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Biomedical subjects

N Risch

Publications and source records attributed to N Risch.

At least 145 records · Page 8Linked to original sources
PubMed1986

The relationship between maternal age and chromosome size in autosomal trisomy.

The pattern of maternal age-specific incidence of autosomal trisomy in spontaneous abortions was examined for each chromosome for which a sufficient number of trisomies was observed. This included chromosomes 2, 4, 7-10, 13-16, 18, and 20-22. The rate of increase after age 30 for each of the small chromosomes (groups D-G) was similar, with the exception of chromosome 16, which showed a significantly shallower rate. The C group chromosomes tended to have an intermediate rate of increase after age 30, with the exception of chromosome 7, which had a pattern similar to the smaller chromosomes. The larger chromosomes (2 and 4) had the smallest rate of increase. There was a significant relationship between chromosome size and rate of increase after age 30 (after excluding chromosome 16), but not with rate of increase before age 30. The results suggest that autosomal trisomies may be of heterogeneous origin, with a maternal age-related factor associated with chromosome size and other sources unrelated to chromosome size. Additional evidence for and against this hypothesis is discussed.

Abortion, Spontaneous↗
PubMed1985

Genetic analysis of platelet monoamine oxidase activity in families of schizophrenic patients.

Platelet monoamine oxidase (MAO) has been implicated in the biology of several psychiatric disorders, including schizophrenia. Genetic factors contribute to the variance of MAO activity; however, its mode of inheritance is unknown. To assess the distribution and familial patterns of platelet MAO activity, we studied 73 chronic schizophrenic patients and 219 of their first-degree relatives. The activity distribution was skewed and admixture of two distributions gave a better fit to the data than a single distribution. Single-major-locus hypotheses were tested by pedigree analysis methods for quantitative traits. Using the transmission probability model, the familial transmission of MAO activity was consistent with either recessive or additive inheritance but not with dominant inheritance; the environmental hypothesis was strongly rejected. No effect of genotype on probability of illness was observed suggesting no relationship between the particular major locus tested and schizophrenia. The implications for genetic research in schizophrenia were discussed.

Adolescent↗
PubMed1985

Genetic analysis of plasma amine oxidase activity in schizophrenia.

Plasma amine oxidase (PAO) activity has been implicated in the biology of schizophrenia. PAO activity is, in part, under genetic control, but its mode of inheritance has not been determined. To assess the genetic pattern of PAO activity and its relation to the transmission of schizophrenia, we studied 73 chronic schizophrenic probands and 217 first-degree relatives (siblings and parents). Single-major-locus hypotheses were tested by pedigree analysis methods for quantitative traits. The distribution of PAO activity indicated significant admixture. When the transmission probability model was used, the familial pattern of PAO activity was consistent with mendelian transmission; the environmental hypothesis was rejected. PAO activity was lower in schizophrenic patients than in unaffected relatives, but the mean reduction in enzyme activity was small (10.7%) and the two groups of subjects overlapped greatly in their PAO values. The difference between ill and well relatives was not statistically significant. However, schizophrenia spectrum disorders segregated with low PAO activity in families of low-activity probands, and a greater proportion of ill than well subjects clustered in the low PAO activity mode. The results are interpreted as follows: (1) The transmission of PAO activity may be determined in part by a single major autosomal gene. (2) Low PAO activity does not qualify as a major risk factor in the schizophrenic population at large; however, a relationship may exist between low PAO activity and the transmission of schizophrenia in families of patients with extremely low enzyme activity.

Adolescent↗
PubMed1984

Genetic Analysis Workshop II: multiple-locus segregation analysis incorporating linkage markers.

The workshop data were examined using a newly developed methodology (MILINK, Risch, 1984) for combined segregation, linkage, and association analysis of a complex disease trait in pedigree data. Results from problems two and three suggest that the method is powerful both for determining mode of disease inheritance and for resolution of linkage disequilibrium versus pleiotrophy (with epistasis) of marker alleles.

Alleles↗
PubMed1984

Segregation analysis of schizophrenia and related disorders.

