Adjudicating neurocognitive endophenotypes for schizophrenia.

Although genetic influences on schizophrenia are well established, localization of the genes responsible for this illness has proven extremely difficult. Given evidence that genes predisposing to schizophrenia may be transmitted without expression of the clinical phenotype, efforts have focused on developing endophenotypes. While several neuropsychological measures have been proposed to be endophenotypes, few studies have systematically assessed batteries of neurocognitive tests to determine which tests are most sensitive to liability for the illness. Two hundred sixty-nine Latino individuals were administered a standard neuropsychological battery. Two hundred fourteen of these were members of families with at least two siblings diagnosed with schizophrenia or schizoaffective disorder. The remaining were community controls without history of major psychiatric illness. Neurocognitive measures found to be heritable were entered into analyses designed to determine which tests covary with the degree of genetic relationship to affected individuals. Although five measures were found to uniquely model genetic liability for schizophrenia, digit symbol coding was the most sensitive. To assess the specificity of these endophenotypes, performance on these measures were compared to family members with bipolar and unipolar affective disorders. These markers clearly distinguished between individuals with psychotic illnesses and those with major depression. As measures contributed uniquely to discriminate individuals at varying risk for schizophrenia, our findings imply multiple independently inherited elements to the liability for the illness. We present a practical model for adjudicating endophenotypes and determining which measures are best suited for use in linkage analyses.     

Symptom clusters in the diagnosis of affective disorder,schizoaffective disorder,and schizophrenia in African Americans

The purpose of this study is to examine intercategory agreement among the symptom clusters associated with diagnoses of affective disorder, schizoaffective disorder, and schizophrenia in 156 African-American patients. It is hypothesized that there will be greater agreement between diagnosed schizoaffective disorder and schizophrenia than either of these two disorders and affective disorder in a sample of African-American patients. Patients' diagnoses and symptoms of psychopathology, recorded by psychiatrists during hospital admission, were abstracted during chart reviews. The symptom clusters for diagnoses of schizoaffective disorders overlapped 41% with those of affective disorders and 71% with those of schizophrenia. The results support the assumption that schizoaffective disorder falls within the spectrum of schizophrenia disorders. Implications for studies involving the differential diagnosis of affective disorder and schizophrenia in African Americans are discussed.     

Diagnostic stability in subjects with multiple admissions for psychotic illness

BACKGROUND: Although studies investigating changes in diagnosis between psychotic episodes have differed in design, some consistent findings have emerged. This study seeks to clarify and extend these findings by describing and comparing clinical and operationally defined diagnostic stability in a group of subjects with multiple episodes of functional psychotic illness. METHODS: The OPCRIT programme was applied to case notes of 204 subjects with multiple admissions for psychotic illness. Clinical and operationally defined diagnoses were compared and the spread and stability of diagnoses determined. RESULTS: An increase in the frequency of diagnosis of schizophrenia from initial to subsequent episodes was demonstrated. High levels of stability were found for schizophrenia (58 to 98%), moderate levels for affective disorders (24 to 83%), low levels for other non-organic psychotic conditions (27 to 54%) and atypical psychosis (27 to 53%), and very low levels for schizoaffective disorder (5 to 39%) and other conditions (0 to 4%). CONCLUSIONS: The stability levels for schizophrenia and affective disorders are adequate, but the low levels for a range of other psychotic conditions raise questions regarding their predictive validity.     

