Biomedical subjects

J P Rice

Publications and source records attributed to J P Rice.

At least 19 recordsLinked to original sources

PubMed2001

Definition of the phenotype.

Definition of the phenotype is a key issue in designing any genetic study whose goal is to detect disease genes. This chapter describes strategies to increase the power to detect susceptibility loci for complex diseases. A narrowly defined disease phenotype can offer advantages over broad definitions. Studies of clinical disease can also benefit from judicious selection of endophenotypes and related quantitative traits for analysis. The effect of diagnostic and measurement error is also discussed; power is maximized when strategies to reduce error are incorporated into a study design.

Alleles↗

PubMed2001

The lod score method.

The lod score method originated in a seminal article by Newton Morton in 1955. The method is broadly concerned with issues of power and the posterior probability of linkage, ensuring that a reported linkage has a high probability of being a true linkage. In addition, the method is sequential, so that pedigrees or lod curves may be combined from published reports to pool data for analysis. This approach has been remarkably successful for 50 years in identifying disease genes for Mendelian disorders. After discussing these issues, we consider the situation for complex disorders, where the maximum lod score (MLS) statistic shares some of the advantages of the traditional lod score approach but is limited by unknown power and the lack of sharing of the primary data needed to optimally combine analytic results. We may still learn from the lod score method as we explore new methods in molecular biology and genetic analysis to utilize the complete human DNA sequence and the cataloging of all human genes.

Genetic Linkage↗

PubMed2000

Genetics of event-related brain potentials in response to a semantic priming paradigm in families with a history of alcoholism.

Event-related brain potentials (ERPs) are altered in patients with a variety of psychiatric disorders and may represent quantitative correlates of disease liability that are more amenable to genetic analysis than disease status itself. Results of a genomewide linkage screen are presented for amplitude of the N4 and P3 components of the ERP, measured at 19 scalp locations in response to a semantic priming task for 604 individuals in 100 pedigrees ascertained as part of the Collaborative Study on the Genetics of Alcoholism. N4 and P3 amplitudes in response to three stimuli (nonwords, primed words [i.e., antonyms], and unprimed words) all showed significant heritabilities, the highest being.54. Both N4 and P3 showed significant genetic correlations across stimulus type at a given lead and across leads within a stimulus, indicating shared genetic influences among the traits. There were also substantial genetic correlations between the N4 and P3 amplitudes for a given lead, even across stimulus type. N4 amplitudes showed suggestive evidence of linkage in several chromosomal regions, and P3 amplitudes showed significant evidence of linkage to chromosome 5 and suggestive evidence of linkage to chromosome 4.

Alcoholism↗

PubMed2000

A genome screen of maximum number of drinks as an alcoholism phenotype.

The Collaborative Study on the Genetics of Alcoholism (COGA) is a multicenter research program to detect and map susceptibility genes for alcohol dependence and related phenotypes. The measure M of "maximum number of drinks consumed in a 24-hour period" is closely related to alcoholism diagnosis in this dataset and provides a quantitative measure to grade nonalcoholic individuals. Twin studies have shown log(M) to have a heritability of approximately 50%. Genome screens for this trait were performed in two distinct genotyped samples (wave 1 and wave 2), and in the combined sample. MAPMAKER/SIBS was used to carry out Haseman-Elston based regression analyses. On chromosome 4, an unweighted all-pairs multipoint LOD of 2.2 was obtained between D4S2407 and D4S1628 in wave 1; in wave 2, the region flanked by D4S2404 and D4S2407 gave a LOD of 1.5. In the combined sample, the maximal LOD was 3.5 very close to D4S2407. This evidence for linkage is in the region of the alcohol dehydrogenase gene cluster on chromosome 4. These findings on chromosome 4 are consistent with a prior report from COGA in which strictly defined nonalcoholic subjects in wave 1 were analyzed. The present analysis on log(M) allows more individuals to be included and thus is potentially more powerful.

Alcohol Drinking↗

PubMed2000

Family-based study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking.

A recent study showed an association between the dopamine D2 receptor gene (DRD2) and smoking. The purpose of this study was to determine if the familial transmission of smoking is linked to variation at the DRD2 locus in a genetically informative sample. Subjects were identified in alcohol treatment centers and their relatives were recruited for study. All subjects were interviewed to assess alcohol dependence, smoking habits, and psychiatric disorders. Two polymorphisms within the DRD2 gene were analyzed, including the TaqIA polymorphism. The sample consisted of 138 nuclear families with at least one offspring with habitual smoking, and analysis was by the transmission disequilibrium test (TDT), which avoids problems due to population stratification. There was no significant difference in the frequency between DRD2 alleles transmitted and not transmitted to habitual smokers. There also was no evidence for unequal transmission of DRD2 alleles for the phenotypes "ever smoker" or comorbid alcohol dependence and habitual smoking. This study does not support linkage of the DRD2 with smoking.

