Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms.

A genomewide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1615 affected and 1602 unaffected genotyped individuals, and the analysis of all 807 families included 1900 affected and 1839 unaffected individuals. Multipoint linkage analysis with correction for marker-marker linkage disequilibrium was carried out with 5861 single nucleotide polymorphisms (SNPs; Illumina version 4.0 linkage map). Suggestive evidence for linkage (European families) was observed on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1 in nonparametric and/or parametric analyses. In a logistic regression allele-sharing analysis of linkage allowing for intersite heterogeneity, genomewide significant evidence for linkage was observed on chromosome 10p12. Significant heterogeneity was also observed on chromosome 22q11.1. Evidence for linkage across family sets and analyses was most consistent on chromosome 8p21, with a one-LOD support interval that does not include the candidate gene NRG1, suggesting that one or more other susceptibility loci might exist in the region. In this era of genomewide association and deep resequencing studies, consensus linkage regions deserve continued attention, given that linkage signals can be produced by many types of genomic variation, including any combination of multiple common or rare SNPs or copy number variants in a region.

Bipolar illness. The sex-polarity effect in affectively ill family members.

We examined the sex ratios of unipolar and bipolar affective disorder in 14 studies of bipolar illness. The data are highly consistent in demonstrating that (1) females are more frequently affected than males; (2) among affected females, the ratio of unipolar depression to bipolar illness is about 2:1; whereas (3) among affected males, the ratio of bipolar to unipolar illness is approximately 1:1. This curious discrepancy between the sexes may hold a clue to understanding familial transmission as well as heterogenicity in bipolar illness.

Reliability of the telephone interview in diagnosing anxiety disorders.

The reliability of psychiatric diagnosis using the Schedule of Affective Disorders and Schizophrenia-Lifetime Version in personal and telephone interviews with 39 subjects was assessed using a 12- to 19-month test-retest design. Interrater reliability was high (kappa, .69 to .84) for the diagnosis of panic disorder, agoraphobia with panic attacks, probable panic disorder, major depression, and alcohol abuse. We conclude that it is possible to reliably make these lifetime diagnoses in a family study using the telephone interview.

Pseudoautosomal locus for schizophrenia excluded in 12 pedigrees.

A pseudoautosomal locus for schizophrenia has been proposed based on observations of an excess of same-sex affected sibling pairs over opposite-sex pairs when the transmitting parent is the father. Such a pattern of partial concordance by sex related to paternal transmission would be difficult to explain by any biologic mechanism other than pseudoautosomal transmission of schizophrenia. To test the pseudoautosomal hypothesis, 37 sibling pairs concordant for the schizophrenia spectrum were identified from 24 nuclear pedigrees. No significant difference in concordance for sex was found between sibships of paternal and maternal transmission of schizophrenia. Next, a linkage analysis was performed in 12 informative pedigrees, examining seven marker loci spanning the pseudoautosomal region. Both strict schizophrenia and a broader schizophrenia spectrum were analyzed as the affected phenotype, and both autosomal dominant and autosomal recessive models were tested. None of the markers supported linkage to either schizophrenia or the schizophrenia spectrum. Lod scores of less than -4 were obtained across the entire pseudoautosomal region by means of multipoint linkage analyses in the autosomal dominant model. In the autosomal recessive model, the respective lod scores were less than -2. We conclude that there is no evidence of a pseudoautosomal locus for schizophrenia in our pedigrees in any of the genetic models we tested.

A linkage study of chromosome 11q in schizophrenia.

The long arm of chromosome 11 is of interest in schizophrenia research because of three independent reports of balanced 11q translocations cosegregating with schizophrenia and other major psychiatric illness in pedigrees. In addition, a number of candidate genes for psychosis are located in the translocated regions. These include the dopamine D2 receptor, porphobilinogen deaminase, which has shown an allelic association with schizophrenia, and neural cell adhesion molecule, a cell surface glycoprotein involved in neuronal cell-cell recognition during brain development. To search for a schizophrenia locus on chromosome 11q, we conducted linkage analyses in 12 multiplex pedigrees. Sixteen DNA markers, including the above three candidate genes, were used to screen the entire long arm of chromosome 11. None of these markers were supportive of linkage to schizophrenia regardless of whether the affected phenotype was defined narrowly or broadly, whether high or low penetrance was assumed. Both dominant and recessive models tested more than 130 centimorgans of chromosome 11q, and therefore, the reported translocation regions. The results provide no evidence for a susceptibility locus for schizophrenia on chromosome 11q in these pedigrees.

