Current smoking is associated with worse cognitive and adaptive functioning in serious mental illness.

OBJECTIVE: Cigarette smoking is highly prevalent among people with bipolar disorder or schizophrenia. Few studies have examined whether smoking history is associated with adaptive functioning among individuals diagnosed with these serious mental illnesses. METHOD: In a large relatively homogenous cohort of patients with either bipolar disorder (n=363) or schizophrenia (n=400), we investigated the association between cigarette smoking status, intensity, and cumulative exposure and performance on a comprehensive battery of neurocognitive, functional capacity, and informant-rated functional measures. The associations were adjusted for variation in sociodemographic indicators, psychopathologic symptoms, and substance use. RESULTS: There was an average of 12 pack years of smoking across the sample. People with schizophrenia reported double the rate of current smoking compared to patients with bipolar disorder. Adjusting for demographic covariates, current smokers had worse composite cognitive functioning and poorer functional outcome than past or never smokers. There were no significant differences between never and past smokers, and these effects were evident in both bipolar disorder and schizophrenia. CONCLUSION: Current smokers with either schizophrenia or bipolar disorder evidence worse cognitive and adaptive functioning functional outcome, even when demographic covariates are considered.

Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21.

Schizophrenia is a common disorder characterized by psychotic symptoms; diagnostic criteria have been established. Family, twin and adoption studies suggest that both genetic and environmental factors influence susceptibility (heritability is approximately 71%; ref. 2), however, little is known about the aetiology of schizophrenia. Clinical and family studies suggest aetiological heterogeneity. Previously, we reported that regions on chromosomes 22, 3 and 8 may be associated with susceptibility to schizophrenia, and collaborations provided some support for regions on chromosomes 8 and 22 (refs 9-13). We present here a genome-wide scan for schizophrenia susceptibility loci (SSL) using 452 microsatellite markers on 54 multiplex pedigrees. Non-parametric linkage (NPL) analysis provided significant evidence for an SSL on chromosome 13q32 (NPL score=4.18; P=0.00002), and suggestive evidence for another SSL on chromosome 8p21-22 (NPL=3.64; P=0.0001). Parametric linkage analysis provided additional support for these SSL. Linkage evidence at chromosome 8 is weaker than that at chromosome 13, so it is more probable that chromosome 8 may be a false positive linkage. Additional putative SSL were noted on chromosomes 14q13 (NPL=2.57; P=0.005), 7q11 (NPL=2.50, P=0.007) and 22q11 (NPL=2.42, P=0.009). Verification of suggestive SSL on chromosomes 13q and 8p was attempted in a follow-up sample of 51 multiplex pedigrees. This analysis confirmed the SSL in 13q14-q33 (NPL=2.36, P=0.007) and supported the SSL in 8p22-p21 (NPL=1.95, P=0.023).

Identification of sequence variants and analysis of the role of the catechol-O-methyl-transferase gene in schizophrenia susceptibility.

BACKGROUND: Deletions of 1.5-2 MB of chromosome 22q11 have been previously associated with schizophrenia. The deleted region includes proximally the region harboring genes involved in DiGeorge and velocardiofacial syndromes. Distally, it includes the gene for catechol-O-methyl-transferase (COMT), an enzyme that catalyzes the O-methylation of catecholamine neurotransmitters, including dopamine, and which therefore is considered a candidate gene for schizophrenia. METHODS: We address the issue of a direct involvement of the COMT gene in the development of schizophrenia by employing the first extensive mutational analysis of this gene in a sample of 157 schizophrenia patients and 129 healthy controls, using single-strand conformation polymorphism and chemical cleavage methodologies. RESULTS: No mutations were found, but several sequence variants were identified, including the genetic polymorphism that underlies the high/low activity of the enzyme (a Val158-->Met change, which results in the creation of an NlaIII restriction site in the low-activity allele). The distribution of the NlaIII genotypes among subsets of schizophrenia patients was analyzed. CONCLUSIONS: The results presented here argue against a major role of COMT in schizophrenia in general (although a minor effect could not be excluded) and represent a first step toward a more refined delineation of the phenotype/genotype relationship between 22q11 microdeletions and schizophrenia susceptibility.

Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes.

