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.     

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.     

Variability of familial risk of Alzheimer disease across the late life span

CONTEXT: The role of genetic factors in Alzheimer disease (AD) varies across the late life span, complicating efforts to quantify the risk of AD for relatives of probands with AD. OBJECTIVES: To visualize the changing levels of familial risk according to proband onset age and the age of the at-risk relative and to determine the familiality of age at onset in AD. DESIGN: A retrospective, informant-based family study. SETTING, PATIENTS, AND OTHER PARTICIPANTS: Siblings and parents of probands with AD (relatives = 4687; probands = 904), ascertained at geriatric clinic and nursing home settings, and of elderly probands without dementia (relatives = 7649; probands = 1525) who were spouses of probands, participants at senior centers, or nursing home residents without dementia. MAIN OUTCOME MEASURES: Informant-based assessments of AD in the relatives were used to generate 3-dimensional surfaces representing the patterns of risk of AD across the late life span depending on the specific onset age of the proband with AD (or assessment age of the elderly proband without dementia). We then constructed a 3-dimensional, age-specific, 10-year hazard rate ratio (HRR) surface representing the relative risk of AD in relatives of probands with AD with smoothly shifting levels of onset age compared with relatives of elderly probands without dementia. RESULTS: The HRR surface peaked (HRR, 13.0) for younger sexagenarian relatives related to probands with AD with onset age in their early 60s. The HRRs dropped sharply both as the proband age at onset and the age of the relative increased. For relatives aged in their late 80s, the HRR fell lower than 2.0 regardless of proband onset age and their lower-limit 95% confidence intervals were less than 1.0. CONCLUSIONS: The role of genetic risk factors decreases with increasing onset age of the proband with AD regardless of the age of the relatives themselves. The familiality of onset age is greatly reduced at later ages. The role of environmental risk factors in AD likely increases with onset age.     

The impact of gender and age at onset on the familial aggregation of schizophrenia

Summary Some recent family studies have shown that the familial risk for schizophrenia is higher in female than in male schizophrenics. It is debated whether the risks for the other disorders, such as schizotypal personality disorder or affective disorders in families of schizophrenics are similarly influenced by the proband's gender. Also, the reason for the effect of proband's gender on the recurrence risk for schizophrenia has not been clarified. This family study (159 probands, 589 first degree relatives) confirms that schizophrenia, but also schizophrenia spectrum disorders were more frequent in families of female compared with male schizophrenics. Neither age at onset in probands nor the interaction between gender and age at onset in probands had a relevant impact on the risk figures in relatives. Affective disorders occurred in families independently of the probands' gender. Aetiological heterogeneity or ascertainment bias may account for the modifying effect of proband's gender in schizophrenia.     

The familial transmission of bipolar illness

As part of the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression study, data were collected on 2225 first-degree relatives of 612 probands. We analyzed 187 families of bipolar patients (149 probands with a diagnosis of bipolar I disorder and 38 with a diagnosis of schizoaffective, manic subtype). Using traditional genetic methods, the morbid risk of bipolar illness in relatives was found to be 5.7% in the relatives of bipolar probands as contrasted with 1.1% in the relatives of probands with major depression. These values compared closely with those obtained using survival analysis. Relatives of probands with early onset were found to have a greater risk than relatives of probands with late onset. The sex of the relative, the sex of the proband, or the subtype of the proband (bipolar I or schizoaffective bipolar) did not influence the risk in the relative. The age at onset was found to be accelerated with birth cohort, with individuals born in more recent cohorts having an earlier onset. Multifactorial analysis found significant heterogeneity for sex-specific sibling correlations (with the brother-sister correlation smaller than the same-sexed correlations), and path analysis estimated transmissibility of liability to be 71%. The mixed model, which allows for a single major locus with a multifactorial background, gave evidence for the presence of a major locus when controlling for the effects of birth cohort and age at onset. However, this evidence is tempered when comparing the mixed model with a more general transmission model.     

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.     

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.     

Heritability of ischaemic stroke in women compared with men: a genetic epidemiological study

BACKGROUND: Ischaemic stroke is partly heritable. However, although the genetic and non-genetic factors responsible could be sex-specific, interactions between the sex of the parent affected and the sex of the proband or affected siblings are unknown. We sought to assess the relation between the sex and phenotype of affected probands and the sex of affected first-degree relatives. METHODS: We determined the prevalence of history of stroke in the mother, father, and other first-degree relatives in female and male probands with ischaemic stroke or transient ischaemic attack in the population-based Oxford Vascular Study (OXVASC). We validated our findings using unpublished individual patient data from two independent Oxford studies. FINDINGS: In OXVASC, detailed family history was available in 806 (93%) probands. Female probands were more likely than males to have at least one affected first-degree relative (146/423 vs 104/383; OR 1.4, 95% CI 1.1-2.0, p=0.02) due entirely to an excess of affected female relatives in female probands (female relative vs male relative OR=1.7, 1.3-2.4, p=0.0004; female only vs male only OR=2.1, 1.4-3.1, p=0.0001). Maternal stroke was more common than paternal stroke in female probands (OR=1.8, 1.2-2.7, p=0.001) but not in males (OR=1.1, 0.7-1.7, p=0.38), and female probands were more likely than males to have an affected sister (OR=3.1, 1.5-6.7, p=0.004) but not an affected brother (OR=1.1, 0.6-2.1, p=0.80). Ages at first stroke were also correlated within families among affected females (r=0.36, p=0.004) but not among affected males, such that the excess of affected female relatives of female probands was greatest when the difference in age at first stroke was less than 5 years (OR=3.7, 1.6-8.6, p=0.0007) and fell as the age difference increased (p for trend=0.004). These findings were independent of traditional risk factors and stroke subtype. Data from the other Oxford studies confirmed the excess maternal history of stroke in female probands (OR=2.3, 1.5-3.8, p<0.00001) and the lack in males (OR=1.0, 0.7-1.4, p=0.58). INTERPRETATION: Heritability of ischaemic stroke is greater in women than in men, with an excess of affected mothers and affected sisters in female probands independent of traditional vascular risk factors, which could be explained by sex-specific genetic, epigenetic, or non-genetic mechanisms.     

