The putative schizophrenia locus on chromosome 6p: a brief overview of the linkage studies.
Explore the source record for details and available documents.
Chromosomes, Human, Pair 6↗
Biomedical subjects
C J MacLean
Publications and source records attributed to C J MacLean.
Support for schizophrenia vulnerability loci on chromosomes 6p and 8p from Irish families.
Explore the source record for details and available documents.
Chromosomes, Human, Pair 6↗
A potential vulnerability locus for schizophrenia on chromosome 6p24-22: evidence for genetic heterogeneity.
In 265 Irish pedigrees, with linkage analysis we find evidence for a vulnerability locus for schizophrenia in region 6p24-22. The greatest lod score, assuming locus heterogeneity, is 3.51 (P = 0.0002) with D6S296. Another test, the C test, also supported linkage, the strongest results being obtained with D6S296 (P = 0.00001), D6S274 (P = 0.004) and D6S285 (P = 0.006). Non-parametric analysis yielded suggestive, but substantially weaker, findings. This locus appears to influence the vulnerability to schizophrenia in roughly 15 to 30% of our pedigrees. Evidence for linkage was maximal using an intermediate phenotypic definition and declined when this definition was narrowed or was broadened to include other psychiatric disorders.
Chromosomes, Human, Pair 6↗
Logistic regression analysis of twin data: estimation of parameters of the multifactorial liability-threshold model.
We extend the DeFries-Fulker regression model for the analysis of quantitative twin data to cover binary traits and genetic dominance. In the proposed logistic regression model, the cotwin's trait status, C, is the response variable, while the proband's trait status, P, is a predictor variable coded as k (affected) and 0 (unaffected). Additive genetic effects are modeled by the predictor variable PR, which equals P for monozygotic (MZ) and P/2 for dizygotic (DZ) twins; and dominant genetic effects, by PD, which equals P for MZ and P/4 for DZ twins. By setting an appropriate scale for P (i.e., the value of k), the regression coefficients of P, PR, and PD are estimates of the proportion of variance in liability due to common family environment, additive genetic effects, and dominant genetic effects, respectively, for a multifactorial liability-threshold model. This model was applied to data on lifetime depression from the Virginia Twin Registry and produced results similar to those from structural equation modeling.
Adult↗
Schizophrenia: sex and familial morbidity.
Several recent studies have found a greater risk of schizophrenia among the relatives of female schizophrenic probands than the relatives of male schizophrenic probands. These results are contradictory to those of earlier studies. The current investigation, using family data collected in the 1950's and 1960's in Sweden, did not find a difference in the risk of schizophrenia among the relatives of male and female schizophrenic probands. However, significantly more relatives of female probands than relatives of male probands had manic-depressive psychosis. These findings suggest that the earlier studies may have included some female schizophrenic probands who would be classified as having manic-depression by modern criteria.
Female↗
A typological model of schizophrenia based on age at onset, sex and familial morbidity.
We investigated the age at onset distributions of schizophrenia in men and women and the relationship of age at onset and sex to the familial rates of schizophrenia and manic-depression in data from a Swedish family study of 270 schizophrenic probands. On the logarithmic scale, the age at onset distribution of schizophrenia in both male and female relatives was bimodal, suggesting that broadly defined schizophrenia may be a mixture of 2 (probably related) disorders. The risk of schizophrenia in relatives decreased as a function of the age at onset of the proband, irrespective of the sex of the proband or relative. In contrast, the risk of manic-depression was significantly higher in relatives of female probands with an age at onset in the twenties than in relatives of female probands with earlier or later onset, or in relatives of male probands. This suggests a third disorder related to affective psychosis, with an intermediate age at onset and female preponderance.
Adolescent↗
Trends in stroke incidence and mortality in Hawaiian Japanese men.
BACKGROUND AND PURPOSE: Vital statistics show a sharp decline in stroke mortality since the late 1960s. It is not clear whether this has been associated with a decline in stroke incidence. METHODS: Since 1966 the Honolulu Heart Program has monitored the incidence and mortality of coronary heart disease and stroke in a target population of 11,136 men of Japanese ancestry living on Oahu. Trends were analyzed from January 1, 1969, through December 31, 1988. RESULTS: Of 7893 men aged 45 to 68 years and free of stroke at entry examination, 530 developed first episodes of stroke in the period 1969 to 1988 (389 cases of thromboembolic stroke, 124 cases of hemorrhagic stroke, and 17 cases of stroke of unknown type). Age-adjusted annual stroke incidence declined from 5.1 per 1000 person-years in 1969 to 1972 to 2.4 in 1985 to 1988. The incidences of thromboembolic stroke, hemorrhagic stroke, and total stroke decreased 3.5%, 4.2%, and 4.4% per year, respectively. The 1-month case-fatality rates for thromboembolic stroke decreased moderately; those for hemorrhagic stroke fell dramatically. CONCLUSIONS: These findings suggest that the decline in stroke mortality in the past two or three decades results from a decline in both incidence rates and early case-fatality rates in thromboembolic and hemorrhagic stroke and stroke of unknown type. The decreases may be related to changes in risk factors, such as the decline in blood pressure and the decrease in cigarette smoking, as well as improvements in diagnosis and treatment.
