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Biomedical subjects

N Risch

Publications and source records attributed to N Risch.

At least 19 recordsLinked to original sources
PubMed1995

Extreme discordant sib pairs for mapping quantitative trait loci in humans.

Analysis of differences between siblings (sib pair analysis) is a standard method of genetic linkage analysis for mapping quantitative trait loci, such as those contributing to hypertension and obesity, in humans. In traditional designs, pairs are selected at random or with one sib having an extreme trait value. The majority of such pairs provide little power to detect linkage; only pairs that are concordant for high values, low values, or extremely discordant pairs (for example, one in the top 10 percent and the other in the bottom 10 percent of the distribution) provide substantial power. Focus on discordant pairs can reduce the amount of genotyping necessary over conventional designs by 10- to 40-fold.

Alleles↗
PubMed1995

Birth cohort and familial risk of epilepsy: the effect of diminished recall in studies of lifetime prevalence.

This study separated the effects of age, birth cohort, and generation (parents, siblings, and offspring) on familial risk of epilepsy. The study population comprised 9,741 parents, siblings, and offspring of 1,957 adult probands with epilepsy ascertained from 10 voluntary organizations in New York, New Jersey, Connecticut, and Massachusetts between 1985 and 1988. Semistructured telephone interviews with probands and selected family members were used to collect data on the history of epilepsy in the relatives. The risk of epilepsy increased in successive generations (cumulative incidence to age 40: parents, 1.8%; siblings, 2.9%; offspring, 5.6%) but, with the exception of one subgroup (offspring of female probands), these differences disappeared after controlling for age and birth year of the relatives. With age and relationship controlled, the risk of epilepsy increased approximately 50% for each 20 advancing years of birth. Population-based data indicate that age-specific incidence rates of epilepsy have not increased during the age and time periods investigated here; thus, the most plausible explanation for the findings is that epilepsy is underreported in persons born in earlier time periods. These results illustrate a general phenomenon of underreporting in studies of lifetime prevalence, and they caution against interpreting apparent cohort effects in such studies as evidence of secular changes in incidence.

Adolescent↗
PubMed1995

Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.

We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (> 90%) of early-onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.

Alleles↗
PubMed1995

Localization of a gene for partial epilepsy to chromosome 10q.

There is strong evidence for a genetic contribution to epilepsy, but it is commonly assumed that this genetic contribution is limited to 'generalized' epilepsies, and that most forms of 'partial' epilepsy are nongenetic. In a linkage analysis of a single family containing 11 affected individuals, we obtained strong evidence for localization of a gene for partial epilepsy. This susceptibility gene maps to chromosome 10q, with a maximum two-point lod score for D10S192 of 3.99 at theta = 0.0. All affected individuals share a single haplotype for seven tightly linked contiguous markers; the maximum lod score for this haplotype is 4.83 at theta = 0.0. Key recombinants place the susceptibility locus within a 10 centimorgan interval.

Adolescent↗
PubMed1995

Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7.

Insulin-dependent diabetes mellitus (IDDM) is characterized by autoimmune destruction of the insulin secreting beta-cells of the pancreas and subsequent disruption of glucose metabolism. The tendency of IDDM to cluster in families and the modest (36%) concordance rate in monozygotic twins indicates that both genetic and environmental factors contribute to IDDM susceptibility. Recent genome-wide searches using the affected sib-pair (ASP) approach have provided evidence for novel loci, in addition to HLA (IDDM1) and insulin (IDDM2), which show evidence of linkage to IDDM (P < 0.05). We have evaluated 35 microsatellite marker loci on human chromosome 7 for linkage to IDDM in 339 affected sib-pair families. Increased sharing of parental haplotypes in affected sib-pairs was detected for two microsatellite markers flanking glucokinase (GCK). Preferential transmission of alleles to affected offspring was observed at one of these marker loci, GCK3, indicating linkage disequilibrium between the marker and a disease susceptibility locus. This combination of linkage and disease association suggests that glucokinase, or a gene in the vicinity, plays an important part in IDDM susceptibility.

Alleles↗
PubMed1995

Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis.

The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult.

Chromosome Mapping↗
PubMed1994

Genetic susceptibility to death from coronary heart disease in a study of twins.

