Searching for susceptibility genes in schizophrenia by genetic linkage analysis.
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Chromosomes, Human, Pair 18↗
Biomedical subjects
N Risch
Publications and source records attributed to N Risch.
A comparison of linkage disequilibrium measures for fine-scale mapping.
Linkage mapping generally localizes disease genes to 1- to 2-cM regions of chromosomes. In theory, further refinement of location can be achieved by population-based studies of linkage disequilibrium between disease locus alleles and alleles at adjacent markers. One approach to localization, dubbed simple disequilibrium mapping, is to determine the relative location of the disease locus by plotting disequilibrium values against marker locations. We investigate the simple mapping properties of five disequilibrium measures, the correlation coefficient delta, Lewontin's D', the robust formulation of the population attributable risk delta, Yule's Q, and Kaplan and Weir's proportional difference d under the assumption of initial complete disequilibrium between disease and marker loci. The studies indicate that delta is a superior measure for fine mapping because it is directly related to the recombination fraction between the disease and the marker loci, and it is invariant when disease haplotypes are sampled at a rate higher than their population frequencies, as in a case-control study. D' yields results comparable to those of delta in many realistic settings. Of the remaining three measures, Q, delta, and d, Q yields the best results. From simulations of short-term evolution, all measures show some sensitivity to marker allele frequencies; however, as predicted by analytic results, Q, delta, and d exhibit the greatest sensitivity to variation in marker allele frequencies across loci.
Alleles↗
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↗
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↗
Use of sibling risk ratios and components of genetic variance in the characterization of a simulated oligogenic disease.
Sibling risk ratios are used to quantify the genetic effect of two simulated disease loci, identified through TDT and association methods and characterized via components of variance derived from a relative penetrance matrix. Inconsistencies between the data set and the simulating model are also discussed.
Alleles↗
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↗
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↗
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↗
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↗
Linkage and association studies in insulin-dependent diabetes with a new dinucleotide repeat polymorphism at the GAD65 locus.
Glutamic acid decarboxylase (GAD) is an important autoantigen in insulin-dependent diabetes mellitus (IDDM). The islet cell specific, 65 kDa form of GAD (GAD65) is encoded by a gene on chromosome 10p. Recently, a putative IDDM susceptibility gene has been localized to the same general region based on allele sharing for the anonymous marker D10S193. To determine whether variation in the GAD65 gene plays a role in genetic susceptibility to IDDM, possibly explaining the reported evidence for linkage on 10p, we isolated cosmid clones containing GAD65, and identified a highly polymorphic dinucleotide repeat physically linked to the gene. This GAD65 microsatellite marker, along with the other 10p markers D10S193 and D10S211, were used to genotype the members of 186 multiplex IDDM families with 2 or more affected siblings. Linkage analysis localized the GAD65 marker 5.6 cM from D10S193. Sharing of alleles identical by descent (IBD) in affected sib pairs for each of the markers was determined and compared to the expected 50:50 distribution under an assumption of no linkage. Analyses were also carried out after stratification of the data for sharing of HLA class.II alleles. The family data for GAD65 were further assessed for allelic association with IDDM using the transmission/disequilibrium test. No significant deviations from expected values were observed in any of these tests, suggesting that variation in the GAD65 gene does not play a significant role in genetic susceptibility to IDDM.
Alleles↗
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↗
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↗
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↗
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↗
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↗
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↗
Male sexual orientation and genetic evidence.
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Genetic Linkage↗
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↗