Using a systematically ascertained sample of 57 families, each having 2 or more members with a consensus diagnosis of schizophrenia (DSM-III-R criteria), we have carried out linkage studies of 520 loci, covering approximately 70% of the genome for susceptibility loci for schizophrenia. A two-stage strategy based on lod score thresholds from simulation studies of our sample identified regions for further exploration. In each region, a dense map of highly informative dinucleotide repeat polymorphisms (heterozygosity greater than .70) was analyzed using dominant, recessive, and "affected only" models and nonparametric sib pair identity-by-descent methods. For one region, 8p22-p21, affected sib-pair analyses gave a P value = .0001, corresponding to a lod score approximately equal to 3.00. For 8p22-p21, the maximum two-point lod score occurred using the "affected only" recessive model (ZMAX = 2.35; theta M = theta F); allowing for a constant sex difference in recombination fractions found in reference pedigrees, ZMAX = 2.78 (theta M/theta F = 3). For a second region, 3p26-p24, the maximum two-point lod score was 2.34 ("affected only" dominant model), and the affected sib-pair P value was .01. These two regions are worthy of further exploration as potential sites of susceptibility genes for schizophrenia.

Sequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: Part 1.

To identify genes responsible for the susceptibility for schizophrenia, and to test the hypothesis that schizophrenia is etiologically heterogeneous, we have studied 39 multiplex families from a systematic sample of schizophrenic patients. Using a complex autosomal dominant model, which considers only those with a diagnosis of schizophrenia or schizoaffective disorder as affected, a random search of the genome for detection of linkage was undertaken. Pairwise linkage analyses suggest a potential linkage (LRH = 34.7 or maximum lod score = 1.54) for one region (22q12-q13.1). Reanalyses, varying parameters in the dominant model, maximized the LRH at 660.7 (maximum lod score 2.82). This finding is of sufficient interest to warrant further investigation through collaborative studies.

Report from the Maryland Epidemiology Schizophrenia Linkage Study: no evidence for linkage between schizophrenia and a number of candidate and other genomic regions using a complex dominant model.

Our collaborative group has undertaken a linkage study of schizophrenia, using a systematic sample of patients admitted to Maryland hospitals. An initial sample of 39 families, each having two or more affecteds, was available for genotyping candidate genes, candidate regions, and highly polymorphic markers randomly distributed throughout the genome. We used a single complex dominant model (with a disease gene frequency of 0.005 and age-dependent penetrance for affected phenotype: for under 35, penetrance = .45; for 35 and older, penetrance = .85). We report here 130 markers, which met the exclusion criteria of LOD score < -2.00 at theta > 0.01 in at least 10 informative families, and no evidence for heterogeneity. We also report here markers that were tested as candidates for linkage to the schizophrenic phenotype. They were selected based on the following criteria: a) proximity to reported chromosomal rearrangements (both 5q and 11q), b) suggestions of linkage from other families (5q), or c) presence of a candidate gene (5q, 11q, 3q: Dopamine receptors 1, 2, and 3, respectively). We also tested for mutations of codon 717 in exon 17 of the amyloid precursor protein (APP) gene and were unable to detect the C to T substitution in our schizophrenic group.

Follow-up of a report of a potential linkage for schizophrenia on chromosome 22q12-q13.1: Part 2.

A collaboration involving four groups of investigators (Johns Hopkins University/Massachusetts Institute of Technology; Medical College of Virginia/The Health Research Board, Dublin; Institute of Psychiatry, London/University of Wales, Cardiff; Centre National de la Recherche Scientifique, Paris) was organized to confirm results suggestive of a schizophrenia susceptibility locus on chromosome 22 identified by the JHU/MIT group after a random search of the genome. Diagnostic, laboratory, and analytical reliability exercises were conducted among the groups to ensure uniformity of procedures. Data from genotyping of 3 dinucleotide repeat polymorphisms (at the loci D22S268, IL2RB, D22S307) for a combined replication sample of 256 families, each having 2 or more affected individuals with DNA, were analysed using a complex autosomal dominant model. This study provided no evidence for linkage or heterogeneity for the region 22q12-q13 under this model. We conclude that if this region confers susceptibility to schizophrenia, it must be in only a small proportion of families. Collaborative efforts to obtain large samples must continue to play an important role in the genetic search for clues to complex psychiatric disorders such as schizophrenia.

No evidence for linkage between schizophrenia and markers at chromosome 15q13-14.