Segregation analysis was applied to 79 nuclear families ascertained through chronic schizophrenic probands. Analysis was performed on the diagnosis of schizophrenia alone and on schizophrenia and schizotypal personality disorder (milder phenotype) combined. The models used were the transmission probability model and the mixed model. Because the disease is associated with reduced fertility, all likelihoods were calculated conditional on parental phenotypes. However, compatibility of the mating-type distribution predicted by each model with the observed was also examined. In all analyses, results suggested consistency with genetic transmission. In the analysis of schizophrenia alone, discrimination among models was difficult. In the analysis including the milder phenotypes, all single-locus models without polygenic background were excluded, while pure polygenic inheritance could not be eliminated. The polygenic model also gave good agreement with supplementary observations (lifetime disease incidences, mating-type distribution, and monozygotic twin concordance). The estimated components of variance for the polygenic model were: polygenes (H) 81.9%; common sib environment (B) 6.9%; random environment (R) 11.2%. Although the polygenic model was parsimonious, segregation analysis and the supplementary observations were also consistent with a mixed model, with a single major locus making a large contribution to genetic liability. Such a locus is more likely to be recessive than dominant, with a high gene frequency and low penetrance. The most likely recessive mixed model gave the following partition of liability variance: major locus, 62.9%; polygenes, 19.5%; common sib environment, 6.6%; and random environment, 11.0%.

Adolescent↗
PubMed1984

Segregation analysis incorporating linkage markers. I. Single-locus models with an application to type I diabetes.

A method is described for segregation analysis that incorporates linkage markers. The model allows for segregation (penetrance), linkage (recombination fraction), and association (linkage disequilibrium) parameters. A single-locus-multiple-allele model underlying the trait phenotype is assumed. When families have been ascertained in a systematic fashion, a joint (markers, phenotypes) likelihood with ascertainment is advocated. When ascertainment correction is not feasible, a conditional (markers given phenotypes) approach is recommended, which is also valid in the presence of reduced fertility and assortative mating. This approach, oriented toward determining mode of inheritance, differs from conventional linkage analysis, which is oriented toward detection of linkage. Therefore, it is more appropriately considered an extension of the affected sib-pair method to arbitrary pedigrees, including association information and allowing for multiple alleles. Incorporation of coupling parameters allows for discrimination between pleiotropy and linkage disequilibrium. The method is demonstrated through a reanalysis of four recently published family studies on type 1 diabetes and HLA. Recessive inheritance is rejected in all four data sets. For three of them, dominant inheritance is not rejected, while in the fourth, all two-allele models are rejected in favor of three alleles. Although association with the DR3 and DR4 alleles is quite strong, pleiotropy with regard to these alleles is unlikely. The results also suggest an additional familial factor(s) (e.g., locus).

Adult↗
PubMed1983

The effects of reduced fertility, method of ascertainment, and a second unlinked locus on affected sib-pair marker allele sharing.

The method of affected sib-pair marker allele sharing has been used not only for the detection of linkage, but also for discerning inheritance. The application of this method has included the tacit assumption of no selective disadvantage for affected individuals. For some of the disorders analyzed by this method, this assumption is not tenable. Also, the method of ascertainment of affected sib pairs is not taken into account. It is shown here that the ascertainment procedure and reduced reproductivity of affected individuals can alter the expected distribution of affected sib-pair marker allele sharing. The effect is greatest for a recessive disease susceptibility locus. While the effect of reduced reproductivity is to inflate the gene frequency necessary to account for the observed distribution, a second unlinked disease susceptibility locus can diminish this effect. Application to type 1 diabetes shows that according to a simple recessive model with 50% penetrance, the observed distribution of affected sib-pair HLA haplotype sharing requires a gene frequency in the range of 0.55-0.60, much greater than estimates previously proposed. According to such a model, the frequency of disease would be around 15%, clearly out of range of the observed frequency of 0.4%.

Alleles↗
PubMed1983

A general model for disease-marker association.

A general model for analysing disease-marker associations from a random sample of patients and controls is given, assuming an arbitrary number of marker and disease susceptibility alleles. A method for testing the goodness-of-fit of various disease susceptibility models to the observed distribution of genotypes at the marker locus in patient and control samples is given. The method is demonstrated using a recently published data set on type I diabetes.

Diabetes Mellitus↗
PubMed1983

Statistical analysis of multilocus recombination.

A general formula for the frequency of different recombinant gamete types, in terms of the underlying distribution of crossovers, is derived. This formula may be applied to any theoretical model of recombination in which it is assumed that there is no chromatid interference. Multiple-locus recombination data may be evaluated by using this formula in conjunction with a maximum likelihood procedure. The validity of any model of recombination may be tested in such a fashion. The possibilities are demonstrated through application to a generalized noninterference model of crossing over described in a previous paper (Risch and Lange, 1979, Annals of Human Genetics 43, 61-70).