Close linkage between panic disorder and alpha-haptoglobin excluded in 10 families.

We previously reported a lod score of 2.3 suggesting linkage between panic disorder and the alpha-haptoglobin locus on chromosome 16q22 in 26 pedigrees. In the present study we tested for linkage between alpha-haptoglobin and panic disorder in 10 new pedigrees and excluded a gene for panic disorder from 6 centimorgans (recombination fraction, 0.06) surrounding the alpha-haptoglobin locus. The data were analyzed under a variety of assumptions about the transmission of panic disorder, and linkage was excluded by all genetic models but one. When lod scores from the present set of 10 pedigrees were pooled with those from the first 26, no evidence of genetic heterogeneity was found, and the maximum lod score was 0.67 at a recombination fraction of 0.17. Taken as a whole, the present findings do not support the presence of a disease gene for panic disorder closely linked to the alpha-haptoglobin locus on chromosome 16q22.

Family study of agoraphobia. Report of a pilot study.

A family study of agoraphobia (n = 20), panic disorder (n = 20), and nonanxious controls (n = 20) showed the morbidity risk for all anxiety disorders to be 32% among first-degree relatives of agoraphobics, 33% among relatives of patients with panic disorder and 15% among relatives of controls. Relatives of agoraphobics were also shown to be at higher risk for alcohol disorders. Female relatives were found to be at greater risk for anxiety disorders, reflecting their increased susceptibility to these illnesses, and male relatives were at greater risk for alcohol disorders. The increased risk for anxiety disorders in the relatives of agoraphobics was not specific for agoraphobia but included panic disorder and other phobias as well. The findings indicate that agoraphobia is a familial disorder and that family data may help to determine whether agoraphobia is separate from other anxiety and phobic disorders.

A family study of panic disorder.

In a family study of panic disorder, we collected data on 278 first-degree relatives of 41 probands with panic disorder and 262 relatives of 41 control probands. The morbidity risk for panic disorder was 17.3% in the first group, and an additional 7.4% were categorized as having probable panic disorder. Both rates were significantly higher than the respective rates in the control relatives, 1.8% and 0.4%. The risk of panic disorder in female subjects was twice that in male subjects. The rate of generalized anxiety disorder was the same in both groups of families. No other psychiatric disorders were increased in the families of patients with panic disorder. In a preliminary genetic analysis, we tested the single major locus and the multifactorial polygenic transmission models. Neither model was excluded by the data. We conclude that panic disorder is a familial disease that affects women twice as frequently as men and is not associated with an increased familial risk of other psychiatric conditions. Its method of transmission remains uncertain.

Stability of psychiatric diagnosis. Schizophrenia and affective disorders followed up over a 30- to 40-year period.

Stability of diagnosis in schizophrenia and affective disorders is high. Patients selected according to research criteria for schizophrenia and affective disorders were followed up in a historical prospective study to evaluate their diagnostic stability over a 30- to 40-year period. Our follow-up, lifetime diagnosis, based on blind diagnostic assessment, showed that 92.5% of the personally interviewed schizophrenics were given the follow-up diagnosis of schizophrenia, which was significantly higher than the 78.3% found in affective disorders. However, no significant difference exists when assessment was made on available records of those who died or refused to be interviewed. These stability coefficients are discussed in light of the methodological assumptions involved in a long-term follow-up study. We concluded that the diagnostic stability in schizophrenia and affective disorders were very high and that rigorous diagnostic criteria should be maintained.

HLA antigens and schizophrenia.