Information processing deficits in relatives of manic depressive patients

BACKGROUND: The importance of genetic factors in the aetiology of manic-depressive illness (MDI) has been repeatedly confirmed and indicators of vulnerability to the illness in families with affective disorders are needed. Abnormal event-related potentials (ERP) may be markers of genetic vulnerability to mental illness. Long latency and low amplitude of P300 have consistently been reported in schizophrenic patients and their relatives. A few studies have also shown P300 deficits in MDI patients, but no ERP study has been performed on their relatives. METHODS: ERPs were recorded during an auditory oddball task in 19 relatives belonging to families with two or more bipolar patients and in controls with no familial or personal history of affective disorders. The relatives were selected as having no affective disorders on a lifetime basis, but eight had an anxiety disorder. RESULTS: In all relatives, a lower P300 amplitude and a longer P300 latency was found, with much longer reaction time and post-N200 duration till button-press than controls. A lack of P300 amplitude dominance in the right hemisphere was also found in relatives in comparison with controls. There also appeared to be a frontal predominance of ERP abnormalities in relatives. CONCLUSION: We report the first evidence of deficits in reaction time and in P300 amplitude and latency, and a lack of P300 right-sided dominance, in relatives of manic-depressive patients. This pattern may constitute an endophenotypic marker of manic-depressive disorder.     

Schizoaffective disorders. Results of a genetic investigation, I.

1004 first degree relatives fo 150 schizoaffective patients (41 males, 109 females) were studied and a total morbidity risk of 29.6% of schizoaffective spectrum disorders were found. The relatives show an increased morbidity risk for schizophrenia (5.26%) and affective disorder (6.55%) with a high incidence of catatonia and unipolar depression; schizoaffective secondary cases were only found in 3%. There is no significant difference in morbidity between parents, siblings and children. The morbidity risk of neuroses is 5.3%, for personality disorders 7.2% and for suicides without spectrum diagnosis 1.8%. Off-spring of affected parents show a morbidity risk twice as high as that of off-spring of non-affected parents. The findings do not support the present concept of the ICD (International Classification of Disorders) of WHO, which subsumes schizoaffective disorders under the major rubric of schizophrenia. From a genetic viewpoint schizoaffective disorder takes an intermediate position between schizophrenia and affective disorders. None of the present hypotheses of the mode of inheritance is supported by the findings.     

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. © 1996 Wiley-Liss, Inc.     

Association study of CHRFAM7A copy number and 2 bp deletion polymorphisms with schizophrenia and bipolar affective disorder.

Schizophrenia and bipolar disorder are major psychiatric diseases that have a strong genetic element. Markers in the vicinity of the CHRNA7 gene at 15q13-q14 have been linked with an endophenotype of schizophrenia, P50 sensory gating disorder, with schizophrenia itself and with bipolar disorder. We have measured the copy number of the polymorphic partial duplication of CHRNA7 (CHRFAM7A) and genotyped a polymorphic 2 bp deletion within exon 6 of CHRFAM7A. In this study, 208 probands with a primary diagnosis of schizophrenia, 217 with a diagnosis of bipolar affective disorder and 28 with schizoaffective or other psychotic disorders were examined together with 197 controls recruited from the same region in Scotland. No significant association was seen for schizophrenia and bipolar disorder by genotype or allele overall for either polymorphism, but a mildly significant association by genotype (P = 0.04) was observed for absence of CHRFAM7A when the sample was analyzed as a single psychosis phenotype.     

Contribution of psychological and social factors to psychotic and non-psychotic relapse after childbirth in women with previous histories of affective disorder.

Twenty-six women with a history of bipolar or schizoaffective disorder, 17 women with histories of major depressive disorder and 45 control women without any previous psychiatric history were assessed in the 9th month of pregnancy on selected psychosocial measures. No subject was a 'case' as defined by the Research Diagnostic Criteria (RDC) from this time until the delivery. Within 6 months postpartum, 22 (51%) of the women with histories of mental illness were categorised as having relapsed (RDC case). Twelve women developed a psychosis (mania, hypomania or schizomania) and these illnesses occurred only in women with histories of affective or schizoaffective psychosis whereas 10 other women who became depressed after delivery came equally from the women with histories of psychosis (N = 5) as from those with histories of major depression (N = 5). Three (7%) control women also developed postpartum non-psychotic depressive disorders. Multivariate analyses suggest that different psychosocial factors contribute to the recurrence of affective and schizoaffective psychosis after delivery as opposed to non-psychotic postpartum affective disorders. A non-psychotic illness was predicted by antenatal neuroticism and a severe life event before illness onset. A recurrence of psychosis postpartum was predicted by a history of mania, hypomania or schizomania, a more recent psychiatric admission and reported marital difficulties. In this sample of women, life stress led to postpartum depression irrespective of the subject's past history and the high rates of recurrence of affective or schizoaffective psychosis (47%) probably mainly reflected a pre-existing physiological or psychological vulnerability which may have been exacerbated by, or contributed to, marital difficulties.     