Animals↗
PubMed1983

Estimating morbidity risks with variable age of onset: review of methods and a maximum likelihood approach.

Various methods for the estimation of morbidity risk in a disease with late variable onset are described, along with a maximum likelihood approach. It is shown that the Strömgren estimator is nearly as efficient as the maximum likelihood estimator when the true risk is low, but may be significantly less efficient for high morbidity risks. The maximum likelihood estimator offers greater protection against risk estimates greater than or equal to 1, and for small samples, may also be less biased than the Strömgren estimator, especially when risk is high. For reasonable sample sizes both estimates are nearly unbiased. The modified Strömgren estimator is too biased, in general, to be practical. Methods for comparing morbidity risks are also described. If an age-of-onset distribution is estimated from the same sample as morbidity risk, a single maximum likelihood procedure is advocated. The methods are applied to a data set on major affective disorder. The sensitivity of morbidity-risk estimates and tests of hypotheses to the form of onset function assumed is examined.

Age Factors↗
PubMed1982

Differential fertility in bipolar affective illness.

The fertility of 134 bipolar probands (60 males, 74 females) was compared with national census data and examined for sex and age-of-onset effects. Fertility was markedly reduced in certain age cohorts in both females and males. When illness onset was taken into account, significant reductions in fertility were observed in the two sexes both before and after onset. The overall reduction in females remained constant over time, but was greater after onset among males. The role of selective forces maintaining affective disorders in the population was discussed in light of genetic and sociodemographic hypotheses.

Adolescent↗
PubMed1982

X-linkage and genetic heterogeneity in bipolar-related major affective illness: reanalysis of linkage data.

It has been suggested that an X-linked dominant allele operates in the genetic transmission of bipolar (manic-depressive) illness. Linkage studies with X-chromosome markers have remained inconclusive, showing both positive and negative results. Some of the ambiguity may be attributed to imprecise analytic methods and genetic heterogeneity. In this report, recently published pedigree series are reanalysed for linkage using a systematic method of pedigree analysis (Liped 3) with an accurate age-of-onset correction. Linkage heterogeneity is assessed through a two-recombination fraction heterogeneity test suggested by Smith (1963). The results are as follows: (1) Close linkage of bipolar illness to colourblindness (deutan and protan) and glucose-6-phosphate dehydrogenase deficiency appears to be present in some pedigrees, with estimated recombination fractions of theta = 0.05 and 0.00, respectively; (2) Linkage with the Xg blood group cannot be supported. These results are consistent with known linkages on the X chromosome.

Age Factors↗
PubMed1982

[Synthesis and structure of new basic enol ethers].

Synthesis of new basic enol ethers with valuable pharmacological properties is described. The structure of these compounds is elucidated by 1H- and 13C-NMR-spectroscopy; the stereochemistry of the double bond is determined by use of the intramolecular nuclear Overhauser effect. An X-ray analysis of an isolated diastereomer confirms the proposed constitution.

Bridged-Ring Compounds↗
PubMed1981

X-linkage in bipolar affective illness. Perspectives on genetic heterogeneity, pedigree analysis and the X-chromosome map.

The search for genetic markers is a powerful strategy in psychiatric genetics. The present article examines four areas relevant to discrepancies among X-linkage studies in bipolar affective disorder. These are questions of ascertainment, analytic methods, the X-chromosome map and genetic heterogeneity. The following conclusions are reached: (a) Positive linkage findings cannot be attributed to ascertainment bias or association between affective illness and colorblindness. (b) The possibility that falsely positive linkage results were obtained by using inappropriate analytic methods is ruled out. (c) Reported linkages of bipolar illness to colorblind and G6PD loci are compatible with known map distances between X-chromosome loci. Linkage to the Xg antigen remains uncertain. (d) The discrepancy among the various data sets on affective illness and colorblindness is best explained by significant linkage heterogeneity among pedigrees informative for the two traits.

Bipolar Disorder↗
PubMed1979

An alternative model of recombination and interference.

A model of four-strand crossing-over is presented in which all non-randomness is attributed to the non-Poisson distribution of the number of exchanges. Nth order recombination fractions and the coefficient of coincidence are calculated in terms of the model. It is shown that coincidence may be greater or less than unity depending on the prior distribution of exchanges. An obligate exchange is a sufficient condition for coincidence to be less than unity if there is a maximum of four exchanges, but not necessarily if five or more are possible. It is also shown that marginal coincidence is an insufficient concept to explain the behaviour of coincidence over its entire two-dimensional domain.

Chromosome Mapping↗