Linkage of bipolar disorder to chromosome 18q and the validity of bipolar II disorder.

BACKGROUND: An analysis of the relationship between clinical features and allele sharing could clarify the issue of genetic linkage between bipolar affective disorder (BPAD) and chromosome 18q, contributing to the definition of genetically valid clinical subtypes. METHODS: Relatives ascertained through a proband who had bipolar I disorder (BPI) were interviewed by a psychiatrist, assigned an all-sources diagnosis, and genotyped with 32 markers on 18q21-23. Exploratory findings from the first 28 families (n = 247) were tested prospectively in an additional 30 families (n = 259), and the effect of confirmed findings on the linkage evidence was assessed. RESULTS: In exploratory analyses, paternal allele sharing on 18q21 was significantly (P =.03) associated with a diagnostic subtype, and was greatest in pairs where both siblings had bipolar II disorder (BPII). Prospective analysis confirmed the finding that BPII-BPII sibling pairs showed significantly (P =.016) greater paternal allele sharing. Paternal allele sharing across 18q21-23 was also significantly greater in families with at least one BPII-BPII sibling pair. In these families, multipoint affected sibling-pair linkage analysis produced a peak paternal lod score of 4.67 (1-lod confidence interval, 12 centimorgans [cM]) vs 1.53 (1-lod confidence interval, 44 cM) in all families. CONCLUSIONS: Affected sibling pairs with BPII discriminated between families who showed evidence of linkage to 18q, and families who did not. Families with a BPII sibling pair produced an increased lod score and improved linkage resolution. These findings, limited by the small number of BPII-BPII sibling pairs, strengthen the evidence of genetic linkage between BPAD and chromosome 18q, and provide preliminary support for BPII as a genetically valid subtype of BPAD.

Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative.

This article reports on the development and reliability of the Diagnostic Interview for Genetic Studies (DIGS), a clinical interview especially constructed for the assessment of major mood and psychotic disorders and their spectrum conditions. The DIGS, which was developed and piloted as a collaborative effort of investigators from sites in the National Institute of Mental Health (NIMH) Genetics Initiative, has the following additional features: (1) polydiagnostic capacity; (2) a detailed assessment of the course of the illness, chronology of psychotic and mood syndromes, and comorbidity; (3) additional phenomenologic assessments of symptoms; and (4) algorithmic scoring capability. The DIGS is designed to be employed by interviewers who exercise significant clinical judgment and who summarize information in narrative form as well as in ratings. A two-phase test-retest (within-site, between-site) reliability study was carried out for DSM-III-R criteria-based major depression, bipolar disorder, schizophrenia, and schizoaffective disorder. Reliabilities using algorithms were excellent (0.73 to 0.95), except for schizoaffective disorder, for which disagreement on estimates of duration of mood syndromes relative to psychosis reduced reliability. A final best-estimate process using medical records and information from relatives as well as algorithmic diagnoses is expected to be more reliable in making these distinctions. The DIGS should be useful as part of archival data gathering for genetic studies of major affective disorders, schizophrenia, and related conditions.

Panic disorder with familial bipolar disorder.

If bipolar disorder is genetically heterogeneous, it may be possible to discern clinically heterogeneous familial subtypes based on differential risk for psychiatric comorbidity, for example panic disorder. We evaluated 528 members of 57 families ascertained for a genetic linkage study of bipolar disorder. Families were assorted according to the panic disorder diagnosis of the bipolar proband; the rates of panic and other disorders in relatives were compared. Eighty-eight percent of the 41 subjects with panic disorder had bipolar disorder. Panic disorder was diagnosed in 18% of family members with bipolar disorder. Ten of 57 bipolar probands had panic disorder. Their bipolar first-degree relatives had a significantly higher prevalence of panic disorder, bipolar II, cyclothymia, and dysthymia, but had lower prevalence of substance abuse than the relatives of the bipolar probands without panic disorder. These findings suggest the testable hypothesis that comorbid panic disorder is a marker of genetic heterogeneity in bipolar disorder.

NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4-2 gene.