X-linkage in bipolar affective illness: Perspectives on genetic heterogeneity,pedigree analysis and the X-chromosome map

The search for genetic markers is a powerful strategy in psychiatric genetics. The present article examines four areas relevant to discrepancies among X-linkage studies in bipolar affective disorder. These are questions of ascertainment, analytic methods, the X-chromosome map and genetic heterogeneity. The following conclusions are reached: (a) Positive linkage findings cannot be attributed to ascertainment bias or association between affective illness and colorblindness. (b) The possibility that falsely positive linkage results were obtained by using inappropriate analytic methods is ruled out. (c) Reported linkages of bipolar illness to colorblind and G6PD loci are compatible with known map distances between X-chromosome loci. Linkage to the Xg antigen remains uncertain. (d) The discrepancy among the various data sets on affective illness and colorblindness is best explained by significant linkage heterogeneity among pedigrees informative for the two traits.     

6p24–22 Region and Major Psychoses in the Eastern Quebec Population

Recent reports of a linkage trend in 6p24–22 for schizophrenia (SZ), in different samples, were tempered by the concurrent evidence of negative reports in other samples. In the studies showing positive results, different definitions of affection and a wide spectrum of diagnoses were used. Our objectives were not only to test for linkage at 6p24–22 in the Eastern Quebec population, but also to test whether this putative vulnerability locus was either selectively linked to schizophrenia (SZ), or to bipolar disorder (BP), or to both major psychoses. Parametric and nonparametric linkage analyses with 12 microsatellite markers in 6p24–p22 were performed on a sample of 18 large multigenerational pedigrees (N = 354) either affected by SZ, or by BP, or equally affected by both major psychoses (i.e., mixed pedigrees). Three affection definitions were usually tested in our program: one on schizophrenia (SZ), one on bipolar disorder (BP), and one that comprised SZ and BP under the hypothesis of a susceptibility locus common to both in major psychoses (common locus, CL). The results of parametric analyses did not support a major gene hypothesis. However, in one large mixed pedigree (#151), we observed with the common locus phenotype (CL) lod scores of 2.49 and 2.15, respectively, at the D6S296 and D6S277 loci under a dominant model. Our data suggest the presence of a potential vulnerability locus at 6p24–22 that could be related to both schizophrenia and bipolar affective disorder. These results may be seen as congruent with former studies that used schizoaffective as well as schizophrenia diagnoses as entry criteria for the affected families, and used an affection definition that comprised affective psychoses as well as schizophrenia. Am. J. Med. Genet. 74:311–318, 1997. © 1997 Wiley-Liss, Inc.     

Chromosomal abnormalities and schizophrenia

Schizophrenia is a common and serious psychiatric illness with strong evidence for genetic causation, but no specific loci yet identified. Chromosomal abnormalities associated with schizophrenia may help to understand the genetic complexity of the illness. This paper reviews the evidence for associations between chromosomal abnormalities and schizophrenia and related disorders. The results indicate that 22q11.2 microdeletions detected by fluorescence in-situ hybridization (FISH) are significantly associated with schizophrenia. Sex chromosome abnormalities seem to be increased in schizophrenia but insufficient data are available to indicate whether schizophrenia or related disorders are increased in patients with sex chromosome aneuploidies. Other reports of chromosomal abnormalities associated with schizophrenia have the potential to be important adjuncts to linkage studies in gene localization. Advances in molecular cytogenetic techniques (i.e., FISH) have produced significant increases in rates of identified abnormalities in schizophrenia, particularly in patients with very early age at onset, learning difficulties or mental retardation, or dysmorphic features. The results emphasize the importance of considering behavioral phenotypes, including adult onset psychiatric illnesses, in genetic syndromes and the need for clinicians to actively consider identifying chromosomal abnormalities and genetic syndromes in selected psychiatric patients.     