Age Factors↗
Two-locus versus one-locus lods for complex traits.
Explore the source record for details and available documents.
Genes, Dominant↗
Smoking and major depression. A causal analysis.
Among 1566 personally evaluated female twins from a population-based register, average lifetime daily cigarette consumption was strongly related to lifetime prevalence and to prospectively assessed 1-year prevalence of major depression (MD). Using the cotwin control method, we evaluated whether the association between smoking and lifetime MD was causal or noncausal. While the relative risk (95% confidence interval) for ever smoking given a lifetime history of MD was 1.48 (1.30 to 1.65) in the entire sample, it was 1.18 (0.88 to 1.47) and 0.98 (0.71 to 1.26), respectively, in dizygotic and monozygotic twin pairs discordant for a history of MD. The relative risk for a history of MD given ever smoking was 1.60 (1.39 to 1.83) in the entire sample, while in dizygotic and monozygotic twins discordant for smoking, it was 1.29 (0.87 to 1.74) and 0.96 (0.59 to 1.42), respectively. Controlling for personal smoking history, family history of smoking predicted risk for MD; controlling for the personal history of MD, family history of MD predicted smoking. The best-fitting bivariate twin model suggested that the relationship between lifetime smoking and lifetime MD resulted solely from genes that predispose to both conditions. These results suggest that the association between smoking and MD in women is not a causal one but arises largely from familial factors, which are probably genetic, that predispose to both smoking and MD.
Adult↗
Exclusion of linkage between schizophrenia and the D2 dopamine receptor gene region of chromosome 11q in 112 Irish multiplex families.
A leading theory hypothesizes that schizophrenia arises from dysregulation of the dopamine system in certain brain regions. As this dysregulation could arise from abnormal expression of D2 dopamine receptors, the D2 receptor gene (DRD2) on chromosome 11q is a candidate locus for schizophrenia. We tested whether allelic variation at DRD2 and five surrounding loci cosegregated with schizophrenia in 112 small- to moderate-size Irish families containing two or more members affected with schizophrenia or schizoaffective disorder, defined by DSM-III-R. Evidence of linkage was assessed using varying definitions of illness and modes of transmission. Assuming genetic homogeneity, linkage between schizophrenia and large regions of 11q around DRD2 could be strongly excluded. Assuming genetic heterogeneity, variation at the DRD2 locus could be rejected as a major risk factor for schizophrenia in more than 50% of these families for all models tested and in as few as 25% of the families for certain models. The DRD2 linkage in fewer than 25% of these families could not be excluded under any of the models tested. Our results suggest that the major component of genetic susceptibility to schizophrenia is not due to allelic variation at the DRD2 locus or other genes in the surrounding chromosomal region.
Alleles↗
Mortality and morbidity among blue and white collar workers in the Honolulu Heart Program cohort.
There has been a controversy regarding occupation, as defined by blue and white collar work, and coronary heart disease (CHD). In a large long-term prospective study of the Honolulu Heart Program cohort, there were no significant differences between these two occupational classifications and the incidence rates of fatal and non-fatal CHD. Nor were there significant differences in total mortality, stroke or total cancer although there were very small but significant differences in some CHD risk factors. Unlike the previous studies, this investigation was free of prevalent cases of CHD at baseline and controlled for the major risk factors of CHD. We question the utility of using this occupational classification to investigate the causes of CHD.
Aged↗
Risk of schizophrenia and age difference with older siblings. Evidence for a maternal viral infection hypothesis?
Recent reports that some influenza epidemics may be followed by a transient increase in the births of schizophrenic patients have led to the hypothesis that maternal viral infections contribute to the aetiology of schizophrenia. It is well known that respiratory viral infections are frequently brought into the home by young children. We tested the predictions that the risk of schizophrenia is decreased in first-born children, and increased in individuals who had siblings of a young age while in utero, using data from a Swedish family study. Our results are consistent with these predictions. In particular, having siblings three to four years older was associated with a significantly increased risk of schizophrenia, even after allowing for birth order, sibship size, and other potential confounders. If replicated, these results provide indirect support for the maternal viral infection hypothesis, although there are alternative explanations.
Adult↗
Joint linkage of multiple loci for a complex disorder.
Many investigators who have been searching for linkage to complex diseases have by now accumulated a drawer full of negative results. If disease is actually caused by genes at several loci, these data might contain multiple-locus system (MLS) information that the investigator does not realize. Trying to obtain this information formally, through the MLS likelihood, leads to severe computational and statistical difficulties. Therefore, we propose a scheme of inference based on single-locus (SL) statistics, considered jointly. By simulation, we find that the MLS lod score is closely approximated by the sum of SL lod scores. However, we also find that for moderately large systems, say three of four loci, both MLS and SL lod scores are likely to be inconclusive. Nonetheless, MLS can often be detected through the correlation of individual pedigree SL lod scores. Significant correlation is itself evidence of an MLS, because, in the absence of linkage, false-positive lod scores are necessarily random. Under epistasis SL lod scores tend to be positively correlated among pedigrees, while under independent action SL lod scores from high-density samples tend to be negatively correlated.
