Chromosome 22 workshop.
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Chromosome Mapping↗
Biomedical subjects
D F Levinson
Publications and source records attributed to D F Levinson.
Genome scan of schizophrenia.
OBJECTIVE: The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. METHOD: A genomewide map of 310 microsatellite DNA markers with average spacing of 11 centimorgans was genotyped in 269 individuals--126 of them with schizophrenia-related psychoses--from 43 pedigrees. Nonparametric linkage analysis was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. RESULTS: Nonparametric linkage scores did not reach a genomewide level of statistical significance for any marker. There were five chromosomal regions in which empirically derived p values reached nominal levels of significance at eight marker locations. There were p values less than 0.01 at chromosomes 2q (with the peak value in this region at D2S410) and 10q (D10S1239), and there were p values less than 0.05 at chromosomes 4q (D4S2623), 9q (D9S257), and 11q (D11S2002). CONCLUSIONS: The results do not support the hypothesis that a single gene causes a large increase in the risk of schizophrenia. The sample (like most others being studied for psychiatric disorders) has limited power to detect genes of small effect or those that are determinants of risk in a small proportion of families. All of the most positive results could be due to chance, or some could reflect weak linkage (genes of small effect). Multicenter studies may be useful in the effort to identify chromosomal regions most likely to contain schizophrenia susceptibility genes.
Chromosome Mapping↗
A linkage study of schizophrenia to markers within Xp11 near the MAOB gene.
A sex chromosome locus for psychosis has been considered on the basis of some sex differences in genetic risk and expression of illness, and an association with X-chromosome anomalies. Previous molecular genetic studies produced weak evidence for linkage of schizophrenia to the proximal short arm of the X-chromosome, while some other regions were not ruled out. Here we report an attempt to expand the Xp findings in: (i) a multicenter collaboration focusing on 92 families with a maternal pattern of inheritance (Study I), and (ii) an independent sample of 34 families unselected for parental mode of transmission (Study II). In the multicenter study, a parametric analysis resulted in positive lod scores (highest of 1.97 for dominant and 1.19 for recessive inheritance at a theta of 0.20) for locus DXS7, with scores below 0.50 for other markers in this region (MAOB, DXS228, and ARAF1). Significant allele sharing among affected sibling pairs was present at DXS7. In the second study, positive lod scores were observed at MAOB (highest of 2.16 at a theta of 0.05 for dominant and 1.64 at a theta of 0.00 for recessive models) and ALAS2 (the highest of 1.36 at a theta of 0.05 for a recessive model), with significant allele sharing (P = 0.003 and 0.01, respectively) at these two loci. These five markers are mapped within a small region of Xp11. Thus, although substantial regions of the X-chromosome have been investigated without evidence for linkage being found, a locus predisposing to schizophrenia in the proximal short arm of the X-chromosome is not excluded.
Chromosome Mapping↗
Pragmatics and statistics in psychiatric genetics.
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Genetic Linkage↗
Linkage analysis of complex disorders with multiple phenotypic categories: simulation studies and application to bipolar disorder data.
The problem of linkage analysis of disorders with multiple possible phenotypes (diagnostic spectrum) is considered. A modification is proposed to Ott's [1994] method of down-weighting the contribution of broader diagnoses by reducing penetrance ratios for affected cases. A "robust weighting" strategy considers only the robustness of a set of ratios across a range of true genetic models. Practical models for lod-score analysis will typically employ a high penetrance ratio (> 10) for "core" cases, and ratios between 2 and 5 for broader cases. Results suggest that an additive parametric analysis correlates highly with dominant, recessive and nonparametric linkage (NPL) analyses. A weighted, additive model is then applied to a modified NIMH bipolar chromosome 18 data set (Genetic Analysis Workshop 10) and compared with NPL analyses under narrow and broad diagnostic models. The weighted model performed well. The introduction of similar weights into nonparametric analyses may prove more useful.
Bipolar Disorder↗
The molecular genetics of schizophrenia: an update.