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.     

Do Women without a Family History of Schizophrenia Have a Later Onset of Schizophrenia ?

Abstract: 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-111 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.     

Estimated yield of early detection of prodromal or first episode patients by screening first degree relatives of schizophrenic patients

Screening a population of relatives of current schizophrenic patients could be an efficient means to accrue a sample of early first episode or prodromal patients for a prediction study or an intervention study. The risk of new onset schizophrenia cases in any one year in a population of relatives depends on the number of schizophrenic probands and three additional factors: (1) the age of onset distribution for schizophrenia; (2) the lifetime risk of the at-risk group of relatives selected; and (3) the number of at-risk relatives per proband and their age distribution. Estimates are made for each of these parameters, and calculations are presented. The base model suggests that screening all siblings and children of patients with schizophrenia would yield approximately 19 new cases of schizophrenia per year per 10,000 relatives screened. The results of the calculation are relatively insensitive to reasonable variation of most model parameter estimates. The yield of new cases obtained by screening relatives of current patients appears to be low if the purpose is to recruit a sample for an early intervention study over a relatively short period of time.     

Familial risk of migraine: A population-based study

Estimates of familial aggregation of migraine have varied considerably due, in part, to methodological differences among studies. We concluded a population-based study of 73 clinically confirmed probands with migraine, 72 matched control probands, and 511 of their first-degree relatives, all of whom were directly interviewed. The risk of migraine was 50% more likely in relatives of migraine probands than in relatives of controls. Migraine risk was considerably higher among relatives of probands with disabling migraine compared with relatives of probands with minimal disability. Moreover, for probands with minimal disability, no excess risk of migraine in female relatives was observed. Finally, in relatives risk of 4.04 was observed. No excess risk was observed among relatives of male probands who had migraine without aura. This study suggests that familial factors (environment related to the family or genetic factors) account for less than one-half of all migaine cases in the population. Degree of disability in the proband appears to influence familial risk. These results suggest that the development of migraine is determined by complex gentic as well as environmental factors.     

Hazard, heredity and depression. A family study

The relationship between proband characteristics and familial aggregation of depression was assessed in an interview study of 83 families ascertained via probands who had a recent onset of depression. Contrary to expectations and to previous reports in the literature there were no differences between the frequencies of depression in the first degree relatives of probands who had or had not experienced adversity prior to the onset of their illness. Depression was actually slightly more common among the first degree relatives of probands who had experienced a threatening life event compared with the relatives of those who had not. Early onset of depression (before 32 yr) and a neurotic pattern of symptoms in probands were associated with significantly higher rates of current illness in relatives. However, both these differences disappeared when lifetime prevalence or morbid risk to age 65 were considered. Indeed the morbid risk of severe depression in the relatives of endogenously depressed probands was nearly twice that in the relatives of neurotic probands.     

Five latent factors underlying schizophrenia: analysis and relationship to illnesses in relatives

Clinical signs and symptoms in a sample of 1,043 individuals with schizophrenia or schizoaffective disorder were subjected to latent class factor analysis. Positive, negative, disorganized, and affective factors were similar in content to factors described in a number of other studies, while a fifth factor representing early onset/developmental signs provided a new area for investigation. The five sets of factor scores were logistically regressed on psychiatric illness indicators in first and second degree relatives. Relatives of probands with higher positive or negative symptom factor scores had a lower risk of depressive illness. Higher affective factor scores in probands predicted more mania and depression in relatives. Both the disorganized and the early onset/developmental factors were related to increased risk of psychiatric hospitalization in relatives, as well as increased risk of psychosis (marginally so for the disorganization factor). Increased early onset/developmental signs in the proband were also associated with increased risk for depression in relatives. These findings suggest a possible endophenotypic role for the factor scores in future studies.     

