17. We did not find an association between age at onset of psychosis in the female probands and familial risk. Cox proportional hazards models permitted us to examine the relationship between age at onset of psychosis in the probands and familial risk while controlling for possible confounding effects.     

精神分裂症家族史性别差异调查

目的 了解不同性别精神分裂症遗传的差异及父系、母系阳性家族史的差异.方法 对长沙市城、乡在我院住院的及同时段各社区进行免费药物求助的共1938例精神分裂症患者进行精神障碍遗传的问卷调查,发现精神分裂症阳性家族史患者253例,其中男性139例,女性114例.对家族史阳性率,先证者父系、母系、同胞子女患病情况作统计分析.结果 男性阳性家族史比率较女性稍低,但无统计学意义;父系、母系、同胞子女的阳性家族史无明显性别差异;母系阳性家族史明显高于父系.结论 遗传因素对精神分裂症有很大的影响,不同性别精神分裂症的阳性家族史无明显差异.精神分裂症中母系后代比父系后代有更高的发病风险.     

Age-of-onset in schizophrenia and schizotypal disorders. Clinical and genetic implications

Age-of-onset data were gathered on 93 chronic schizophrenic probands and 57 affected (mainly schizotypal) siblings. 55% of affected individuals were ill before age 20 and 14% had their onset before age 14. The risk period for schizophrenia and schizotypal personality disorders terminated at age 40. Age-of-onset did not distinguish paranoid from nonparanoid schizophrenics, or definite from probable schizotypal personalities. Schizophrenic and schizotypal subjects were similar in their age-of-onset patterns. Sex effect on age-of-onset was not present. A square-root normal distribution gave the best fit to the data. The implications of these findings for schizophrenia research were discussed.     

Familial-genetic and reproductive epidemiology of schizophrenia in rural Ireland: age at onset,familial morbid risk and parental fertility

Waddington JL and Youssef HA. Familial-genetic and reproductive epidemiology of schizophrenia in rural Ireland: age at onset, familial morbid risk and parental fertility Acta Psychiatr Scand 1996: 93: 62–68. © Munksgaard 1996. Among all ascertainable cases of DSM IIIR schizophrenia within an unusually homogeneous region of rural Ireland, family history information was sought from multiple sources. Morbid risk for schizophrenia among probands' first degree relatives was 6.1% and did not differ between male (6.5%) and female (5.5%) probands; risk among probands' siblings (8.3%) exceeded that among their parents (1.4%), with only 2% of male and 31% of female probands being themselves married. Both age at onset <25 and having >7 siblings were associated with elevated morbid risk, particularly among relatives of male probands (11.9% vs. 2.2% and 11.8% vs. 3.7%, respectively). Increased fertility particularly among parents of male patients with high familial-genetic loading may contribute to perpetuation of the disorder in the face of those patients' own extremely low fecundity.     

The risk for psychiatric illness in siblings of schizophrenics: the impact of psychotic and non-psychotic affective illness and alcoholism in parents

Clarification of the nature of the liability to schizophrenia transmitted within families is a major goal of family studies. In the Roscommon Family Study, the risk in relatives of schizophrenic vs. control probands was significantly increased for psychotic affective illness (PAI), but not for non-psychotic affective illness (NPAI) or alcoholism (ALC). We attempt to confirm these findings independently by examining, within families of schizophrenia spectrum probands, the relationship between PAI, NPAI and ALC in parents and the risk for schizophrenia spectrum disorders in siblings. A parental diagnosis of PA1 predicted a significantly increased risk for schizophrenia, affective illness and anxiety disorders in siblings. In particular, schizophrenia in siblings was predicted by a parental diagnosis of mood-incongruent PAI. By contrast, neither a parental diagnosis of NPAI nor a parental diagnosis of ALC was associated with an increased risk for schizophrenia spectrum disorders in siblings. Consistent with our earlier findings, these results suggest that (a) the familial liability to schizophrenia is neither extremely nonspecific nor extremely specific and (b) PAI, and particularly mood-incongruent PAI, may occur particularly in parents of schizophrenics because, although it reflects a significant familial liability to schizophrenia, it does not markedly impair the ability to marry and reproduce.     

Schizophrenia: gender and familial risk.