The validation of full-length cDNA represents a crucial step in gene identification and subsequent functional analysis. In searching for candidate genes for bipolar disorder on chromosome 18q21, a novel gene homologous to NEDD4 (Neural precursor cells expressed developmentally down-regulated) was identified using exon trapping and cDNA cloning. This novel gene is termed NEDD4L (Human Gene Nomenclature Committee symbol). Typical NEDD4 orthologues that contain a C2 (Ca(2+)/lipid-binding) and a HECT (Homologous to the E6-AP Carboxyl Terminus) ubiquitin-protein ligase domain, and multiple WW domains have been shown to regulate the epithelial sodium channel (ENaC). In mice, Nedd4 has two distinct isoforms termed Nedd4-1 that belongs to the typical NEDD4 class, and Nedd4-2 that is homologous to Nedd4-1 but lacks the C2 domain. NEDD4L contains the WW and HECT domains seen in the NEDD4 gene family, but lacks the C2 domain in the N-terminus. BLAST database search showed that the deduced polypeptide of NEDD4L has 97 and 62% sequence identity to mouse Nedd4-2 and human NEDD4, respectively. Multiple forms of transcripts of NEDD4L have been isolated, which differ in transcription start and termination sites together with the presence or absence of an alternative spliced exon. Northern blot analysis showed a 3.4 kb mRNA species was specifically expressed in heart and skeletal muscle, while a 3.2 kb band and/or an additional 3.6 kb band is seen in other tissues tested. Striking homology of NEDD4L to mouse Nedd4-2 suggests it is the human homologue of mouse Nedd4-2. Its position in a region of linkage for autosomal dominant orthostatic hypotensive disorder and its potential role in regulating ENaC make NEDD4L a candidate gene for this disorder.

Assessment of lineality in bipolar I linkage studies.

OBJECTIVE: To assess lineality in families of bipolar I probands, the authors used direct interviews of family members to reclassify families initially categorized as unilineal by family history. METHOD: The families of 1,800 treated bipolar I probands were screened by the family history method with multiple informants. If the proband had one or more affected sibs and one apparently unaffected parent, the parents (and then other available first- and second-degree relatives) were directly interviewed by psychiatrists. RESULTS: Of the 1,800 families screened, 56 were apparently suitable unilineal families with multiple affected members; 46 families were interviewed directly. After interviews with the parents, 12 families (26.1%) were found to be bilineal. Direct interviews of all available relatives in the 34 remaining families revealed that only 22 (47.8% of the 46 interviewed families) were unilineal or probably unilineal and 12 were probably bilineal. The probably bilineal families had a significantly higher proportion of siblings with unipolar disorder. In addition, the affected sibs from the probably bilineal families tended to have earlier onsets but had significantly fewer symptoms in the most severe depressive episode. CONCLUSIONS: Fewer than 50% of bipolar I families appearing unilineal according to family history were found to be unilineal by direct interviews. The phenotypic differences between the affected sibs from the probably bilineal families and those from the unilineal and probably unilineal families suggest differences in genetic mechanisms. These findings highlight the need to systematically assess lineality in all families considered for bipolar I linkage studies and support the preferential inclusion of unilineal families in linkage studies.

Attempted suicide and alcoholism in bipolar disorder: clinical and familial relationships.

OBJECTIVE: This study examined the clinical and familial relationships between comorbid alcoholism and attempted suicide in affectively ill relatives of probands with bipolar I disorder. METHOD: In 71 families ascertained for a genetic linkage study, 337 subjects with major affective disorder were assessed by using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version. RESULTS: Subjects with bipolar disorder and alcoholism had a 38.4% lifetime rate of attempted suicide, whereas those without alcoholism had a 21.7% rate. Attempted suicide among subjects with bipolar disorder and alcoholism clustered in a subset of seven families. Families with alcoholic and suicidal probands had a 40.7% rate of attempted suicide in first-degree relatives with bipolar disorder, whereas other families had a 19.0% rate. CONCLUSIONS: Comorbid alcoholism was associated with a higher rate of attempted suicide among family members with bipolar disorder. Attempted suicide and alcoholism clustered in a subset of families. These relationships may have a genetic origin and may be mediated by intoxication, mixed states, and/or temperamental instability.