BACKGROUND: A family history of premature coronary heart disease has long been thought to be a risk factor for coronary heart disease. Using data from 26 years of follow-up of 21,004 Swedish twins born between 1886 and 1925, we investigated this issue further by assessing the risk of death from coronary heart disease in pairs of monozygotic and dizygotic twins. METHODS: The study population consisted of 3298 monozygotic and 5964 dizygotic male twins and 4012 monozygotic and 7730 dizygotic female twins. The age at which one twin died of coronary heart disease was used as the primary independent variable to predict the risk of death from coronary heart disease in the other twin. Information about other risk factors was obtained from questionnaires administered in 1961 and 1963. Actuarial life-table analysis was used to estimate the cumulative probability of death from coronary heart disease. Relative-hazard estimates were obtained from a multivariate survival analysis. RESULTS: Among the men, the relative hazard of death from coronary heart disease when one's twin died of coronary heart disease before the age of 55 years, as compared with the hazard when one's twin did not die before 55, was 8.1 (95 percent confidence interval, 2.7 to 24.5) for monozygotic twins and 3.8 (1.4 to 10.5) for dizygotic twins. Among the women, when one's twin died of coronary heart disease before the age of 65 years, the relative hazard was 15.0 (95 percent confidence interval, 7.1 to 31.9) for monozygotic twins and 2.6 (1.0 to 7.1) for dizygotic twins. Among both the men and the women, whether monozygotic or dizygotic twins, the magnitude of the relative hazard decreased as the age at which one's twin died of coronary heart disease increased. The ratio of the relative-hazard estimate for the monozygotic twins to the estimate for the dizygotic twins approached 1 with increasing age. These relative hazards were little influenced by other risk factors for coronary heart disease. CONCLUSIONS: Our findings suggest that at younger ages, death from coronary heart disease is influenced by genetic factors in both women and men. The results also imply that the genetic effect decreases at older ages.

Adult↗
PubMed1994

Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction.

BACKGROUND: Improvements in screening techniques have made significant contributions to the early detection of breast cancer. Physicians thus face the task of providing appropriate screening schedules for their patients. One group for whom this is particularly important are those women with a family history of breast cancer. METHODS: In this report, data from the Cancer and Steroid Hormone Study, a population-based, case-control study conducted by the Centers for Disease Control, are used to provide age-specific risk estimates of breast cancer for women with a family history of breast cancer. The data set includes 4730 patients with histologically confirmed breast cancer age 20-54 years and 4688 control subjects who were frequency matched to patients by geographic region and 5-year age intervals. The data set also includes family histories of breast cancer in mothers and sisters of both patients and control subjects. RESULTS: Genetic models fit previously to these data by the authors have provided evidence for a rare autosomal dominant allele that results in increased susceptibility to breast cancer. In addition, these models predict that women who carry the allele are at greater risk of developing breast cancer at any age than are women who do not carry the allele. The increase in risk in carriers versus noncarriers does, however, decrease with increasing age. Based on the parameters of this model, age-specific risks for a woman with one or more relatives affected with breast cancer at various ages at onset are given. CONCLUSIONS: These tables can be used for the purpose of counseling women at high risk of breast cancer development, that is, women with a family history of breast cancer.

Adult↗
PubMed1994

Feasibility of half-sibling designs for detecting a genetic component to a disease.

In genetic epidemiology, adoption and twin study designs are the most commonly used designs to identify genetic and common environmental components underlying familial aggregation. Other fixed family set designs such as a half-sibling design can also be applied to test the same hypothesis. The feasibility of half-sibling designs for detecting a genetic (single-locus or multifactorial) source of familial aggregation of a disease is studied and is compared to both adoption and twin study designs. Results are presented for two types of design when the sampling units are relative pairs reared apart (I) or reared together (II). Although they generally require more observations to achieve the same power, designs involving half-siblings may be more feasible in situations where there is greater availability of these relatives.

Adoption↗
PubMed1994

Diminished recall and the cohort effect of major depression: a simulation study.

Several large-scale epidemiological surveys have reported increasing lifetime rates of psychopathology among recently born cohorts. In the case of Major Depressive Disorder (MDD) younger cohorts tend to manifest higher lifetime prevalences of the condition than older cohorts, at any given age. In some studies, cohort differences are so large that the youngest cohort exceeds the lifetime prevalence of the oldest cohort well before passing through their total period of risk. The data on lifetime prevalences that support the existence of secular differences, however, has typically been collected in cross-sectional studies. Thus, individuals are interviewed at a single point in time and asked to recall all prior psychopathology. Due to poor recall, this design may greatly underestimate earlier experiences. In fact, cohort differences are not limited to MDD; similar results have been reported for a wide range of psychopathology, suggesting methodological problems at data collection. We have conducted a simulation study to examine the magnitude of annual rates of forgetting that could produce the secular trends reported for MDD. Small, but constant annual rates produce striking, 'cohort effect-like' curves. The rates needed to reconstruct the reported effect are compatible with published values for test-retest studies of lifetime recall of MDD. This simulation study does not rule out the existence of a cohort effect in some psychiatric disorders, but stresses the possible limitations of using cross-sectional studies to investigate secular trends.

Adolescent↗
PubMed1994

Gene loss and gain in the evolution of the vertebrates.