The morbid risks for schizophrenia and any nonaffective psychosis in the first degree relatives of male and female schizophrenic probands were compared utilizing Cox proportional hazards models. The schizophrenic probands (275 male; 106 female) were drawn from a larger sample of hospitalized patients obtained by systematically screening all psychiatric admissions to 15 facilities over a six-year period. Proband diagnoses (DSM-III) were based on a direct assessment of the patient and a review of medical records. The family history method was used to obtain information about the first degree relatives of the probands. Cox proportional hazards models were adjusted for duration of illness of the proband and gender of the relatives. First degree relatives of female probands had significantly higher morbid risks for schizophrenia and nonaffective psychosis than relatives of male probands. The differential risk for schizophrenia in the relatives of male and female probands demonstrated in this study, as well as others, suggests that males and females may be at different risk for subtypes of the disorder.     

Winter birth and biological family history in adopted schizophrenics

To investigate relationships between birth season and biological family history in schizophrenia, this study used a sample of schizophrenics that had the advantages of (a) particularly thorough diagnostic assessments of schizophrenics' relatives, including information from direct interviews as well as chart reviews, and (b) schizophrenic probands who were adopted at early age, mitigating the usual confounding of genetic and postnatal environmental influences of the family. Adopted schizophrenics with no biological family history of schizophrenia-spectrum disorders were significantly more likely to be born in winter months than were either (a) their own biological relatives, including their sibs and half-sibs, (b) schizophrenics with a positive family history for schizophrenia-spectrum disorders, or (c) people in the general population. Family-history-positive schizophrenics and their schizophrenic relatives were, in turn, significantly less likely than their own non-schizophrenic biological relatives to be born in the winter; schizophrenics in these families tended to be born in the milder-weather seasons, particularly the spring and fall. Results suggest that environmental factors associated with winter birth may be etiologically important in schizophrenia, particularly for cases in which familial liability factors are weak. By contrast, a familial, probably genetic, liability factor may be especially important in schizophrenics born in mild weather.     

The role of gender in identifying subtypes of schizophrenia: a latent class analytic approach

Past literature suggests that schizophrenic men and women may be at different risks for developing different subtypes of schizophrenia. This hypothesis was tested using data from the well-known retrospective cohort family studies, the Iowa 500 and the Iowa non-500. The sample consisted of 171 male and 161 female DSM-III schizophrenic patients and 713 of their first-degree relatives. First, bivariate tests for gender differences were conducted regarding family morbidity, age of onset, premorbid history, season of birth, and expression of deficit and affective symptoms. Restricted maximum likelihood latent class analysis was then used to test whether there was a subgroup of schizophrenic men who were more likely to have a low familial risk for schizophrenia or schizophrenia spectrum disorders, deficit symptoms, poor premorbid history, and birth in the winter months, suggesting possible early environmental insults, compared to schizophrenic women. Results showed that although men were more likely to meet these criteria, women also met them, thus suggesting gender differences in the prevalence of the subtype. Schizophrenic women were more likely to express a form of the illness characterized by dysphoria, persecutory delusions, and a higher family morbidity risk for schizophrenia than schizophrenic men. Results for spectrum disorders among relatives were equivocal with regard to gender.     

Gender and the familial risk for schizophrenia. Disentangling confounding factors.

Recent studies of the effect of gender on the familial risk for schizophrenia have shown that relatives of females have a higher risk for schizophrenia than relatives of males. This study attempts to explain the effect by examining factors found to differentiate schizophrenic men and women and found to be related to the familial risk for schizophrenia. Cox proportional hazard regression model was used to examine the simultaneous effects of age at onset, season of birth, and premorbid history, controlled for symptoms that have been found to differ by gender (dysphoria, paranoia, and flat affect). Results showed that the effect of gender on the transmission of schizophrenia could not be explained by gender differences in age at onset, symptom expression, premorbid history, and winter birth. However, premorbid history had an effect on familial risk independent of gender, indicating that probands with a poor premorbid history had a lower familial risk for schizophrenia than those with a good premorbid history. Implications of the findings are discussed.     

精神分裂症遗传的性别差异

目的：比较不同性别精神分裂症遗传的差异。方法：在同期出院的877例精神分裂症患者中，整群连续抽取精神分裂症阳性家族史患者107例：按性别分为男性组45例，女性组62例。对家族史阳性率，先证者父系、母系、同胞、子女患病情况，一、二、三级亲属患病情况，胎次，患病个数及疗效作统计分析。结果：男性阳性家族史比率较女性低，且疗效差异有显著性；女性患者4胎及以上者显著较多。结论：不同性别精神分裂症的遗传有差异。     

Age of onset in familial and sporadic schizoph4.4.renia

We have studied the gender and family history differences with regard to age of onset of schizophrenia. These differences have often been viewed as an important clue to the aetiology of the illness. Patients from three centres in Europe and Canada were included in the study. A sample of 1089 subjects was categorized according to the subject's sex, family history of schizophrenia, and the centre. The principal statistical method was analysis of variance. Patients with no family history of schizophrenia had a consistently higher average age of onset. This effect was seen in both male and female subjects across all three groups. These results support the relationship between familial risk and early onset, but no interaction of gender and family history was found.     