OBJECTIVE: This paper aims to summarise the latest molecular genetic findings in schizophrenia, while providing background information on a number of relevant methodological issues. METHOD: Accumulative genetic data indicate that schizophrenia is a genetically complex disease with an unclear mode of transmission. The development and rapid progression of molecular genetics have provided a wide variety of methods to search for genes predisposing to human disease. The genetic basis for a number of the simpler diseases has been identified and characterised using these methods. More recently, progress has been made in identifying genes predisposing to the genetically more complex diseases such as diabetes mellitus, multiple sclerosis, bipolar disorder and schizophrenia. RESULTS: The latest findings on chromosomes 3, 6, 8, 13, 18 and 22 and on the X chromosome are reviewed. CONCLUSIONS: There is now suggestive support for three susceptibility loci (6p24-22, 8p22-21 and 22q12-q13.1) for schizophrenia, and it is likely that other regions will emerge from studies now in progress. Finding and then characterising genes within these loci will require long-term commitment and systematic efforts in clinical, laboratory and analytical fields.
Chromosome Mapping↗
Penetrance of schizophrenia-related disorders in multiplex families after correction for ascertainment.
Penetrance of schizophrenia and related disorders was calculated in 27 multiplex pedigrees ascertained by a consistent set of screening and selection criteria. The rationale for the study was that single major locus linkage models are frequently used on a pragmatic basis to analyze data for schizophrenia which is most likely to have a polygenic mechanism. Penetrance estimates assuming Mendelian inheritance represent maximum values and thus can provide guidance for construction of appropriate linkage models. Four diagnostic models were considered: narrow (schizophrenia and chronic schizoaffective disorder), intermediate (including other non-affective psychoses), broad (including schizotypal and paranoid personality disorders), and broad + suspected (including suspected schizophrenia spectrum disorders). Penetrance was calculated in the youngest affected adult sibship, under both dominant and recessive inheritance assumptions, either without correction, or with a correction that excluded individuals necessary to meet pedigree selection criteria. Without correction, penetrance values ranged from 0.70 to 0.90 assuming dominant and 1.0 to > 1.0 assuming recessive inheritance. After correction, the ranges were 0.30-0.51 for dominant and 0.47-0.59 for recessive models. The corrected values are likely to be overestimates given that the penetrance of any one locus in a multilocus model must be lower. It is suggested that lod score analyses of schizophrenia should attempt to derive information primarily from affected diagnoses, because information derived from unaffecteds under high penetrance models is likely to be spurious.
Adult↗
Family burden of schizophrenia and bipolar disorder: perceptions of relatives and professionals.
OBJECTIVE: The study compared the burden that specific problem behaviors of patients with schizophrenia or bipolar disorder placed on relatives and evaluated the accuracy of mental health professionals' judgment of the burden. METHODS: A questionnaire was developed to assess the burden of 20 common problem behaviors associated with manic, positive, and negative symptoms. The questionnaire was given to 48 relatives of patients with schizophrenia or bipolar disorder. In addition, 39 mental health professionals completed separate questionnaires indicating the amount of burden they believed relatives experienced due to these behaviors. RESULTS: Relatives of patients with bipolar disorder rated manic symptoms as more burdensome than did relatives of patients with schizophrenia, but relatives of patients in the two groups did not differ in their ratings of burden associated with positive or negative symptoms. Professionals' perceptions of the burden associated with manic symptoms were relatively accurate, but they tended to underestimate the burden of positive and negative symptoms experienced by relative of patients with bipolar disorder. CONCLUSIONS: Psychiatric diagnosis may be of limited value in understanding the burden relatives experience due to specific psychiatric symptoms. Professionals are encouraged to assess the burden that is associated with specific problem behaviors regardless of psychiatric diagnosis.
Activities of Daily Living↗
Detection of vulnerability loci by association and sib-pair methods.