Homeobox cluster genes (Hox genes) are highly conserved and can be usefully employed to study phyletic relationships and the process of evolution itself. A phylogenetic survey of Hox genes shows an increase in gene number in some more recently evolved forms, particularly in vertebrates. The gene increase has occurred through a two-step process involving first, gene expansion to form a cluster, and second, cluster duplication to form multiple clusters. We also describe data that suggests that non-Hox genes may be preferrentially associated with the Hox clusters and raise the possibility that this association may have an adaptive biological function. Hox gene loss may also play a role in evolution. Hox gene loss is well substantiated in the vertebrates, and we identify additional possible instances of gene loss in the echinoderms and urochordates based on PCR surveys. We point out the possible adaptive role of gene loss in evolution, and urge the extension of gene mapping studies to relevant species as a means of its substantiation.

Amino Acid Sequence↗
PubMed1994

Comments on the statistical aspects of the NRC's report on DNA typing.

The goal of the NRC report on DNA typing was to answer a "crescendo of questions concerning DNA typing," many of them in the areas of population genetics and statistics. Unfortunately, few of these questions were answered adequately. In lieu of answering these questions, the panel proposed another conservative method of forensic inference, the "ceiling principle." Aside from its extreme conservativeness, this new method is difficult to justify because it is based on inadequate population genetics and statistical theory. Moreover, in its ultimate implementation, the panel's method will depend on a population genetics study whose rationale is questionable. In this article, we elaborate some of the general comments we made about the NRC report in a recent article [1]. Specifically we cover three topics. First we question the statistical basis for the ceiling principle, showing that the empirical results that motivated the method are likely to be misinterpreted and showing, by power calculations, that the effects of population substructure cannot be substantial. Second, we show that the study design to determine "ceiling" allele frequencies has several undesirable statistical properties. Finally, we discuss the estimation of handling errors from the statistical perspective, a subject treated inadequately by the report.

DNA Fingerprinting↗
PubMed1993

An association between the risk of cancer and mutations in the HRAS1 minisatellite locus.

BACKGROUND: The role of mutations in protooncogenes and their regulatory sequences in the pathogenesis of cancer is under close scrutiny. Minisatellites are unstable repetitive sequences of DNA that are present throughout the human genome. The highly polymorphic HRAS1 minisatellite locus just downstream from the protooncogene H-ras-1 consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. We previously observed an association of the rare mutant alleles with many forms of cancer, and we undertook the present study to pursue this observation further. METHODS: We conducted a case-control study, typing 736 HRAS1 alleles from patients with cancer and 652 from controls by Southern blotting of leukocyte DNA. We also carried out a meta-analysis of this study and 22 other published studies, estimating the relative risk of cancer (such as bladder, breast, or colorectal cancer) when one of the rare HRAS1 alleles was present. RESULTS: Both the present case-control study (odds ratio, 1.83; 95 percent confidence interval, 1.28 to 2.67; P = 0.002) and the present study combined with our previous study (odds ratio, 2.07; 95 percent confidence interval, 1.47 to 2.92; P < 0.001), as well as the meta-analysis of all 23 studies (odds ratio, 1.93; 95 percent confidence interval, 1.63 to 2.30; chi-square = 57.58; P < 0.001), replicated our original finding and demonstrated a significant association of rare HRAS1 alleles with cancer. We found significant associations for four types of cancer: carcinomas of the breast, colorectum, and urinary bladder and acute leukemia. We also identified suggestive but not statistically significant associations for cancers of the lung and prostate and for non-Hodgkin's lymphoma. CONCLUSIONS: Mutant alleles of the HRAS1 minisatellite locus represent a major risk factor for common types of cancer. Although the relative risk associated with the presence of one rare allele is moderate, the aggregate prevalence of one rare allele is moderate, the aggregate prevalence of this class of mutant alleles implies an extremely important attributable risk: 1 in 11 cancers of the breast, colorectum, and bladder.

Aged↗
PubMed1993

The A1 allele at the D2 dopamine receptor gene and alcoholism. A reappraisal.