Influence of clinical subtype, sex, and lineality on age at onset of major affective disorder in a family sample.

OBJECTIVE: The authors analyzed data from a family sample ascertained for a genetic linkage study of bipolar disorder to address the following questions: Do the major clinical subtypes of familial affective disorder have distinct distributions of age at onset? What factors other than clinical subtype affect these distributions? After controlling for these factors, do the differences in age at onset persist among the subtypes? METHODS: Eighty-two families were ascertained through a treated proband with bipolar disorder who had a family history of two or more affected siblings or one affected sibling and one affected parent. After participating in an interview conducted by a psychiatrist using the Schedule for Affective Disorders and Schizophrenia--Lifetime Version, 274 probands and their first-degree relatives were diagnosed as having bipolar I, bipolar II, or recurrent unipolar disorder according to Research Diagnostic Criteria. Age at first major affective episode and other clinical data were collected. RESULTS: Onset age distributions were similar for bipolar I and bipolar II disorder but significantly different for recurrent unipolar disorder. This finding persisted after adjustment for a significantly earlier onset among females. Subjects with affective disorder in both parental lines (bilineal) also experienced a significantly earlier onset. Substance abuse, physical illness, and sex of the affected parent had no significant impact on onset age. CONCLUSIONS: Although differences in age at onset may reflect several factors, these results provide indirect support for the view that bipolar I and bipolar II disorders are genetically related phenotypes and suggest that bilineal families may be more complex than previously assumed.

Bipolar II: the most common bipolar phenotype?

OBJECTIVE: The purpose of this study was to compare the pattern of affective psychopathology in families ascertained for genetic linkage studies through bipolar I probands to that in families ascertained through bipolar II probands. METHOD: All available first-degree relatives (N = 266) of 48 bipolar I and eight bipolar II probands were interviewed with the Schedule for Affective Disorders and Schizophrenia--Lifetime Version by one of two psychiatrists who had attained high interrater reliability for bipolar II disorder and other diagnoses. RESULTS: Bipolar II disorder was the most common affective disorder in both family sets. Forty percent of the 47 first-degree relatives of the bipolar II probands and 22% of the 219 first-degree relatives of the bipolar I probands were diagnosed with bipolar II disorder. On the other hand, only one bipolar I relative was found in the bipolar II families. CONCLUSIONS: Bipolar II disorder was the most prevalent affected phenotype in both bipolar I and bipolar II families and was the only expressed phenotype in half of the bipolar II families. This suggests that bipolar II disorder is genetically related to but less complex than bipolar I disorder. Accurate diagnosis of bipolar II disorder may be crucial in finding the genetic loci underlying bipolar disorders generally.

Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data.

OBJECTIVE: The authors performed an analysis of their published chromosome 18 linkage data on 28 families in which there was bipolar disorder to test the potential of comorbid panic disorder to define a genetic subtype of bipolar disorder. METHOD: Families ascertained through probands with bipolar I disorder were stratified into three groups based on a history of panic disorder, panic attacks, or no panic attacks in the probands. Multipoint nonparametric linkage analysis was performed on data from bipolar I and II family members in each group. RESULTS: Linkage scores for five consecutive 18q marker loci were highest in the families of the probands with panic disorder and lowest for the families of the probands without panic attacks. CONCLUSIONS: This study supports the authors' previously reported clinical hypothesis of a genetic subtype of bipolar disorder identified by comorbid panic disorder. The hypothesis merits prospective testing.

The familial aggregation of psychotic symptoms in bipolar disorder pedigrees.