A haplotype-based haplotype relative risk (HHRR) analysis of simulated data for 200 affected offspring and their parents (Genetic Analysis Workshop 9, Problem 1) detected linkage disequilibrium at 2 of 360 marker loci. An additive model was suggested but not proven by haplotypes of affected vs. unaffected offspring. These findings were consistent with the generating model. Affected sib pair analysis failed to detect additional loci. Discussion among workshop participants suggested that the chi-square test used here (2 [transmitted vs. nontransmitted] x n [alleles] for each locus) was invalid because of the nonindependence of proportions of transmitted alleles. In post-workshop analyses, transmission disequilibrium tests (TDTs) for each allele at each locus detected only the true associations if p values were corrected by one of two methods: Bonferroni correction for 2,035 TDTs, or correcting each test for n (number of tests at the locus) minus 1 and then for the number of loci tested. Screening loci for linkage disequilibrium requires careful attention to correction for multiple comparisons.
Alleles↗
Fluphenazine plasma levels, dosage, efficacy, and side effects.
OBJECTIVE: The authors sought to determine whether fluphenazine dose or plasma level predicts clinical improvement or side effects during acute treatment. METHOD: Oral fluphenazine was given in fixed, randomized, double-blind doses (10, 20, or 30 mg/day) for 4 weeks to 72 inpatients with acute schizophrenic exacerbations. Outcome measures included percentage improvement in ratings of positive symptoms (hallucinations, delusions, and thought disorder), percentage improvement in negative symptoms, and maximum score for extrapyramidal symptoms. Response was defined as an improvement in positive symptoms of 40% or more. RESULTS: The 42 responders had a shorter duration of illness, less chronic course, and lower rate of akathisia. Plasma level and dose did not differentiate responders and nonresponders, but they did predict percentage improvement in positive symptoms within the responder subgroup. Akathisia was more common and extrapyramidal symptoms were more severe at higher plasma levels. CONCLUSIONS: Responders showed the greatest improvement at fluphenazine plasma levels above 1.0 ng/ml and doses above 0.20-0.25 mg/kg per day. Since the literature suggests that optimal plasma levels are similar during acute and maintenance treatment, monitoring of plasma levels may thus be useful. Conditions for applying the "responder-only" analytic strategy in future studies are discussed.
Acute Disease↗
Delusions in schizophrenia spectrum disorders: diagnostic issues.
Family studies of schizophrenia frequently include relatives of schizophrenia probands with diagnoses falling within the schizophrenia spectrum. As part of an ongoing genetic linkage study of schizophrenia, the authors examined case material from 50 relatives (of schizophrenia probands) who received a DSM-III-R diagnosis of a nonaffective psychotic disorder or schizotypal or paranoid personality disorder. Eleven exhibited episodic or chronic delusions that resulted in diagnostic dilemmas, often arising from issues pertaining to the classification of delusional phenomena. Four of these cases are presented here. Unusual beliefs were often difficult to classify as odd beliefs versus full delusions, brief/transient versus persistent delusions, bizarre versus non-bizarre delusions. It is suggested that these might be considered continuous rather than dichotomous dimensions. Several possible implications for genetic studies of schizophrenia are discussed.
Adult↗
Power to detect linkage with heterogeneity in samples of small nuclear families.
Computer simulation methods were used to investigate the power of genetically homogeneous or heterogeneous samples of nuclear families to detect linkage of a rare dominant disease allele to flanking DNA markers (three-point analysis, admixture text). Phase was assumed to be unknown (no grandparents available), and unaffected siblings were not considered. A sample of 95 families with an ill parent and two ill offspring, or 45 families with three ill offspring, demonstrated 90% power to detect a lod score of 3.0 when 50% of families were assumed to be segregating for a disease allele located midway between two DNA markers (PIC = .70) that were .05 M apart. When the proportion of linked families (alpha) = .25, 90% power required 380 and 160 families, respectively. For alpha < .25, samples size requirements become prohibitive. Issues are reviewed concerning the use of the admixture test in the case of more complex disease models. Screening of the genome with adequate sample sizes for low values of alpha is likely to require multiple large collaborative efforts.
Computer Simulation↗
Continuity and discontinuity of affective disorders and schizophrenia. Results of a controlled family study.
