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N Risch

Publications and source records attributed to N Risch.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1993

Linkage studies of psychiatric disorders.

Linkage analysis has been successful in identifying the genetic basis of numerous Mendelian diseases. These successes were due in part to the rapid developments in molecular biology, which have yielded a plethora of informative genetic markers. Although there is strong evidence that the manifestation of schizophrenia and bipolar affective disorders is controlled by genes, no evidence for linkage has been established. For psychiatric disorders, the most important limiting factor is likely to be the lack of single loci with very large effects that occur with any relevant frequency. The difficulties of linkage studies in psychiatric disorders are discussed with reference to non-psychiatric genetic diseases for which linkage to genetic markers has been successful. Recommendations for collecting information to clarify the patterns of transmission of the psychiatric disorders are described.

Genetic Linkage↗
PubMed1993

Low-density lipoprotein cholesterol responsiveness to diet in normolipidemic subjects.

Both apolipoprotein E genotype (apo E) and diet predict very-low-density (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. In a retrospective pooled analysis of six studies, we sought to identify the predictors of VLDL-C and LDL-C change, or "responsiveness," to a diet crossover. "Response" to diet was studied in 67 normolipidemic subjects of common apo E genotype. Subjects were fed two contrasting, metabolically controlled diets: one had a low polyunsaturated to saturated fatty acid ratio (P:S), and the other had a high P:S ratio. Multiple blood samples were analyzed for VLDL-C and LDL-C levels at the end of each metabolic diet period, and values were averaged and differences were calculated. Despite adjustment for significant predictors across the component studies, a wide range of LDL-C responsiveness was found, with an average decrease of 28 mg/dL. Multivariate regression analysis was used to identify the most significant predictors of LDL-C response to the diet crossover. All dietary and clinical variables were entered by stepwise regression for potential inclusion in a "best-fit" model. The degree of change in saturated fat content and age were the most significant predictors of LDL-C responsiveness. Neither dietary cholesterol nor apo E phenotype were significant predictors of responsiveness. The most LDL-C-responsive subjects were older and required smaller reductions in dietary saturated fat levels than did less-responsive subjects to achieve a comparable reduction in LDL-C levels. Multiple regression analysis suggested a precursor-product relationship between VLDL-C and LDL-C responsiveness.

Adult↗
PubMed1993

Diminished support for linkage between manic depressive illness and X-chromosome markers in three Israeli pedigrees.

The hypothesis that chromosomal region Xq27-28 harbours a gene for manic-depression has been a focus of interest in human genetics. X-linked inheritance of manic depressive illness has been re-examined in 3 multigeneration Israeli kindreds. Extension and re-evaluation of pedigree data, including new individuals, diagnostic follow-up, and analysis with DNA markers, shows greatly diminished support for linkage to Xq28. The peak lod scores in two of the pedigrees have dropped several lod units to clearly negative values at the RCP-F8-G6PD gene cluster. On the other hand, positive lod scores (Zmax = 2.09) are sustained in another pedigree at the same map location. None of the pedigrees show linkage to more proximal markers, including the Xq27 locus DXS98. Our analysis underscores the uncertainties in studying complex disorders.

Adult↗
PubMed1993

Correlates of genetic risk for non-syndromic cleft lip with or without cleft palate.

Multivariate analysis was used to determine which characteristics: sex of the proband, sibling sex, severity of the proband's defect or family history, are the best predictors of recurrence risk among siblings of individuals with non-syndromic cleft lip with or without cleft palate (CL +/- P). Sibling recurrence risks are not significantly related to the sex of the proband. Severity of the proband's defect, classified by the extent of the lip defect (unilateral versus bilateral), was found to be a significant predictor of sibling recurrence, whereas involvement of the palate in the proband's defect was not. A positive family history of clefting (i.e. at least one affected first-degree relative in addition to the proband) and the sex of the sibling were also found to be significant predictors of sibling recurrence. The associations between sibling risk and family history, and sibling risk and bilaterality of the proband's defect appear to be mildly confounded. After adjusting for the effects of family history, the risk to siblings of probands with bilateral lip defects is twice the risk to siblings of probands with unilateral defects (O.R. = 2.00; 95% C.I. 1.25-3.19). A positive family history of clefting increases the risk to siblings by greater than 4-fold (O.R. = 4.49; 95% C.I. 2.74-7.35), after adjusting for the extent of the proband's lip defect. These results provide a rational strategy for identifying subsets of the 'at risk' population which have markedly different recurrence risks. This information is important for genetic counseling, since it allows for more precise estimation of sibling recurrence risks in individual cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Cleft Lip↗
PubMed1993

Population genetics of the HRAS1 minisatellite locus.

Several years ago it was reported that rare HRAS1 VNTR alleles occurred more frequently in U.S. Caucasian cancer patients than in unaffected controls. Such an association, in theory, could be caused by undetected population heterogeneity. Also, in a study clearly relevant to this issue, it was recently reported that significant deviations from Hardy-Weinberg equilibrium exist at this locus in a sample of U.S. Caucasians. These considerations motivate our population genetic analysis of the HRAS1 locus. From published studies of the HRAS1 VNTR locus, which classified alleles into types, we found only small differences in the allele frequency distributions of samples from various European nations, although there were larger differences among ethnic groups (African American, Caucasian, and Oriental). In an analysis of variation of rare-allele frequencies among samples from four European nations, most of the variance was attributable to molecular methodology, and very samples from four European nations, most of the variance was attributable to molecular methodology, and very little of the variance was accounted for by nationality. In addition, we showed that mixture of European subpopulations should result in only minor deviations from expected genotype proportions in a Caucasian database and demonstrated that there was no significant deviation from Hardy-Weinberg equilibrium in our HRAS1 data.