OBJECTIVE: Symptomatic overlap between affective disorders and schizophrenia has long been noted. More recently, family and linkage studies have provided some evidence for overlapping genetic susceptibility between bipolar disorder and schizophrenia. If shared genes are responsible for the psychotic manifestations of both disorders, these genes may result in clustering of psychotic symptoms in some bipolar disorder pedigrees. The authors tested this hypothesis in families ascertained for a genetic study of bipolar disorder. METHOD: Rates of psychotic symptoms-defined as hallucinations or delusions-during affective episodes were compared in families of 47 psychotic and 18 nonpsychotic probands with bipolar I disorder. The analysis included 202 first-degree relatives with major affective disorder. RESULTS: Significantly more families of psychotic probands than families of nonpsychotic probands (64% versus 28%) contained at least one relative who had affective disorder with psychotic symptoms. Significantly more affectively ill relatives of psychotic probands than of nonpsychotic probands (34% versus 11%) had psychotic symptoms. An analysis of clustering of psychotic subjects across all families revealed significant familial aggregation. Clustering of psychosis was also apparent when only bipolar I disorder was considered the affected phenotype. CONCLUSIONS: Psychotic bipolar disorder may delineate a subtype of value for genetic and biological investigations. Families with this subtype should be used to search for linkage in chromosomal regions 10p12-13, 13q32, 18p11.2, and 22q11-13, where susceptibility genes common to bipolar disorder and schizophrenia may reside. Putative schizophrenia-associated biological markers, such as abnormal evoked response, oculomotor, and neuroimaging measures, could similarly be explored in such families.

Integrating clinical and laboratory data in genetic studies of complex phenotypes: a network-based data management system.

The identification of genes underlying a complex phenotype can be a massive undertaking, and may require a much larger sample size than thought previously. The integration of such large volumes of clinical and laboratory data has become a major challenge. In this paper we describe a network-based data management system designed to address this challenge. Our system offers several advantages. Since the system uses commercial software, it obviates the acquisition, installation, and debugging of privately-available software, and is fully compatible with Windows and other commercial software. The system uses relational database architecture, which offers exceptional flexibility, facilitates complex data queries, and expedites extensive data quality control. The system is particularly designed to integrate clinical and laboratory data efficiently, producing summary reports, pedigrees, and exported files containing both phenotype and genotype data in a virtually unlimited range of formats. We describe a comprehensive system that manages clinical, DNA, cell line, and genotype data, but since the system is modular, researchers can set up only those elements which they need immediately, expanding later as needed.

The risk of suicide in patients with bipolar disorders.

Patients with bipolar disorder have a high risk of committing suicide, but determining the exact risk is complicated. For many years, the lifetime suicide risk in bipolar disorder was accepted as 15%, but recent researchers have suggested that the lifetime suicide risk may be lower. The group of bipolar patients at highest risk of suicide are young men who are in an early phase of the illness, especially those who have made a previous suicide attempt, those abusing alcohol, and those recently discharged from the hospital. The risk is also increased in patients who are in the depressed phase of bipolar illness, who have mixed states, or who have psychotic mania. Lithium prophylaxis appears to decrease suicide attempts.

Bipolar II disorder in six sisters.

Several studies have suggested the utility of separating the type II (BPII) from type I bipolar affective disorder (BPI). The data supporting this suggestion include differences in the course of BPII illness, poorer response of BPII to medications, the higher frequency in BPII patients of non-affective co-morbidity and an increased risk of BPII disorder among relatives of BPII patients. This report of a family in which six sisters and several other family members share the disorder further supports the suggestion that BPII disorder 'breeds true', at least in some families. Since the diagnosis of the BPII disorder is relatively unstable, further study will be needed to establish BPII as distinct from BPI and unipolar disorders. Among others, molecular genetic methods will be useful in the resolution of this issue.

Lung cancer and housing characteristics.

Lung cancer incidence in Washington County, Maryland, was determined for a 12-yr period and was correlated with personal and housing data from a nonofficial 1963 census. Because indoor radon measurements were not available, two housing characteristics reported to be related to indoor radon concentration--type of basement construction and type of building materials--were used as surrogate measures. An adjusted rate of lung cancer incidence was obtained for each characteristic. Only age, male sex, amount smoked, and standard of living were significantly associated with lung cancer. Rates were highest in houses which had concrete walls and no basements, although the differences were slight and could have occurred by chance.

Are you recognizing depression in your patients?

