Validity of the family history method for identifying schizophrenia-related disorders.

We examined the family history method's validity for identifying schizophrenia related disorders (SRD) by comparing family history and family study derived diagnoses. First degree relatives (n = 284) of 48 psychiatrically disordered probands, predominantly with schizophrenia, were diagnosed using the Family History RDC (FH-RDC) which include three psychotic schizophrenia related disorders (P-SRD): schizophrenia, chronic SAD and chronic unspecified functional psychosis (CUFP). Supplementary criteria for schizophrenia related personality disorders (SRP), derived to identify schizotypal and paranoid personality disorders (PD), were also assessed. About two thirds of these relatives (n = 196; 69.0%) were independently diagnosed by RDC and DSM-III-R on both axis I and axis II in a family study. The specificity was 1.0 (178/178) and the sensitivity of the family history derived diagnosis for P-SRD was 0.72 (13/18). Sensitivity for P-SRD was improved, however, by inclusion of SRP which captured three of the five false negative relatives. The sensitivity of SRP for schizotypal or paranoid PD was 0.39 (15/38) and the specificity was 0.92 (127/138). The FH-RDC have moderately good sensitivity and excellent specificity for the psychotic schizophrenia related disorders. While family history criteria for SRP are not a good proxy for schizotypal or paranoid PD, they can enhance the family history method's sensitivity for SRD.

Evidence of a locus for schizophrenia and related disorders on the short arm of chromosome 5 in a large pedigree.

We attempted to identify a locus for schizophrenia and related disorders in 24 nuclear families of schizophrenic probands using a predefined classification system for affected cases that included those disorders most clearly identified as sharing a genetic relationship with schizophrenia--schizoaffective disorder and schizotypal personality disorder. Initially, we evaluated 8 markers on chromosome 5 on the first 12 families with available genotyping and diagnostic assessments and, assuming autosomal dominant transmission, found a lod score of 2.67 for the D5S111 locus (5p14.1-13.1) in one large nuclear family (no. 17; sibship: n = 12; schizophrenia: n = 3; schizotypal personality disorder: n = 2); the other 11 families were much smaller, less complete, and provided little additional information. Other branches of no. 17 were then assessed and the 2-point lod score for family 17 rose to 3.72; using multipoint analysis the lod score in 17 was 4.37. When only schizophrenia was used to define affectedness, the positive evidence for linkage to D5S111 was greatly reduced. Sensitivity analysis indicated that the lod score is heavily dependent upon the predefined diagnostic criteria. Our studies of other families of schizophrenic probands eventually totalled 23, but linkage to D5S111 in these yielded a -2.41 lod score. The results provide evidence for genetic linkage of the D5S111 locus to schizophrenia and related disorders in one family. It may be of interest that over several generations, almost all the ancestors of family 17 could be traced back to a small, relatively isolated, hill region of Puerto Rico.

Age at onset and familial risk in Alzheimer's disease.

OBJECTIVE: The authors investigated the relationship between probands' age at onset of Alzheimer's disease with the risk of primary progressive dementia in the probands' first-degree relatives. METHOD: Two hundred probands with clinically diagnosed Alzheimer's disease and 179 nondemented elderly probands were recruited from the Mount Sinai Alzheimer's Disease Research Center, located at Mount Sinai Hospital and the Bronx Veterans Affairs Medical Center. Demographic and diagnostic data were collected on 1,398 of the first-degree relatives of the probands with Alzheimer's disease and 955 first-degree relatives of the nondemented probands. RESULTS: Cox proportional hazards regression analysis showed a significant inverse relationship between age at onset of Alzheimer's disease in probands and greater familial risk in their relatives. Follow-up analyses indicated that the most commonly used age at onset cutoff point--65 years--was one of the points where an association with familial aggregation is least likely to be revealed; other onset cutoff ages (e.g., 55, 70, and 75) better identified Alzheimer's disease groups with differing familial/genetic risks. CONCLUSIONS: The authors conclude that patients with an earlier age at onset of Alzheimer's disease are more likely to have relatives with Alzheimer's disease than are patients with a later age at onset of the disease. An onset age of 70 best differentiated probands whose relatives were at higher risk from those whose relatives were at lower risk.

Patterns of risk in first-degree relatives of patients with Alzheimer's disease.

BACKGROUND: Although an increased cumulative risk for primary progressive dementia (PPD) has been repeatedly demonstrated in relatives of probands with Alzheimer's disease (AD), an examination of their rates of illness at different ages has not been previously undertaken. Such an examination might reveal possible age-related characteristics associated with a more familial variety of AD. METHODS: Using family history interviews and survival analysis, the cumulative risk for and 5-year age-specific hazard rates of PPD were assessed in the first-degree relatives of 200 probands with AD and two nondemented control groups--179 elderly ascertained through the Alzheimer's Disease Research Center (ADRC-derived controls) and 427 elderly ascertained from community senior centers (community controls). RESULTS: The PPD risk curve for the relatives of probands with AD rose to about 30% and was significantly higher than the curves for the relatives of the ADRC-derived and community controls, where comparable rates were observed (approximately 12%). The age-specific hazard rates of PPD were calculated in three groups of relatives for each 5-year interval from ages 45 to 49 years through ages 85 to 89 years. The age-specific relative risk (RRi) for PPD in the relatives of probands with AD began to steadily diminish from the 75- to 79-year age interval (RRi = 13.49) through the 85- to 89-year age interval (RRi = 0.96) compared with the relatives of ADRC-derived controls and from the 60- to 64-year age interval (RRi = 16.15) through the 85- to 89-year age interval (RRi = 2.03) compared with the relatives of the community controls. CONCLUSIONS: These data indicate that, for relatives of probands with AD, while the lifetime risk for PPD is greater than in relatives of controls, the familial contribution to the risk for PPD decreases with increasing age. The higher risk for PPD in relatives of probands with AD may be substantially diminished or even eliminated by the latter half of the ninth decade.