Freedman et al. [1997: Proc Natl Acad Sci USA 94:587-592] reported linkage in nine multiplex schizophrenia families to markers on chromosome 15, using impaired neuronal inhibition to repeated auditory stimuli (P50), a neurophysiological deficit associated with schizophrenia, as the phenotype. The highest LOD score obtained (5.3 at theta = 0) was for marker D15S1360 mapped to chromosome 15q13-14, less than 120 kb from the alpha7-nicotinic receptor (CHRNA7) gene. The study also reported a small positive LOD score for D15S1360 when examined for linkage to the schizophrenia phenotype. Following these findings, we examined three polymorphic markers (D15S1360, L76630, and ACTC) on chromosome 15q13-14 near the CHRNA7 gene for linkage to schizophrenia, using 54 pedigrees from an independent study. Alleles for these three markers were genotyped and analyzed using parametric and nonparametric methods. No LOD score above 1.00 was obtained for any marker, and affected sib-pair analysis likewise showed no evidence for linkage. We conclude that in our families the region around the CHRNA7 locus does not contain a major locus for susceptibility to schizophrenia.

Schizophrenia: gender and familial risk.

The morbid risks for schizophrenia and any nonaffective psychosis in the first degree relatives of male and female schizophrenic probands were compared utilizing Cox proportional hazards models. The schizophrenic probands (275 male; 106 female) were drawn from a larger sample of hospitalized patients obtained by systematically screening all psychiatric admissions to 15 facilities over a six-year period. Proband diagnoses (DSM-III) were based on a direct assessment of the patient and a review of medical records. The family history method was used to obtain information about the first degree relatives of the probands. Cox proportional hazards models were adjusted for duration of illness of the proband and gender of the relatives. First degree relatives of female probands had significantly higher morbid risks for schizophrenia and nonaffective psychosis than relatives of male probands. The differential risk for schizophrenia in the relatives of male and female probands demonstrated in this study, as well as others, suggests that males and females may be at different risk for subtypes of the disorder.

Psychiatric morbidity in the relatives of patients with DSM-III schizophreniform disorder: comparisons with the relatives of schizophrenic and bipolar disorder patients.

Risks for psychiatric disorders (RDC) among first degree relatives of DSM-III schizophreniform, bipolar, and schizophrenic probands obtained from an epidemiologic sample using family history methods were examined. The relatives of the schizophreniform probands differed from the relatives of the schizophrenic and bipolar probands. The relatives of schizophreniform probands had significantly higher rates of affective illnesses (with the exception of bipolar illness) than the relatives of schizophrenic probands, and they had a significantly higher rate of psychotic affective disorders than the relatives of the bipolar probands.

Age-incidence artifacts do not account for the season-of-birth effect in schizophrenia.

Contrary to the position taken by Lewis (1989), several articles have demonstrated an association between season of birth and the risk of schizophrenia after controlling for the age-incidence effect. The method used by Pulver et al. (1983) was misinterpreted by Lewis. Clarification of this method is provided along with additional references related to the season-of-birth issue.

Differences in social class among psychotic patients at inpatient admission.

A cross-sectional assessment of differences in social class and other sociodemographic variables at hospital admission for patients with psychotic disorders was carried out through a systematic survey of psychotic patients admitted to greater Baltimore psychiatric facilities between 1983 and 1989. Female patients, first-admission patients, and patients with bipolar disorder or other, nonschizophrenic psychosis were more likely to have been admitted to community, university, and private hospitals than to state hospitals. Patients in medium and higher social class categories were 1.29 to 2.57 times more likely to be admitted to community, university, and private hospitals than to state hospitals.

Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients.

Despite the strongly held view that schizophrenia (SZ) shows substantial genetic heterogeneity, pathway heterogeneity, as seen in cancer where different pathways are affected in similar tumors, has not been explored. We explore this possibility in a case-only study of the neuregulin signaling pathway (NSP), which has been prominently implicated in SZ and for which there is detailed knowledge on the ligand- and receptor-processing steps through ß- and γ-secretase cleavage. We hypothesize that more than one damaging variants in the NSP genes might be necessary to cause disease, leading to an apparent clustering of such variants in only the few patients with affected NSP. We analyze linkage and next-generation sequencing results for the genes encoding components of the pathway, including NRG1, NRG3, ERBB4, ß-secretase and the γ-secretase complex. We find multiple independent examples of supporting evidence for this hypothesis: (i) increased linkage scores over NSP genes, (ii) multiple positive interlocus correlations of linkage scores across families suggesting each family is linked to either many or none of the genes, (iii) aggregation of predicted damaging variants in a subset of individuals and (iv) significant phenotypic differences of the subset of patients carrying such variants. Collectively, our data strongly support the hypothesis that the NSP is affected by multiple damaging variants in a subset of phenotypically distinct patients. On the basis of this, we propose a general model of pathway heterogeneity in SZ, which, in part, may explain its phenotypic variability and genetic complexity.