Irish study of high-density schizophrenia families: Field methods and power to detect linkage

Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/or hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one of whom had schizophrenia (S) or poor-outcome schizoaffective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. The phenotypic sample contained 277 pedigrees and 1,770 individuals and the linkage sample 265 pedigrees and 1,408 individuals. Using the intermediate definition of affection, the phenotypic sample contained 837 affected individuals and 526 affected sibling pairs. Parallel figures for the linkage sample were 700 and 420. Individuals with schizophrenia from these multiplex pedigrees resembled epidemiologically sampled cases with respect to age at onset, gender distribution, and most clinical symptoms, although they were more thought-disordered and had a poorer outcome. Power analyses based on the model of linkage heterogeneity indicated that the ISHDSF should be able to detect a major locus that influences susceptibility to schizophrenia in as few as 20% of families. Compared to first-degree relatives of epidemiologically sampled schizophrenic probands, first-degree relatives of schizophrenic members from the ISHDSF had a similar risk for schizotypal personality disorder, affective illness, alcoholism, and anxiety disorders. With sufficient resources, large-scale ascertainment of multiplex schizophrenia pedigrees is feasible, especially in countries with catchmented psychiatric care and stable populations. Although somewhat more severely ill, schizophrenic members of such pedigrees appear to clinically resemble typical schizophrenic patients. Our ascertainment process for multiplex schizophrenia families did not select for excess familial risk for affective illness or alcoholism. With its large sample ascertained in a standardized manner from a relatively homogeneous population, the ISHDSF provides considerable power to detect susceptibility loci for schizophrenia. © 1996 Wiley-Liss, Inc.     

Neurochemical and genetic bases of psychopathology: Current status

A review, which does not attempt to be exhaustive, is presented. Evidence for the operation of genetic factors in the etiology of mental disorders, including studies of natural families, twins, and adoptees and their biological and adoptive relatives, is briefly summarized and discussed. Environmental influences are also clearly involved, and observations bearing on their nature are described. Certain neurochemical correlates of psychopathology, particularly those related to chemical neurotransmitters, are discussed. Since schizophrenia and the affective disorders are phenomenological syndromes, it is likely that they represent heterogeneous collections of more specific disorders with common symptomatic features. Attempts to delineate, more homogeneous subgroups in these disorders on the basis of morphological or biochemical features have achieved some success, and an example of each approach is described.     

Schizoaffective psychoses: Genetical clues to classification

The diagnostic classification of schizoaffective psychoses has varied much since Kasanin introduced the concept in 1933. The various classifications have agreed that schizoaffective psychoses present a combination of schizophreniform and affective symptoms, but the diagnostic criteria differ as to the number, quality, and time sequence of the symptoms even in recent classifications like RDC, DSM-III-R, and ICD-10. The classifications are syndromatical, and the etiology of the schizoaffective psychoses is still undetermined apart from evidence for a strong genetic factor. Results from family, twin, and adoption studies are divergent, but all the same, support a separate classification of broadly defined schizoaffective psychoses as possibly being phenotypical variations or expressions of genetic interforms between schizophrenia and affective psychoses. © 1995 Wiley-Liss, Inc.     

Outcomes on lithium treatment as a tool for genetic studies in affective disorders

From a genetic point of view, the application of mathematical models to affective disorders has not yet been useful, since they do not indicate a specific mode of transmission. To use these models correctly, we need to identify homogeneous genetic subgroups among those sharing the common phenotypic feature of affective illness. Our useful criterion for this is outcome on long-term lithium therapy, since experimental data suggest the existence of a close relationship between the genetic mechanisms that underly the affective disorders and those that underly outcome on lithium. We have studied 145 subjects with primary affective disorders, 92 of whom did not relapse during lithium treatment and 53 of whom did, together with 864 of their first-degree relatives. The data for both groups fit both single major locus and multifactorial polygenic models for genetic analysis, including a sex effect and therefore neither mode of transmission can be excluded.     