BACKGROUND: It is widely acknowledged that the genetic diatheses for schizophrenia and affective disorders are independent. However, there are increasing doubts about this classic view, and empirical evidence for a dichotomy of these two prototypes of functional psychoses is limited. A controlled family study of consecutive admissions was conducted to determine whether familial risks for schizophrenic (SCZ) and affective disorders were independent or overlapping. METHODS: Index probands met Research Diagnostic Criteria for SCZ (n = 146), schizoaffective (SA [n = 115]), bipolar (BP [n = 80]), or unipolar major depressive (UP [n = 184]) disorder. Comparison probands met Research Diagnostic Criteria for alcoholism (n = 64) or were sampled from the general population (n = 109). A total of 2845 first-degree relatives were blindly diagnosed from interview, informant, and/or record data, with direct interviews completed in 2070 (82% of living first-degree relatives). RESULTS: By Cox's proportional hazards analysis, SCZ, SA, BP, and UP disorders were familial, in that each group of relatives had an increased lifetime morbid risk (vs those with alcoholism and those from the general population) for the proband's diagnosis. The SCZ and BP disorders were transmitted independently: only probands with manic disorders (BP or SA-BP subtype) showed increased familial risks of BP disorder, and only probands with prominent SCZ features (SCZ or SA) showed increased familial risks of SCZ disorder. However, SCZ probands had an increased familial risk for UP disorder (as did SA, BP, and UP probands) and for the SA-UP subtype. Aggregation of depression in families of SCZ probands could not be explained by the subtype of depression, broad or narrow definition of SCZ disorder, presence or absence of history of depression in SCZ probands, whether onset of depression in a relative occurred before or after onset of a proband's SCZ disorder, or assortative mating. CONCLUSIONS: These data suggest that there could be a familial relationship between the predispositions to schizophrenia and to major depression. We discuss a number of alternative hypotheses about the nature of this possible relationship.
Adult↗
Schizotypal and paranoid personality disorder in the relatives of patients with schizophrenia and affective disorders: a review.
This review considers the possible familial relationship of schizotypal and paranoid personality disorders (SPD, PPD) to schizophrenia (SCZ) and affective disorders (AD). There have been few controlled studies on familial risk of SPD and PPD based on direct semi-structured interviews of relatives, blind to proband diagnosis. Three of six studies reported increased familial risk of SPD for SCZ probands, but with considerable variability in estimates of this risk. None of four studies reported a significant relationship between AD and familial SPD. There is substantial but less consistent evidence for a familial relationship between PPD and SCZ: three of six studies supported such a relationship, but one large study reported increased familial risk of PPD for AD and not for SCZ probands. There is also some evidence that negative symptoms are most characteristic of SPD in relatives of SCZ probands. Also discussed are issues concerning the adequacy of current criteria for defining schizophrenia spectrum pathology, and of diagnostic methods in this area.
Adoption↗
Genetic linkage and schizophrenia: methods, recent findings and future directions.
Family, twin and adoption studies have shown that familial clustering in schizophrenia is predominantly due to genetic factors. On the basis of segregation analyses of the illness distribution in relatives of patients, various models of the mode of transmission have been put forward but as yet there is no consensus. Linkage analysis based on molecular genetic techniques provides a more direct approach to discovering precisely what is inherited (one gene, a small number of genes or many genes?) that generates vulnerability to schizophrenia. To date there has been no sufficiently replicated finding of one or more linked genes and many methodological complexities remain. However, the rate of progress in addressing these issues gives hope that genetic linkage analysis of schizophrenia will provide some answers.
Chromosome Mapping↗
The treatment and management of neuroleptic malignant syndrome.