We typed 45 schizophrenic patients for 35 HLA antigens and compared their frequencies with 1,263 population controls. No significant differences between schizophrenics and controls were found. When the schizophrenics were subtyped, a significant (P less than .05) excess of Aw26 was found among the hebephrenics, compared with the population controls. When the published literature on schizophrenia-HLA associations was surveyed, none of the reported associations were found to be consistent across studies. Some possible explanations for the heterogeneity among studies are discussed and it is concluded that an association between schizophrenia and any of the HLA antigens has not yet been demonstrated.

A linkage study of panic disorder.

We tested for linkage between panic disorder and a battery of 29 genetic markers in 26 families. Linkage between panic disorder and 18 of the marker loci could be excluded at a recombination fraction of 0.00, nine at a recombination fraction of 0.05, and four at a recombination fraction of 0.10. The 18 loci are distributed over ten chromosomes. One locus was suggestive of linkage. The maximum lod score for alpha-haptoglobin was 2.27 at a recombination fraction of 0.0, representing odds in favor of linkage of 186.1. alpha-Haptoglobin has been mapped to chromosome 16q22. The results demonstrate that linkage studies of psychiatric disorders can yield informative results by identifying tentative linkages that merit further investigation and by excluding regions of the genome from future linkage searches.

Relationship between panic disorder and agoraphobia. A family study.

A family study of patients with agoraphobia (n = 40), panic disorder (n = 40), and nonanxious controls (n = 20) showed that the morbidity risk for panic disorder was increased among the relatives of agoraphobics (8.3%) and the relatives of patients with panic disorder (17.3%). The morbidity risk for agoraphobia was also increased among the relatives of agoraphobics (11.6%) but not the relatives of panic disorder patients (1.9%). Male relatives of agoraphobics were shown to be at higher risk for alcohol disorders (30.8%). No greater risk for primary affective disorders was found among the relatives of agoraphobic or panic disorder patients or among the relatives of probands with secondary depression compared with relatives of probands without secondary depression. Probands and relatives with agoraphobia reported an earlier onset of illness, more persistent and disabling symptoms, more frequent complications, and a less favorable outcome than probands and relatives with panic disorder. The findings suggest that agoraphobia is a more severe variant of panic disorder. They also lend support to the separation between anxiety disorders and affective disorders.

Lack of linkage to chromosome 5q11-q13 markers in six schizophrenia pedigrees.

We examined linkage between schizophrenia and five genetic markers on chromosome 5 in six pedigrees. Analyses were run considering the affected phenotype to be schizophrenia, schizophrenia plus a spectrum of related disorders, and these disorders plus any axis I diagnosis. None of the analyses were suggestive of linkage at any of the markers, either considering the pedigrees individually or in the aggregate. In our pedigrees, multipoint linkage analyses excluded much of the region that had supported linkage in an earlier study. These findings are consistent with other attempts to replicate the chromosome 5 linkage finding.

Propranolol in chronic anxiety disorders. A controlled study.

In a double-blind crossover study the beta-adrenergic blocking drug propranolol hydrochloride reduced symptoms in 17 of 26 patients with chronic anxiety disorders. Both somatic and psychic symptoms improved as judged by patient and observer ratings. The most frequent side effects (dizziness, fatigue, and insomnia) were difficult to distinguish from anxiety symptoms and were, for the most part, mild. The therapeutic and side effects observed suggested CNS activity of the drug. Although propranolol is of benefit to patients with anxiety, its efficacy, compared with that of other antianxiety drugs, has not been established.

Exercise and anxiety neurosis: comparison of patients with and without mitral valve prolapse.

It has been hypothesized that mitral valve prolapse may account for a substantial number of patients who have symptoms of chronic anxiety neurosis. In a previous investigation, this hypothesis was confirmed in eight of 21 patients who had anxiety neurosis. In the present investigation, we reevaluated the hypothesis that persons with anxiety neurosis have impaired exercise ability by exercising 20 of the anxiety neurotics according to a standard treadmill exercise protocol. Compared with the control group, the anxiety neurotics required less exercise to achieve an equivalent heart rate and therefore their estimated maximum oxygen consumption was less, thus confirming the hypothesis. However, this difference was due entirely to the anxiety neurotics with mitral valve prolapse, and those without prolapse did not differ significantly from the controls. This suggests that impaired exercise tolerance in anxiety neurotics may be attributable to a subgroup of these patients with mitral valve prolapse.