Dense SNP association study for bipolar I disorder on chromosome 18p11 suggests two loci with excess paternal transmission.

Parent-of-origin effects have been implicated as mediators of genetic susceptibility for a number of complex disease phenotypes, including bipolar disorder. Specifically, evidence for linkage on chromosome 18 is modified when allelic parent-of-origin is accommodated in the analysis. Our goal was to characterize the susceptibility locus for bipolar I disorder on chromosome 18p11 and investigate this parent-of-origin hypothesis in an association context. This was achieved by genotyping single nucleotide polymorphisms (SNPs) at a high density (1 SNP/5 kb) along 13.6 megabases of the linkage region. To increase our ability to detect a susceptibility locus, we restricted the phenotype definition to include only bipolar I probands. We also restricted our study population to Ashkenazi Jewish individuals; this population has characteristics of a genetic isolate and may therefore facilitate detection of variants for complex disease. Three hundred and forty-four pedigrees (363 parent/child trios) where probands were affected with bipolar 1 disorder were genotyped. Transmission disequilibrium test analysis revealed no statistically significant association to SNPs or haplotypes within this region in this sample. However, when parent-of-origin of transmitted SNPs was taken into account, suggestive association was revealed for two separate loci.

Psychotic inpatients' social class and their first admission to state or private psychiatric Baltimore hospitals.

Social class differences were investigated among patients admitted to public and private psychiatric hospitals. Participants included first admission White psychotic men admitted to Baltimore metropolitan area hospitals between 1983 and 1989. After adjusting for age and diagnosis, patients with low levels of skills/credentials were found to be more likely than patients with higher levels to be admitted to state psychiatric hospitals. These findings underscore the persistence of social class as a determinant of differences in the use of psychiatric care.

Arrest among psychotic inpatients: assessing the relationship to diagnosis, gender, number of admissions, and social class.

The present study of psychotic patients investigates the relationship of specific psychotic diagnoses (i.e., psychoactive-substance-induced psychosis, schizophrenia, bipolar disorder, other DSM-III Axis I psychotic disorders), social class, gender, and number of admissions to the rate of arrest in the community. All admissions with psychotic symptoms to hospitals providing inpatient psychiatric services in the Baltimore area were surveyed during a 6-year period. Study participants were assessed using a modified version of the Diagnostic Interview Schedule. During the course of the interview, patients were asked whether they had ever been arrested as a juvenile or as an adult. After adjusting for age, gender, number of admissions, and social class, we found that patients admitted for psychoactive-substance-induced psychosis were more likely to report having been arrested than patients with other psychotic diagnoses. Patients with schizophrenia were not more likely to have an history of arrest than patients with other psychotic disorders. Number of admissions and social class were independent predictors of history of arrest. The relationship between psychotic diagnosis and history of arrest was modified by gender. Psychotic patients with substance-induced diagnosis who were male were more likely to report a prior arrest in the community than their female counterparts. Our results suggest that type of psychotic diagnosis and social class, in addition to gender and number of admissions, are important predictors of differences in arrest-rate histories among psychotic patients. Gender appears to be an effect modifier of the relationship between psychotic diagnosis and history of arrest.

An epidemiologic investigation of alcohol-dependent schizophrenics.

Most clinicians agree that alcoholism is frequent in schizophrenic patients. However, little is known about the clinical or familial characteristics of this group. We compared alcoholic schizophrenics and nonalcoholic schizophrenics with respect to sociodemographic and clinical characteristics and the rate of various psychiatric illnesses among their first-degree relatives. The only difference in the sociodemographic characteristics was a higher proportion of males among the alcoholic schizophrenics. Clinically, the alcoholic schizophrenics were more likely to report experiencing hallucinations, depressive episodes, manic episodes (females only) and multiple substance abuse (males only). In addition, the male alcoholic schizophrenics were younger at first hospitalization than the male nonalcoholic schizophrenics. This effect was reversed for females. The relatives of alcoholic schizophrenics were 2.6 times more likely to be alcoholic than the relatives of the nonalcoholic schizophrenics. The morbidity for other psychiatric disorders was similar in the two groups.

Season of birth of siblings of schizophrenic patients.

The hypothesis that mothers of winter-spring-born schizophrenics have an unusual pattern of conception which results in an excess of winter-spring births was tested by studying the distribution of birth-dates of 401 siblings of 120 winter-spring-born schizophrenics and 157 siblings of 59 winter-spring-born controls. All analyses were gender-specific. The results suggest there is no association between the probability of a winter-spring date of birth and being a sibling of a winter-spring-born schizophrenic or control.