OBJECTIVE: An allelic association between the TaqI "A" system A1 allele at the D2 dopamine receptor locus (DRD2) and either alcoholism or severe alcoholism has been proposed. Our purpose was to evaluate whether, based on all of the accumulated evidence, this association could be considered to be proven. DATA SOURCES: We considered data from all published reports of DRD2 allele frequency in alcoholics, controls, or both. STUDY SELECTION: We concentrated on the issue of replication. We therefore considered all data reported (on white samples, because DRD2 allele frequency varies by race and ethnicity) since the first report by Blum et al in 1990. DATA SYNTHESIS: We analyzed the set of data for differences in allele frequencies between alcoholics and controls, and for heterogeneity among samples. We also investigated the influence of the data from the first group to report an association (including a subsequent report from that group) on the findings. Our analysis shows that, when all studies subsequent to the original study are considered, there is no significant difference in DRD2 A1 allele frequency between alcoholics and controls, there is significant heterogeneity among reported alcoholics and reported controls, and there is no significant difference in DRD2 A1 allele frequency between severe and not severe alcoholics. Also, the two reports of Blum et al account for all of the (nonsignificant) differences seen between controls, alcoholics, and severe alcoholics. CONCLUSIONS: In general, heterogeneity among studies (for alcoholics or controls) is considerably greater than differences between alcoholics and controls overall. The findings to date can best be explained by more conservative interpretations than a confirmed physiologically important allelic association between DRD2 alleles and alcoholism. These other possibilities include sampling error and ethnic variation in those studies that individually showed a large effect.

Alcoholism↗
PubMed1993

Relationship between breast histopathology and family history of breast cancer.

BACKGROUND: The relationship between breast cancer histology and a number of epidemiologic risk factors associated with breast cancer was examined in 4071 histologically confirmed breast cancer cases aged 20 to 54 years from the Cancer and Steroid Hormone Study. METHODS: The distribution of risk factors, which included a family history of breast cancer, age at onset of breast cancer, laterality, race, age at menarche, age at menopause, history of benign breast disease, parity, number of livebirths and number of stillbirths, and age at first childbirth, were examined by histologic subgroup. To determine whether histology is associated with familial risk of breast cancer, a Cox proportional hazards model was used, modeling time to onset of breast cancer among mothers and sisters. RESULTS: Cases with medullary carcinoma were found to be significantly younger than cases with other tumor types in these data. In addition, medullary carcinoma was reported more frequently among black cases than among white cases. Cases with lobular carcinoma in situ were significantly more likely to have a mother and/or sister affected with breast cancer than cases with other tumor types and were also more likely to be bilateral, although few of these cases were both bilateral and reported a family history of breast cancer. The highest reported rates of benign breast disease occurred in cases with carcinoma in situ (both ductal and lobular) and tubular carcinoma. The remaining risk factors showed no association with histology. CONCLUSIONS: The current study clarifies the extent and nature of the relationship between breast cancer histology and epidemiologic risk factors including a family history of breast cancer.

Adult↗
PubMed1993

The genetics of infantile hypertrophic pyloric stenosis. A reanalysis.

OBJECTIVE: To determine whether the existing family data for infantile hypertrophic pyloric stenosis (IHPS) are sufficient for the purposes of establishing the mode of inheritance of this condition. DESIGN: Reanalysis of the familial aggregation patterns exhibited by IHPS, using data from several published family studies. CONCLUSIONS: Due to several limitations of the available family data for IHPS, the results of this analysis should be interpreted cautiously. Within the context of these limitations, the familial recurrence pattern among monozygotic cotwins and more remote relatives of IHPS probands was found to be inconsistent with generalized single major locus inheritance. The familial recurrence pattern of IHPS is, however, compatible with multifactorial threshold inheritance or the effects of multiple interacting loci. Under a model of multiple interacting loci, no single locus can account for more than a fivefold increase in the risk to first-degree relatives of IHPS probands. In contrast to several earlier reports, this analysis does not support the existence of a maternal factor that contributes to the risk of IHPS in the offspring of affected females.

Diseases in Twins↗
PubMed1993

The calculation of breast cancer risk for women with a first degree family history of ovarian cancer.

Recent linkage analyses demonstrate the strength of the genetic association between breast and ovarian cancer in some families. These findings highlight the importance of considering a woman's family history of ovarian cancer in the calculation of her risk of breast cancer. In this study, data on breast and ovarian cancer from the Cancer and Steroid Hormone Study, a large, population-based, case-control study conducted by the Centers for Disease Control, are used to calculate age-specific and cumulative risks of developing breast cancer for a woman with a first degree family history of ovarian cancer. These risks are calculated using maximum likelihood estimates from an autosomal dominant genetic model fit previously to the observed age-specific recurrence data of breast cancer among first degree relatives of the breast cancer cases and controls in these data as well as from genotype-specific estimates of lifetime ovarian cancer risk derived from this model. Under this model, the lifetime risk of developing breast cancer for a woman with one or two first degree relatives affected with ovarian cancer is estimated to be approximately 13% and 31%, respectively. A woman with one first degree relative affected with ovarian cancer and one first degree relative affected with breast cancer has an estimated risk of 40 percent of developing breast cancer by age 79 years if the relative with breast cancer was diagnosed in her thirties. This risk decreases with increasing age of onset of the relative affected with breast cancer.

Adult↗