Heritability of schizophrenia and major affective disorder as a function of age, in the presence of strong cohort effects

It remains unclear whether age at onset for major psychiatric disorders is a useful marker of etiologic and genetic heterogeneity. The authors examined how heritability of schizophrenia and major affective disorders varied with age at onset. The sample was drawn from a large archival data set collected by Lionel Penrose, comprising 3,109 families with two or more members first hospitalized in Ontario between 1874 and 1944. The authors studied 1,295 sibships with schizophrenia (n = 487), major affective disorder (n = 378), both (n = 234) or neither (n = 196) of these disorders. Proportional hazards models were used to estimate how the hazard of hospitalization for each disorder (schizophrenia or major affective disorder) varied with proband age at onset, adjusted for changes in age at onset distribution between 1874 and 1944. A sibling's risk of hospitalization for the same illness significantly increased for each 10–year decrease in age at onset of the proband both for schizophrenia (hazard ratio = 1.21, 95 % confidence interval: 1.06, 1.39), and for affective disorder (hazard ratio = 1.29,95 % CI: 1.14, 1.45). Gender of proband was unrelated to sibling risk of the same illness, and tests of interaction effects between proband age at onset and gender on sibling risk were nonsignificant.     

Clinical Indicators of Genetic Susceptibility to Epilepsy

Summary: We evaluated clinical indicators of genetic susceptibility to epilepsy in the families of 1,957 adults with epilepsy (probands) ascertained from voluntary organizations. Very few of the probands in this series had idiopathic epilepsy syndromes. Among relatives of probands with postnatal CNS insults, risks of epilepsy were no higher than in the general population. Risk was increased in relatives of probands without identified CNS insults (i.e., those with idiopathic/cryptogenic epilepsy) or with neurological deficit presumed present at birth, compared with relatives of probands with postnatal CNS insults. Among relatives of probands with idiopathic/cryptogenic epilepsy, risks were higher in parents and siblings, but not in offspring, of probands with generalized onset as compared with partial onset seizures. Risks in offspring were higher if the probands had onset of idiopathic/cryptogenic epilepsy before age 10 as compared with age 10 years, but risks in parents and siblings were not associated with the proband's age at onset. These results suggest that genetic susceptibility increases risk of some forms of cryptogenic epilepsy and of epilepsy associated with neurological deficit presumed present at birth, but not of postnatal symptomatic epilepsy. The influences on risk in offspring may differ from those in parents and siblings.     

Morbidity Risk of Schizophrenia to Parents and Siblings of Schizophrenic Patients

Abstract: In order to estimate the familial morbidity risk of schizophrenia, parents and siblings of 1,691 inpatients meeting the DSM-III criteria for schizophrenia were investigated on the basis of a review of medical records, family history data and/or personal interviews. The morbidity risks of schizophrenia to parents and siblings of the schizophrenic probands were 4.0% and 4.1%, respectively, which were greater than the morbidity risk in the general population. Siblings of 118 probands whose parents suffered from schizophrenia were at a significantly greater risk of schizophrenia than siblings of 1,493 probands whose parents did not have schizophrenic illness. These findings support thenotion of familial transmission of schizophrenia. A total of 16.4% of the schizophrenic probands had at least one first-degree relative with schizophrenia. This is significantly greater in the female probands than in the male probands.     

Morbidity risk of schizophrenia to parents and siblings of schizophrenic patients

In order to estimate the familial morbidity risk of schizophrenia, parents and siblings of 1,691 inpatients meeting the DSM-III criteria for schizophrenia were investigated on the basis of a review of medical records, family history data and/or personal interviews. The morbidity risks of schizophrenia to parents and siblings of the schizophrenic probands were 4.0% and 4.1%, respectively, which were greater than the morbidity risk in the general population. Siblings of 118 probands whose parents suffered from schizophrenia were at a significantly greater risk of schizophrenia than siblings of 1,493 probands whose parents did not have schizophrenic illness. These findings support the notion of familial transmission of schizophrenia. A total of 16.4% of the schizophrenic probands had at least one first-degree relative with schizophrenia. This is significantly greater in the female probands than in the male probands.     