Diazepam and propranolol in panic disorder and agoraphobia.

The response to diazepam and propranolol hydrochloride was compared in 21 patients who (with one exception) met DSM-III criteria for panic disorder and agoraphobia. Each drug was administered for two weeks in double-blind fashion according to a crossover design. The response to diazepam was significantly superior on all measures. By observer rating, 18 patients showed at least moderate improvement with diazepam compared with seven receiving propranolol. Panic attacks and phobic symptoms responded to diazepam, but not to propranolol. The results suggest that benzodiazepines constitute effective short-term treatment for these newly defined disorders.

Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism.

BACKGROUND: Alcoholism and substance dependence frequently co-occur. Accordingly, we evaluated the familial transmission of alcohol, marijuana, and cocaine dependence and habitual smoking in the Collaborative Study on the Genetics of Alcoholism. METHODS: Subjects (n=1212) who met criteria for both DSM-III-R alcohol dependence and Feighner definite alcoholism and their siblings (n=2755) were recruited for study. A comparison sample was also recruited (probands, n=217; siblings, n=254). Subjects were interviewed with the Semi-Structured Assessment for the Genetics of Alcoholism. The familial aggregation of drug dependence and habitual smoking in siblings of alcohol-dependent and non-alcohol-dependent probands was measured by means of the Cox proportional hazards model. RESULTS: Rates of alcohol, marijuana, and cocaine dependence and habitual smoking were increased in siblings of alcohol-dependent probands compared with siblings of controls. For siblings of alcohol-dependent probands, 49.3% to 50.1% of brothers and 22.4% to 25.0% of sisters were alcohol dependent (lifetime diagnosis), but this elevated risk was not further increased by comorbid substance dependence in probands. Siblings of marijuana-dependent probands had an elevated risk of developing marijuana dependence (relative risk [RR], 1.78) and siblings of cocaine-dependent probands had an elevated risk of developing cocaine dependence (RR, 1.71). There was a similar finding for habitual smoking (RR, 1.77 in siblings of habitual-smoking probands). CONCLUSIONS: Alcohol, marijuana, and cocaine dependence and habitual smoking are all familial, and there is evidence of both common and specific addictive factors transmitted in families. This specificity suggests independent causative factors in the development of each type of substance dependence.

Increased levels of a mitochondrial DNA deletion in the brain of patients with bipolar disorder.

Mutations in mitochondrial DNA (mtDNA) have been implicated in the pathophysiology of affective disorders. To examine possible pathophysiological significance of mtDNA deletions in bipolar disorder, the concentration of the 4977-base-pair deletion in mtDNA in the autopsied brains of 7 patients with bipolar disorder, 9 suicide victims, and 9 controls was examined using a quantitative polymerase chain reaction method. The ratio of deleted to wild-type mtDNA in cerebral cortex was significantly higher in patients with bipolar disorder [0.23 +/- 0.18 (mean +/- SD)%] compared with that in age-matched controls (0.06 +/- 0.07%, p < 0.05). This result supports a hypothesis that mtDNA deletions may play a role in the pathophysiology of bipolar disorder.

Quantitative analysis of leukocyte mitochondrial DNA deletion in affective disorders.

Mutations in mitochondrial DNA (mtDNA) are implicated in the pathophysiology of affective disorders. To determine whether the 4977-base-pair deletion in mtDNA is more frequent in affective disorders, we quantitated the concentration of this deletion in leukocyte mtDNA in 34 probands with affective disorders (20 bipolar and 14 unipolar) and 20 controls. We found no significant difference in the quantitative ratio of deletion to wild-type mtDNA between patients and controls. One patient with unipolar depression and 1 of 2 patients previously reported as having a large quantity of the deleted mtDNA did have a markedly high ratio; however, the deletion did not segregate with the disease in these two families. These results do not support a hypothesis that the 4977-base-pair deletion plays an important role in the pathophysiology of affective disorders.