Major depression is a prevalent condition that causes significant morbidity and mortality. Diagnosis may be complicated in depressed patients who offer a medical symptom as their chief complaint. Once the diagnosis is established, treatment is relatively straightforward. In prescribing an antidepressant, consideration should be given to the patient's previous response to medications, the documented efficacy of various agents, their side-effect profiles, and their potential for toxicity. Although the more severe and complicated cases should be referred to a psychiatrist, most depressed patients can be treated by their primary care physician.

Farm machinery injuries.

Agriculture is the most hazardous occupation in North America, with a work injury death rate higher than that of any other major industry. Farm machinery is involved in approximately half of all farm injuries. A Canadian series of 42 farm machinery injury cases hospitalized in Saskatoon, Saskatchewan, in 1980 showed that tractors were most frequently involved. Injuries resulting from power take-offs and grain augers were particularly severe and disabling. Amputations were the most common injuries associated with power take-offs, while crush injuries and compound fractures of the distal extremities were the most common auger-related injuries. Most of these injuries could have been prevented by the incorporation of automatic protective devices such as safety shields. It is recommended that the federal governments of Canada and the U.S. require manufacturers to equip farm machinery with approved safety features.

Fluoxetine treatment of bipolar II depression.

We have previously reported on the familial aggregation of bipolar II affective disorder and have speculated that new treatment approaches might be required for this difficult disorder. Based on Reimherr's report that fluoxetine responders were more likely to have poor prior responses to tricyclics and to have chronic depressions with "atypical" clinical features, we used fluoxetine to treat the chronic atypical depression in selected bipolar II outpatients. The 16 bipolar II patients in our series had been depressed for an average of 5.3 years prior to starting fluoxetine and had had poor responses to tricyclics, MAOIs, and lithium. All but one have had some response to fluoxetine. Ten of the 13 patients who have been taking fluoxetine for 10 or more months have had a good to very good response and the other 3 have had a fair response. Only one patient discontinued fluoxetine because of side effects. These findings should encourage further treatment research using fluoxetine and other serotonin reuptake blockers as well as research into the pathophysiologic identity of bipolar II as a possible distinct form of affective disorder.

Therapeutic and genetic prospects of an atypical affective disorder.

The utility of bipolar type II affective disorder subgrouping is discussed. There is low diagnostic agreement among clinicians for this putative condition. However, the clustering of cases in families and the poor response to standard treatments suggest that it is a distinct subgroup. The clinical features of the depressive phase of this condition including chronicity, intermittency, hyperphagia, hypersomnia, and reactivity relate it to the constructs of "hysteroid dysphoria," atypical depression, and seasonal affective disorder. Its association to several abnormal motivated behaviors such as alcoholism and eating disorders allows the speculation that a distinct morbid mechanism involving serotonin may underlie it and that new serotonin reuptake blocking drugs may be useful in treating it. Finally, the genetic identity of this subgroup in all likelihood will be established or rejected by genetic linkage studies utilizing the restriction fragment length polymorphism map of the genome.

Genetic linkage studies of bipolar affective disorder.

Underrecognition and undertreatment of affective disorders constitute a serious public health problem in this country. The recent availability of improved methods of genetic linkage analysis make the definition of the genetic basis of some types of bipolar affective disorders feasible within the foreseeable future.

Injuries among the Hopi Indians. A population-based survey.

Injuries are the leading cause of death among American Indians. An epidemiologic study was conducted on the Hopi reservation to assess the incidence, circumstances, and outcome of injuries. The incidence of hospitalized or fatal injuries during 1979-1980 was 12 per 1,000 persons per year, with the highest incidence in the age group of those older than 84 years. Overall, falls, motor vehicle crashes, self-inflicted injuries, and assaults were the leading causes of injuries. Suicides and crashes were the leading causes of death. The 15- to 29-year age group, which constituted only a quarter of the population, accounted for 46% of all injuries. This age group had especially high rates of self-inflicted injuries, crashes, and assaults. Injury problems of special importance to the Hopis included single-vehicle rollover crashes, falls from pickup trucks, falls from mesas and pueblo roofs, and suicide attempts in jails.