Children of depressed parents. Increased psychopathology and early onset of major depression

Data on the psychiatric diagnosis, overall functioning, and treatment of 220 6- to 23-year-old subjects who were at high or low risk for major depression are presented. The subjects' diagnoses were made by a child psychiatrist based on best-estimate evaluation of diagnostic information derived from structured interviews (Schedule for Affective Disorders and Schizophrenia for School-Aged Children, Epidemiologic Version) with the subjects and separately with their mothers about their children. The major findings were an increased overall prevalence of major depression and substance abuse, psychiatric treatment, poor social functioning, and school problems in the children of depressed proband parents compared with children of normal proband parents. Overall prepubertal depression was uncommon and the sex ratios were equal. After 12 years of age, there was an increasing preponderance of female subjects in the group with major depression. The mean age at onset of major depression was similar for male and female subjects. However, it was significantly earlier in the children of depressed probands (mean age at onset, 12 to 13 years) compared with the children of normal probands (mean age at onset, 16 to 17 years). Symptom profiles and additional types of diagnoses in the depressed children from either proband parent group did not differ. These children are being followed up longitudinally to determine the prognostic significance, persistence, recurrence, and recall of their symptoms. Several research and clinical strategies are suggested by these data.     

Recurrent and nonrecurrent depression. A family study

The morbidity risks for unipolar depression were determined from all 763 first-degree relatives of 75 probands with unipolar depression who had been followed up for 12 to 18 years after their first lifetime admission. Significant independent differences were found according to the proband's age at onset and whether the proband had had a single episode or recurrent depression. The lowest morbidity risk in the relatives (3.4%) was associated with single-episode depression with late age at onset in the probands and the highest risk (17.4%) with early age at onset and recurrent depression, other results being intermediate. These findings offer a subclassification of unipolar depression based on age at onset and on whether the illness is single episode or recurrent, and they may explain some of the variability in morbidity risk found in well-conducted studies where these factors were not considered.     

Evidence for homogeneity of major depression and bipolar affective disorder

This study compared the morbidity risk for affective disorder in relatives of probands who had bipolar (BP) or major depression (UP). Other risk factors were also evaluated. 112 consecutively admitted inpatients yielded 621 relatives with diagnostic information based on either the Renard diagnostic interview, hospital records or information from at least two reliable relatives using the Feighner diagnostic criteria. Similar age corrected morbid risk estimates were found for family members of UP and BP probands of 0.243 and 0.246. There was a 50% increase in morbidity risk for women in all three generations but no relationship to the diagnosis of the proband. A proportional hazards (life table) analysis demonstrated that probands with onset prior to age 40 had relatives with younger onset and higher risk. None of the analyses, including logistic regression and proportional hazards, differentiated UP from BP illness.     

Modest familial aggregation of eating disorders in restrictive anorexia nervosa with adolescent onset in a Romanian sample

The study of the familial psychopathology in relatives of restrictive anorexia nervosa (AN) probands whose diagnosis was verified during a long-term follow-up was aimed at determining behavioural phenotypes with which AN could share the genetic liability. A total of 185 first degree relatives of 68 restrictive AN patients with adolescent onset followed up for 5 to 18 years and 198 first degree relatives of 68 normal women were investigated. DSM-III-R criteria were used. The lifetime rate of clinical AN was 1% and the rate of any eating disorders was 2% in female proband relatives versus 0 in control relatives. No case of bulimia nervosa (BN) was found in proband relatives. The heritability of AN was low (0.18) when only the full-blown AN was considered in relatives and modest (0.36) when also a case of subthreshold AN was added. There were significantly higher rates of anxiety disorders (14.6%) and unipolar major depression (8.3%) in female proband relatives and "schizo"-spectrum disorders (8.3%) and alcoholism (13.1%) in male proband relatives compared to relatives of controls. Restrictive AN might share partial liability with phenotypes expressing emotional restraint and anxiety. A sex effect of the heterotypically affected relative on the vulnerability for AN was suggested.     

Late-onset schizophrenia: an overview

Onset of schizophrenia after the age of 40 has been a controversial topic. We reviewed more than 30 publications (mainly from Europe) on this subject. Many of the studies had methodological shortcomings, including problems in precisely dating the onset of schizophrenia. Nonetheless, it appears that a certain proportion of patients present for the first time with diagnosable schizophrenia after age 40. Late-onset schizophrenia is characterized by paranoid symptomatology, a high female:male ratio, an elevated prevalence of hearing loss and ocular pathology, schizoid or paranoid traits in premorbid personality, a tendency toward chronicity, and symptomatic improvement with neuroleptics. Family studies suggest that the prevalence of schizophrenia in relatives of late-onset schizophrenic probands is higher than that in the general population, but lower than that in relatives of earlier-onset schizophrenic probands. We believe that late-onset schizophrenia is a valid entity (or group of entities). Studies of the course, biological associations, neuropsychological performance, and pharmacological characterization of late-onset schizophrenia are warranted.     

Pick's disease. Clinical genetics and natural history

The relatives of 18 probands with neuropathologic evidence of Pick's disease were assessed with the main aim of estimating their risk for dementing illness. Fifteen secondary cases of dementia were discovered among relatives. The risks were significantly greater for probands' first-degree relatives than for second-degree relatives, which suggests an etiologic contribution from genes. Although numbers are small, the distribution of cases and their ages at onset are consistent in suggesting a sex effect, with male subjects more at risk than female subjects.