Chromosome Mapping↗

PubMed2000

Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees.

As part of a four-center NIMH Genetics Initiative on Bipolar Disorder, a genome screen using 365 markers was performed on 540 DNAs from 97 families, enriched for affected relative pairs. This is the largest uniformly ascertained and assessed linkage sample for this disease, and includes 232 subjects diagnosed with bipolar I (BPI), 32 with schizo-affective, bipolar type (SABP), 72 with bipolar II (BPII), and 88 with unipolar recurrent depression (UPR). A hierarchical set of definitions of affected status was examined. Under Model I, affected individuals were those with a diagnosis of BPI or SABP, Model II included as affected those fitting Model I plus BPII, and Model III included those fitting Model II plus UPR. This data set was previously analyzed using primarily affected sib pair methods. We report the results of nonparametric linkage analyses of the extended pedigree structure using the program Genehunter Plus. The strongest finding was a lod score of 2.5 obtained on chromosome 10 near the marker D10S1423 with diagnosis as defined under Model II. This region has been previously implicated in genome-wide studies of schizophrenia and bipolar disorder. Other chromosomal regions with lod scores over 1.50 for at least one Model Included chromosomes 8 (Model III), 16 (Model III), and 20 (Model I). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:18-23, 2000

Bipolar Disorder↗

PubMed2000

Psychosocial disability during the long-term course of unipolar major depressive disorder.

BACKGROUND: The goal of this study was to investigate psychosocial disability in relation to depressive symptom severity during the long-term course of unipolar major depressive disorder (MDD). METHODS: Monthly ratings of impairment in major life functions and social relationships were obtained during an average of 10 years' systematic follow-up of 371 patients with unipolar MDD in the National Institute of Mental Health Collaborative Depression Study. Random regression models were used to examine variations in psychosocial functioning associated with 3 levels of depressive symptom severity and the asymptomatic status. RESULTS: A progressive gradient of psychosocial impairment was associated with a parallel gradient in the level of depressive symptom severity, which ranges from asymptomatic to subthreshold depressive symptoms to symptoms at the minor depression/dysthymia level to symptoms at the MDD level. Significant increases in disability occurred with each stepwise increment in depressive symptom severity. CONCLUSIONS: During the long-term course, disability is pervasive and chronic but disappears when patients become asymptomatic. Depressive symptoms at levels of subthreshold depressive symptoms, minor depression/ dysthymia, and MDD represent a continuum of depressive symptom severity in unipolar MDD, each level of which is associated with a significant stepwise increment in psychosocial disability.

Adaptation, Psychological↗

PubMed2000

Clustering methods applied to allele sharing data.

Here we focus on using clustering methods to disentangle the interacting factors that lead to the presentation of complex diseases. Relative pairs are placed in discrete subgroups, or classes, based upon their pattern of allele sharing at a sequence of markers and on concomitant risk factors. The relationship between the locus information and the affectation status of the relative pairs within each subgroup then can be assessed. Cluster analysis (CLA) and latent class analysis (LCA) were applied to sibling allele sharing data from GAW11 simulated data, and to an existing Alzheimer's disease (AD) dataset. Both methods were able to identify markers linked to all 3 disease loci in the GAW11 data. LCA and CLA also replicated regions of chromosomes identified in an analysis of the AD data using affected-sib-pair methods. These analyses indicate that classification tools may be useful for detecting susceptibility genes for complex traits.

Aged↗

PubMed2000

Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28.

Linkage disequilibrium (LD), or the non-random association of alleles, is poorly understood in the human genome. Population genetic theory suggests that LD is determined by the age of the markers, population history, recombination rate, selection and genetic drift. Despite the uncertainties in determining the relative contributions of these factors, some groups have argued that LD is a simple function of distance between markers. Disease-gene mapping studies and a simulation study gave differing predictions on the degree of LD in isolated and general populations. In view of the discrepancies between theory and experimental observations, we constructed a high-density SNP map of the Xq25-Xq28 region and analysed the male genotypes and haplotypes across this region for LD in three populations. The populations included an outbred European sample (CEPH males) and isolated population samples from Finland and Sardinia. We found two extended regions of strong LD bracketed by regions with no evidence for LD in all three samples. Haplotype analysis showed a paucity of haplotypes in regions of strong LD. Our results suggest that, in this region of the X chromosome, LD is not a monotonic function of the distance between markers, but is more a property of the particular location in the human genome.

Finland↗

PubMed1999

Genome screen for platelet monoamine oxidase (MAO) activity.