1. The neuroleptic malignant syndrome was initially described as a disorder specifically related to neuroleptic usage with frequent fatal outcome. The observations of variant or mild cases of this syndrome as well as case reports on neuroleptic-malignant-like syndromes in the absence of neuroleptics raises the issue of the usefulness of this terminology and highlights the potential for inappropriate management of this "malignant" syndrome. It has been suggested that hypothalamic thermoregulatory responses may involve an interplay among noradrenergic, cholinergic and serotonergic pathways. Out treatment strategy is based on the pharmacology of neuroleptics and empirical data, verified in our own clinical practice and considers that it is often difficult to determine whether certain physiologic states are a consequence to or specific triggering factors. 2. If a patient's temperature is less than 101, we emphasize vigorous treatment with anticholinergic agents, while simultaneously assessing the psychiatric need for neuroleptics versus medical risks. Given that the severe rigidity of NMS represents severe extrapyramidal effects of dopamine blockade, there is no reason to withhold anticholinergics in the absence of higher temperatures. Neuroleptics can be stopped at the discretion of the clinician even during circumstances when there is fever below 101. 3. In cases of severe EPS with fever greater than or equal to 101, we recommend stopping neuroleptics, treating with anticholinergics and starting with dopamine agonists. In the event of a poor response to dopamine agonists, a brief trial of dantrolene and/or benzodiazepines is recommended. Dantrolene should not be introduced for prolonged periods, since abnormal liver function studies have been observed in approximately 1.8% of patients. 4. In cases of extreme hyperpyrexia (fever greater than 103), clinicians should consider transfer to an ICU or another medical support. Extreme temperatures have been associated with potentially irreversible cerebellar or other brain damage, if not aggressively treated. If neuroleptics are later indicated, a 2 week interval after resolution of symptoms should be maintained before reinstituting neuroleptics. 5. In patients with severe EPS without fever, we emphasize aggressive use of anticholinergic therapy, while simultaneously considering the psychiatric need for neuroleptics versus medical risks. In all cases where a patient's swallowing, respirations or physical mobility is severely compromised, we suggest stopping neuroleptics. Anticholinergic agents should be continued for 7 days after neuroleptics are stopped. If anticholinergic agents are unsuccessful after 2-3 dosages, dopamine agonists may be added, while simultaneously monitoring vital signs. It should be emphasized that severe EPS sometimes takes days to improve even after neuroleptic cessation and the addition of anticholinergics.(ABSTRACT TRUNCATED AT 400 WORDS)
Humans↗
Timing of acute clinical response to fluphenazine.
The time course of clinical improvement was studied in 41 schizophrenic and schizoaffective acute in-patients treated for 28 days with 10, 20 or 30 mg/day of oral fluphenazine hydrochloride in a double-blind, randomised study. Significant improvement was seen in the four BPRS factors: thinking disturbance, hostile-suspiciousness, withdrawal-retardation and anxious depression. The first two of these factors were improved by day 5. Significant improvement was seen up to day 22 for three of the four factors, but without significant improvement during the last week (although scores continued to drop). The half of the sample showing greater overall improvement did not improve faster than the sample as a whole. These more improved subjects did not differ significantly from the less improved subjects in the thinking disturbance factor until day 15, suggesting that at least a two-week neuroleptic trial would be necessary to begin to differentiate more and less responsive patients. The longer-term course of improvement cannot be determined from these data. The withdrawal-retardation and anxious depression factors showed their greatest improvement later than the 'positive' symptom factors, suggesting that the former may improve as a result of change in the latter.
Acute Disease↗
Skin conductance orienting response in unmedicated RDC schizophrenic, schizoaffective, depressed, and control subjects.
In an evaluation of the skin conductance orienting response (SCOR) as a marker for schizophrenia, skin conductance (SC) activity was studied in 36 Research Diagnostic Criteria (RDC) schizophrenic (SCZ), 17 schizoaffective--mainly schizophrenic (SA), 24 depressed (DEP), and 25 psychiatrically well control (CONT) subjects. All subjects were unmedicated. Data are presented from four paradigms: a series of 1 s 70 dB tones in a no-task habituation paradigm; a similar series of 103 dB tones; a series of tones with a button-press (reaction time) task; and a loud white noise stimulus (without task). The proportion of SCOR nonresponse to the first 70 dB tone was 39% for SCZ, 82% for SA, 46% for DEP, and 36% for CONT subjects; the response rate for SA subjects was significantly lower than for all other groups. The CONT group was less responsive than in most previous studies. SCZ subjects did not show increased responsivity to more intense and to task-relevant stimuli, although SA subjects did show such increases. DEP subjects showed some evidence of autonomic hyperarousal (higher tonic SC level, trend toward more spontaneous SC responses). The overall pattern of results does not support SCOR to neutral, moderate-intensity tones as a specific marker for schizophrenia, although there was some evidence for a generalized decrease in autonomic responsivity to stimuli.
Acoustic Stimulation↗