These data suggest that there could be a familial relationship between the predispositions to schizophrenia and to major depression. We discuss a number of alternative hypotheses about the nature of this possible relationship.

Previously reported linkage of bipolar affective disorder to DNA markers on chromosome 18 was reexamined in a large sample of German bipolar families. Twenty-three short tandem repeat markers were investigated in 57 families containing 103 individuals with bipolar I disorder (BPI), 26 with bipolar II disorder (BPII), nine with schizoaffective disorder of the bipolar type (SA/BP), and 38 individuals with recurrent unipolar depression (UPR). Evidence for linkage was tested with parametric and non-parametric methods under two definitions of the affected phenotype. Analysis of all 57 families revealed no robust evidence for linkage. Following previous reports we performed separate analyses after subdividing the families with respect to the sex of the transmitting parent. Fourteen families were classified as paternal and 12 families as maternal. In 31 families the parental lineage of transmission of the disease could not be determined ('either' families). Evidence for linkage was obtained for chromosomal region 18p11.2 in the paternal families and for 18q22-23 in the 'either' families. The findings on 18p11.2 and 18q22-23 support prior evidence for susceptibility loci in these regions. The parent-of-origin effect on 18p11.2 is confirmed in our sample. The delineation of characteristics of 'either' families requires further study.Although the etiology of bipolar affective disorder is unknown, strong support for an important genetic component comes from the results of family, twin, and adoption studies. 1 Linkage studies of bipolar disorder to date have provided suggestive evidence in favor of locus heterogeneity. Promising chromosomal regions suggested by recent linkage studies include regions on chromosome 18.Berrettini et al 2 first reported linkage of bipolar disorder to a region near the centromere on chromosome 18p in 22 families using the affected-sib-pair (ASP) method and the affected-pedigree-member (APM) method. Parametric LOD score analysis of all 22 families revealed negative LOD scores. However, individual families yielded LOD scores Ͼ1 assuming dominant or recessive genetic models. Confirmatory evidence for a bipolar susceptibility locus in this chromosomal region was found by Stine et al. 3 Both parametric LOD score analysis and ASP analysis supported linkage in their study of 28 families. In addition, the same study reported a second susceptibility locus on the long arm of chromosome 18 (18q21). Interestingly, linkage to loci on both 18p and 18q was strongest in those families, in which the father or one of the father's siblings was affected, suggesting a parent-of-origin effect operating in bipolar disorder. Gershon et al 4 re-analyzed the 18p marker data of Berrettini et al 2 by the sex of the transmitting parent. Although no kindred with limited paternal transmission was observed, ASP analysis yielded highly significant excess allele sharing in the pedigrees with mixed maternal-paternal transmission (in different pedigree branches) but not in pedigrees with exclusively maternal transmission confirmin...

In light of current linkage studies in schizophrenia, research on the "schizophrenia spectrum" deserves increased attention for an exact determination of the affected phenotype: Those disorders that have a much higher prevalence among biological relatives of schizophrenia patients are supposed to share common etiological factors with "core" schizophrenia. However, there is controversy over which of the DSM-III-R personality disorders should be included in the spectrum. In a controlled family study of inpatients with a DSM-III-R diagnosis of schizophrenia (n = 101), schizophreniform and schizoaffective disorders (n = 69), and unipolar major depression (n = 160), familial rates of personality disorders were assessed through personal interviews and compared with prevalence rates in 109 control families from the community. As predicted, schizotypal personality disorder occurred more frequently in the nonpsychotic relatives of schizophrenia probands (2.1%) than in the families of unscreened controls (0.3%). Paranoid personality disorder was more frequent in relatives of probands with unipolar depression (2.9%) than in relatives of schizophrenia patients (1.7%), and controls revealed the lowest rate (0.9%). Schizoid personality disorder, however, was extremely rare in all sample groups (between 0.3% and 0.7%), providing no sufficient statistical power for detection of group differences. Further analysis of the DSM-III-R criterion symptoms of schizotypal personality disorder demonstrated that items describing "negative" symptomatology are the main source of familial aggregation, but "psychotic-like" personality features are also contributing factors.

The joint-rater and test-retest reliability study of two translated versions of the SADS-LA (Schedule for Affective Disorders and Schizophrenia--Lifetime version--modified for the study of anxiety disorders), one in French and the other in German, have been tested in family study settings, in a sample of patients and first-degree relatives. The test-retest reliability study demonstrated that identification of major affective disorders and schizophrenia was performed with sufficient reliability; however, diagnoses of subtypes of major disorders (e.g. bipolar II disorder) and identification of minor disorders was less reliable. The implications of these findings in phenotype identification during family studies in psychiatry are discussed.

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In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25-q26. The highest two-point LOD score (2.86, = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26. Molecular Psychiatry (2001) 6, 342-349.Bipolar affective disorder (BPAD), also known as manic depressive illness, is characterized by severe aberrant mood swings in alternating periods of mania and depression. The disorder is common with a lifetime prevalence of about 1% in all human populations and results in high costs in terms of morbidity as well as mortality. BPAD is substantially responsive to drug treatment, but episodes tend to recur throughout life. Although the etiology and pathophysiology is widely unknown, family, twin and adoption studies argue for a strong genetic determination of the disease. 1 Theories concerning the possible involvement of multiple genes of small effect and/or the occurrence of major allelic effects in epistasis have been advanced. In order to identify genes predisposing to BPAD, in the absence of substantial molecular pathophysiological knowledge, linkage analysis is one of the best available methods. Early linkage studies were conducted in large families and were based on the implausible assumption that a single major gene was responsible for the disorder: loci for BPAD on the X chromosome 2-4 and on chromosome 11p15 5 were reported and attracted considerable attention, but have not withstood molecular studies in independent samples 6-8 as well as updated and extended analyses by the original groups. 9,10 The reason for these inconclusive results were, for the most part, problems concerning diagnosis, ascertainment of pedigrees, statistical analysis, and lack of availability of dense genetic link...

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