D-amino acid oxidase (DAO) genotype and mood symptomatology in schizophrenia

A series of genetic studies have identified the D-amino acid oxidase (DAO) gene as potentially contributing to schizophrenia susceptibility. An interacting gene, D-amino acid oxidase activator (DAOA) has also been implicated and it has been suggested that variation at these genes may influence the efficiency of glutamate gating at N-methyl-D-aspartate-type (NMDA) receptors. However, recent data suggests that DAOA may influence susceptibility to mood episodes across the spectrum of psychotic disorders rather than contributing to a specific psychosis phenotype. The aim of this study was to determine whether risk variation at DAO is similarly associated with affective or other clinical symptoms in psychosis. We have previously reported association between risk variation at DAO and schizophrenia in an Irish case-control sample. In this study we investigated the relationship between a defined genetic risk variant at DAO and PANSS-derived clinical symptom factors in a sample of 249 patients using principal component and Kruskal-Wallis analyses. Carriers of the DAO risk variant scored significantly higher on the 'depression/anxiety' factor than non-carriers (H=9.02, d.f.=2, p=0.01). These data suggest a potential role for DAO in susceptibility to depressive symptoms in schizophrenia, but a more general role for DAO in affective disorders cannot be excluded.     

A twin study of schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes

The nosological status of schizoaffective disorders remains controversial. Twin studies are potentially valuable for investigating relationships between schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes, but no such study has yet been reported. We ascertained 224 probandwise twin pairs [106 monozygotic (MZ), 118 same-sex dizygotic (DZ)], where probands had psychotic or manic symptoms, from the Maudsley Twin Register in London (1948-1993). We investigated Research Diagnostic Criteria schizoaffective-mania, schizoaffective-depression, schizophrenia, mania and depressive psychosis primarily using a non-hierarchical classification, and additionally using hierarchical and data-derived classifications, and a classification featuring broad schizophrenic and manic syndromes without separate schizoaffective syndromes. We investigated inter-rater reliability and co-occurrence of syndromes within twin probands and twin pairs. The schizoaffective syndromes showed only moderate inter-rater reliability. There was general significant co-occurrence between syndromes within twin probands and MZ pairs, and a trend for schizoaffective-mania and mania to have the greatest co-occurrence. Schizoaffective syndromes in MZ probands were associated with relatively high risk of a psychotic syndrome occurring in their co-twins. The classification of broad schizophrenic and manic syndromes without separate schizoaffective syndromes showed improved inter-rater reliability, but high genetic and environmental correlations between the two broad syndromes. The results are consistent with regarding schizoaffective-mania as due to co-occurring elevated liability to schizophrenia, mania, and depression; and schizoaffective-depression as due to co-occurring elevated liability to schizophrenia and depression, but with less elevation of liability to mania. If in due course schizoaffective syndromes show satisfactory inter-rater reliability and some specific etiological factors they could alternatively be regarded as partly independent disorders.     

Familial rates of affective and substance use disorders in patients with first-episode mania