Chi-Square Distribution↗
Distribution of lod scores under uncertain mode of inheritance.
We consider probability distributions of alternative lod statistics, differing in their treatment of segregation parameters when mode of inheritance is uncertain. A particular pedigree structure and a dominant genetic system displaying incomplete penetrance are analyzed. Lod scores calculated assuming an incorrect segregation model appear to conform quite well to the chi 2 distribution in the absence of linkage. In the presence of linkage, some power is lost. However, if lod scores are calculated under several different segregation models and the best one is accepted, opportunity for chance occurrence of high lod scores is enhanced. The distribution is still chi 2, but with extra degrees of freedom. These results hold over a wide range of sample sizes and segregation models, including small samples and low levels of penetrance.
Chi-Square Distribution↗
Interactions of the beta carboline abecarnil with the high pressure neurological syndrome in a primate model.
The neurophysiological interactions between the high pressure neurological syndrome (HPNS) and a new beta carboline, abecarnil, were studied in the non-human primate Papio anubis. Abecarnil is a partial agonist at the benzodiazepine site on the GABA/benzodiazepine receptor. Six animals were exposed on two occasions to pressures of 91 ATA in an environment of helium and oxygen. One exposure was pretreated with a total dose of abecarnil 1.0 mg/kg, the other with an equivalent volume of vehicle. Treatment with abecarnil prevented the severe signs of HPNS occurring between 51 and 91 ATA. Onset pressures of the various signs were unaffected. Some signs, e.g. myoclonus, became more frequent when abecarnil was used. A residual protective effect of abecarnil was present 4 weeks after the dose was given, active at pressures less than 71 ATA. Changes with pressure in the EEG were recorded primarily from the frontal cortex, but were also present in the parietal and occipital areas of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the four conventional wavebands, plus two others, analysed. The most striking change was the prevention by abecarnil of the pressure-induced 100% increase in alpha wave amplitude in the frontal region. It is concluded that modulation of GABA transmission is important in controlling the expression of HPNS.
Animals↗
A new test for linkage in the presence of locus heterogeneity.
The detection of linkage in complex traits, although potentially of the greatest value, has proved very difficult. One reason may be the drastic effect that locus heterogeneity has on statistical power. We propose a new test for linkage in the presence of heterogeneity, based upon the sum of individual pedigree maximum lod scores, combined with a bootstrap method for estimating the null-hypothesis distribution. The technique is designed to exploit modern computer capability and to avoid reliance on asymptotic-distribution theory. Numerical comparisons indicate that for small pedigrees this new test can detect linkage with 30%-50% less data than are required by standard methods. A computer program for simulating the distribution and for performing the test of linkage is available from the authors.
Female↗
Long-term precision of bone loss rate measurements among postmenopausal women.
Repeated measurements of bone mineral content can indicate the rate of bone loss among postmenopausal women. The clinical utility of such loss rate measurements will depend upon the long-term precision of the measurements. We have analyzed the precision of appendicular bone measurements among 495 Japanese-Americans followed for an average of 5.3 years and of both appendicular and axial measurements among 70 clinical trial participants followed for 2 years. Tables were derived from these analyses to quantitate the precision of individual loss rates under varying measurement conditions that might be encountered in clinical practice. The results demonstrate that only unusually rapid loss rates could be identified with confidence within short intervals, such as 1 year or 2. Extending the length of follow-up, however, appreciably improved the measured loss rate precision. In comparisons between bone sites, appendicular sites were determined to achieve a specified precision within the shortest intervals, followed by spine dual photon absorptiometry measurements. Spine quantitative computerized tomography measurements and measurements of hip sites required considerably longer follow-up intervals to achieve comparable precision.
Aged↗
The effects of the competitive NMDA receptor antagonist CPP on the high pressure neurological syndrome in a primate model.
Neurophysiological interactions between the competitive N-methyl-D-aspartate (NMDA) preferring receptor antagonist, CPP (3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonate) and the high pressure neurological syndrome (HPNS) have been investigated in the non-human primate Papio anubis. Eight animals were exposed on two occasions to environmental pressures of 81 atmospheres absolute (ATA) in a hyperbaric chamber, using helium and oxygen. One exposure followed pretreatment with CPP (either 5 or 10 mg/kg i.v. plus 5 mg/kg/hr infusion), the other a saline control. Pretreatment with CPP delayed moderate signs of face tremor and myoclonus and abolished severe signs of whole body tremor and seizure activity. By 81 ATA, scores representing severity of HPNS were significantly reduced by CPP to a mean score, reflecting a level of just mild to moderate limb tremoring (P less than 0.001). Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the 4 conventional wavebands were analysed. The most striking change was the complete prevention by CPP of the 100% increase in the amplitude of alpha waves at 81 ATA in the frontal region (P less than 0.001). It is concluded that NMDA transmission has a major role in the expression of HPNS.
Animals↗