Alleles↗
PubMed1993

Physical properties of VNTR data, and their impact on a test of allelic independence.

In this article we describe the physical properties of VNTR data, as well as their effects on the two-dimensional distribution of fragment pairs. Tests of independence of alleles at a locus may confound those physical properties with allele independence. A recently proposed test by Geisser and Johnson is an example. We show that alleles can be strictly independent, yet the proposed test suggests large violations of allele independence because it is sensitive to well-known electrophoretic phenomena.

Alleles↗
PubMed1993

Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM).

Common, familial human disorders generally do not follow Mendelian inheritance patterns, presumably because multiple loci are involved in disease susceptibility. One approach to mapping genes for such traits in humans is to first study an analogous form in an animal model, such as mouse, by using inbred strains and backcross experiments. Here we describe methodology for analyzing multiple-locus linkage data from such experimental backcrosses, particularly in light of multilocus genetic models, including the effects of epistasis. We illustrate these methods by using data from backcrosses involving nonobese diabetic mouse, which serves as an animal model for human insulin-dependent diabetes mellitus. We show that it is likely that a minimum of nine loci contribute to susceptibility, with strong epistasis effects among these loci. Three of the loci actually confer a protective effect in the homozygote, compared with the heterozygote. Further, we discuss the relevance of these studies for analogous studies of the human form of the trait. Specifically, we show that the magnitude of the gene effect in the experimental backcross is likely to correlate only weakly, at best, with the expected magnitude of effect for a human form, because in humans the gene effect will depend more heavily on disease allele frequencies than on the observed penetrance ratios; such allele frequencies are unpredictable. Hence, the major benefit from animal studies may be a better understanding of the disease process itself, rather than identification of cells through comparison mapping in humans by using regions of homology.

Animals↗
PubMed1992

Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer.

This study examined risk factors for development of a contralateral breast cancer among 4,660 US women diagnosed with a first primary breast cancer between 1980 and 1982. The authors believe it to be the first prospective cohort study on this topic that has employed direct patient interviews. All subjects were interviewed within 6 months of the diagnosis of their initial tumor as part of the multi-center, population-based, case-control Cancer and Steroid Hormone Study, and they were followed until the end of 1986 through the Surveillance, Epidemiology, and End Results program. Exclusive of those diagnosed during the initial 6 months after diagnosis of a first primary, 136 second primary breast cancers were identified. Proportional hazards models were used to assess the independent effects of multiple predictors. Specific risk factors evaluated included: age at diagnosis of first primary, exposure to exogenous hormones, menstrual and reproductive histories, tumor characteristics, demographic variables, and treatment modalities. The age-specific incidence rates of second primary breast cancer were higher in all age categories than are the incidence rates of breast cancer in the general population, yet the age at diagnosis of first primary breast cancer was not an important predictor of contralateral breast cancer. The risk of contralateral breast cancer was increased among cohort members who reported a personal history of benign breast biopsy (multivariable-adjusted rate ratio (RR) = 1.69, 95% confidence interval (CI) 1.13-2.53) and in those with an initial tumor that was classified as lobular carcinoma (multivariable-adjusted RR = 1.96, 95% CI 1.17-3.27). Treatment with chemotherapy for the first primary was associated with a lower risk of development of a second breast cancer (multivariable-adjusted RR = 0.56, 95% CI 0.33-0.96), while radiation therapy had little effect on the risk (multivariable-adjusted RR = 1.19, 95% CI 0.78-1.80).

Adult↗
PubMed1992

The genetic epidemiology of second primary breast cancer.

It is well established that women with a family history of breast cancer run a higher risk of breast cancer than do women without a family history. The evidence, however, is less clear regarding a possible association between a family history of breast cancer and risk of second primaries. The purpose of this prospective study was to estimate the risk for second primary breast cancer associated with having a family history of breast, endometrial, and ovarian cancers. A cohort of 4,660 women with a first primary breast cancer diagnosed between 1980 and 1982 were interviewed as part of the Cancer and Steroid Hormone Study, a multi-center population-based case-control study, and followed through eight Surveillance, Epidemiology, and End Results (SEER) program registries for 4 to 6 years. Of these women, 136 developed a second primary breast cancer in the contralateral breast at least 6 months after diagnosis of the first primary. Cox proportional hazards modeling techniques were used to model the time to onset of second primary breast cancer while adjusting for multiple predictors. The risk of contralateral breast cancer was elevated among cohort members who reported a history of breast cancer in a first-degree relative (multivariable-adjusted rate ratio (RR) = 1.91, 95% confidence interval (CI) = 1.22-2.99). Early age at onset (< 46 years) in the relative further increased the risk of developing contralateral breast cancer (sister: multivariable-adjusted RR = 3.36, 95% CI 1.62-6.98; mother: multivariable-adjusted RR = 2.35, 95% CI 1.02-5.43). Bilateral breast cancer in mothers was also associated with more than a two and a half-fold increase in risk (multivariable-adjusted RR = 2.55, 95% CI 1.02-6.35). The association between family history of breast cancer and risk of contralateral breast cancer did not vary substantially according to age at onset of the first primary breast cancer. The age-adjusted rate ratio for development of a second primary breast cancer among women with a first-degree relative with endometrial cancer was 2.13 (95% CI 1.04-4.35), while the corresponding rate ratio among women with a family history of ovarian cancer was 1.69 (95% CI 0.42-6.83). There was little evidence that age at onset among the relatives with endometrial or ovarian cancer affected the risk. Some of these findings have not been previously reported and need replication in future studies.

Adult↗