BACKGROUND: One explanation for the high co-occurrence between bipolar and substance use disorders is that substance abuse may precipitate affective symptoms in patients who otherwise may have not had the genetic risk for developing an affective illness. Previous studies comparing familial rates of affective illness between bipolar patients with and without alcohol use have provided conflicting results. We hypothesized that patients with bipolar disorder and antecedent alcohol abuse would have lower familial rates of affective illness than bipolar patients without antecedent alcohol abuse. METHODS: Family history data were obtained on 275 first-degree relatives of 51 patients hospitalized for a first manic episode using the Family History Research Diagnostic Criteria. RESULTS: Patients with bipolar disorder and antecedent alcohol abuse had lower familial rates of affective illness than patients with bipolar disorder without antecedent alcohol abuse (two-tailed Fisher's exact, P = 0.003). There was no statistically significant difference in the familial rates of affective illness between bipolar patients with and without antecedent drug abuse (other than alcohol). Patients with bipolar disorder and antecedent alcohol abuse had a significantly older age of onset of affective illness (27.6 years) than patients with bipolar disorder without antecedent alcohol abuse (20.6 years, z = 3.3, df = 1, P = 0.0009). There was no statistical difference in age of onset of affective illness between the patients with antecedent drug abuse and the patients without antecedent drug abuse. LIMITATIONS: Future studies with a larger number of bipolar patients, direct structured interviews of family members and better differentiation between substance abuse and dependence syndromes are needed to extend and replicate this pilot study. CONCLUSIONS: Our study suggests that there may be a subset of bipolar patients who have antecedent alcohol abuse and a subset who develop alcohol abuse after the onset of bipolar disorder. We further speculate that alcohol abuse may precipitate mania in some patients with bipolar disorder.     

Exploring the borders of the schizoaffective spectrum: a categorical and dimensional approach

BACKGROUND: Schizoaffective disorder has long been considered as an intermediate condition between major mood disorders and schizophrenia, however, the nature of the relationship to these diagnoses remains unclear. We aimed at examining the nature of such a relationship in a mixed sample of psychotic disorders by using a dimensional and categorical approach to psychopathology. METHODS: Six-hundred and sixty psychotic inpatients were assessed for lifetime ratings of mania, depression, psychosis and incongruence, diagnosed according to Research Diagnostic Criteria, and classified as having nonaffective psychosis without mood syndromes (n=429), nonaffective psychosis with mood syndromes (n=101), schizoaffective disorder mainly schizophrenic (n=41), schizoaffective disorder mainly affective (n=42) or mood disorder with psychotic symptoms (n=47). We tested for associations of illness-related features including risk factors, premorbid, clinical and outcome variables with classes of disorders and lifetime ratings of psychopathology, and examined the relative contribution of categorical and dimensional representations of psychopathology in explaining disease characteristics. RESULTS: While categories at the extreme end of the psychotic spectrum meaningfully differed across a number of the illness-related variables, no substantial discontinuity was apparent between adjacent categories of psychotic disorders. Risk factors, premorbid adjustment, clinical features and impairment appeared to be present in a mostly monotonic continuous fashion from nonaffective psychoses to mood disorders with psychotic features. The overall association pattern of illness-related variables with mood and psychotic syndromes was largely independent of specific diagnostic categories, and the dimensional approach was neatly superior to the traditional diagnostic approach in explaining the characteristics of the illness. LIMITATIONS: This was a cross-sectional study with retrospective assessment of illness-related-variables and lifetime psychopathology. CONCLUSION: The results are compatible with the notion of the schizoaffective spectrum and with a continuum model of the psychotic illness.     

The inheritance of affective disorders: A review of data and of hypotheses

A genetic factor in affective disorders is suggested by twin and family history studies. The form of disorder (BP or UP) is transmitted within families. Early onset of affective disorder is associated with increased morbid risk of the disorder in relatives, but age at onset is not itself a transmitted factor. Female relatives have higher prevalence of illness, but sex of the ill person does not appear to be a factor in transmission. Genetic models of multifactorial or single-gene autosomal inheritance are compatible with some but not all of the family history studies reported. The hypothesis of sex-linked transmission of BP illness has been proposed, and some pedigrees compatible with X-linkage have been reported, but family studies do not suggest that this is generally present. Other possible modes of inheritance remain to be tested. Investigative strategies for identification of the affective genotype are discussed on the basis of biochemical, pharmacological, or other characteristics of persons with the disorders and their relatives, and on the basis of studies of known linkage markers.This was presented, in part, at the Annual Meeting of the American Society of Human Genetics, Portland, Oregon, October 18, 1974.