Schizophrenia among first-degree relatives of paranoid and nonparanoid schizophrenics

In 1971, McCabe et al.¹ conducted a blind family study of a group consisting of 28 good-prognosis and 25 poor-prognosis schizophrenics. The results of that study showed that the families of poor-prognosis schizophrenics contained significantly more schizophrenia, neurosis, and overall illness, but significantly less affective disorder, than the families of good-prognosis schizophrenics. On the basis of their study, the data seemed to support the idea of at least two illnesses in schizophrenia: namely, that which could be called “good prognosis,” which tends toward affective disorder, and that which could be called “poor prognosis,” which tends toward process schizophrenia.Subsequently, Fowler et al.² reported a similar blind family study of a group consisting of 35 additional poor-prognosis schizophrenics and the 25 poor-prognosis schizophrenics from the McCabe study,¹ for a total of 60. Probands and their families were classified and then compared, according to paranoid (32) and nonparanoid (28) subgroups, to determine if there are still further distinct illnesses in schizophrenia on the basis of familial data. Family differences between the two groups were limited to a greater risk for the combination of schizophrenia, undiagnosed psychosis, and paranoid personality in the nonparanoid probands' families.This paper presents the results from the further analysis of data gathered for the 60 probands and their families. In addition to the overall frequency of schizophrenia in this group, frequency is calculated for the combined variables of sex, relationship to proband, and diagnostic subtype (of both the proband and of the ill family member).     

Do women without a family history of schizophrenia have a later onset of schizophrenia?

The relation among age at onset of schizophrenia, sex and the presence or absence of first-degree relatives with schizophrenia was investigated in 2,417 inpatients meeting the DSM-III criteria for schizophrenia. The mean age at onset of female schizophrenic patients without a family history of this illness was slightly later than that of any of the other three groups (male familial, female familial and male nonfamilial groups). The female nonfamilial group developed schizophrenia after the age of 25 and 30 more frequently than the male familial group and female familial or male nonfamilial group, respectively.     

No association between season of birth of patients with schizophrenia and risk of schizophrenia among their siblings

Previous studies on the relationship between the season of birth of patients with schizophrenia and the risk of schizophrenia among their siblings have yielded contradictory results. We investigated whether proband's month of birth affects siblings' risk of developing schizophrenia. We used the Finnish Hospital Discharge Register to identify all patients born in Finland from 1950 to 1976 who had been hospitalized because of schizophrenia at least once between 1969 and 1995. Their siblings were identified from the National Population Register, and data on siblings were linked to the Hospital Discharge Register to obtain information on any hospitalizations. We used logistic regression to investigate a sibling's probability of developing schizophrenia, defining the proband initially as the first sibling in calendar time to develop schizophrenia, then as the affected sibling with lowest onset age. Within-family dependence was taken into account by using robust standard error estimates. Neither models found any association between proband's month of birth and siblings' odds of developing schizophrenia. Our results support those previous studies that found no association between proband's month of birth and family history of schizophrenia, and suggest that the winter-spring excess of births among patients with schizophrenia is not caused by any genetic or environmental risk factor that operates independently of other risk factors.     

Has familial aggregation in Alzheimer's disease been overestimated?

Studies of the familial aggregation of Alzheimer's disease have primarily used samples ascertained from tertiary care clinics which may not be representative of many AD patients, for example those residing at geriatric nursing homes. Survival analysis was used to investigate whether estimates of familial aggregation of AD based on a clinic-based AD proband (C-AD) sample (probands: N=544; first degree relatives; N=4267) differ from one ascertained at a nursing home (NH-AD; probands: N=225; first degree relatives; N=1772). The cumulative survival from AD was significantly worse in relatives of the C-AD probands and the overall relative risk (RR) of AD in this group was greater than twice that of relatives of the NH-AD probands. However, age at onset in C-AD probands was significantly earlier than in the NH-AD group and in both groups this factor was negatively associated with familial aggregation. When, for this reason, the proband samples were matched one-to-one by age at onset, dropping those probands with no match, the two curves were close to identical and the RR for the C-AD group of relatives was 1.0 The results suggest that estimates of familial risk of AD based on C-AD samples are not applicable and overestimate the extent of increased risk for relatives of more prevalent, later onset AD probands. However, the overestimate can be explained by the typically earlier age at onset in C-AD samples as opposed to a sampling bias related to the proband's family history status per se. The relationship between onset age and familial aggregation suggests that no single estimate of the age-dependent risk (survival curve) is uniformly appropriate for relatives of AD probands.