To identify loci involved in the control of platelet monoamine oxidase B (MAO-B) activity, a genomewide linkage screen was performed using 291 markers in 148 nuclear families containing a total of 1,008 nonindependent sib-pairs. Participants were genotyped and their platelet MAO-B activity levels were measured as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Sib-pair analysis using Haseman-Elston regression was carried out with two programs. Two-point analysis on all pairs with SIBPAL indicated three markers with p-values below 0.01: D6S1018 (p = 0.0004), D2S1328 (p = 0.008), and D2S408 (p = 0.003). MAPMAKER/SIBS multipoint analyses using independent pairs(N = 409) gave maximal lod scores of 2. 0 on chromosome 6 and 1.1 and 1.4 for the two regions on chromosome 2. These results are consistent with linkage, but do not provide definitive evidence. We are currently creating a denser map in these regions and have begun genotyping a second sample in COGA.

Blood Platelets↗

PubMed1999

Covariates in linkage analysis.

We apply a novel technique to detect significant covariates in linkage analysis using a logistic regression approach. An overall test of linkage is first performed to determine whether there is significant perturbation from the expected 50% sharing under the hypothesis of no linkage; if the overall test is significant, the importance of the individual covariate is assessed. In addition, association analyses were performed. These methods were applied to simulated data from multiple populations, and detected correct marker linkages and associations. No population heterogeneity was detected. These methods have the advantages of using all sib pairs and of providing a formal test for heterogeneity across populations.

Genetic Linkage↗

PubMed1999

Mapping genotype to phenotype for linkage analysis.

We model functions that use genetic information as input and trait information as output to understand genetic linkage in complex diseases. Using simulated data from GAW11, we have applied categorical classification methods and neural network analysis. We use sharing at selected markers as input, and the classification of the sib pair (for example, affected-affected or affected-unaffected) as output. In addition, our methods include environmental risk factors as predictors of phenotype. Categorical and neural network methods each led to results consistent with findings from other methods such as the logistic regression method of Rice et al. [this issue]. Post-analysis comparison with the GAW11 answers showed that these methods are capable of detecting correct signals in a single replicate. One advantage of our methods is that they allow analysis of the entire genome at once, so that interactions among multiple trait-influencing loci may be detected. Furthermore, these methods can use a variety of sib pairs rather than affected pairs only.

Chromosome Mapping↗

PubMed1998

Familial neuronal intranuclear inclusion disease with ubiquitin positive inclusions.

Female monozygotic twins developed upper and lower limb neurogenic weakness in their thirties, followed by cerebellar ataxia, dysarthria and death after an illness duration of about 20 years. Autopsy revealed pathological features typical of neuronal intranuclear inclusion disease (NIID) and positive ubiquitin immunostaining of the inclusions. Two adult sons of one of the twins have now developed an identical illness. This family provides strong evidence of an hereditary form of NIID.

Adult↗

PubMed1998

Anxiety proneness linked to epistatic loci in genome scan of human personality traits.

A genome-wide scan between normal human personality traits and a set of genetic markers at an average interval of 13 centimorgans was carried out in 758 pairs of siblings in 177 nuclear families of alcoholics. Personality traits were measured by the Tridimensional Personality Questionnaire. We detected significant linkage between the trait Harm Avoidance, a measure of anxiety proneness, and a locus on chromosome 8p21-23 that explained 38% of the trait variance. There was significant evidence of epistasis between the locus on 8p and others on chromosomes 18p, 20p, and 21q. These oligogenic interactions explained most of the variance in Harm Avoidance. There was suggestive evidence of epistasis in other personality traits. These results confirm the important influence of epistasis on human personality suggested by twin and adoption studies.

Anxiety↗

PubMed1998

Genome-wide search for genes affecting the risk for alcohol dependence.

Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3-8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50-60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. Multipoint methods provided the strongest suggestions of linkage with susceptibility loci for alcohol dependence on chromosomes 1 and 7, and more modest evidence for a locus on chromosome 2. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.

Adolescent↗

PubMed1998

Quantitative trait loci analysis of human event-related brain potentials: P3 voltage.

The P3 event-related brain potential (ERP) is a positive-going voltage change of scalp-recorded electroencephalographic activity that occurs between 300-500 ms after stimulus onset. It is elicited when a stimulus is perceived, memory operations are engaged, and attentional resources are allocated toward its processing. Because this ERP component reflects fundamental cognitive processing, it has found wide utility as an assessment of human mental function in basic and clinical studies. In particular, P3 attributes are heritable and have demonstrated considerable promise as a means to identify individuals at genetic risk for alcoholism. We have conducted a quantitative linkage analysis on a large sample from families with a high density of affected individuals. The analyses suggest that several regions of the human genome contain genetic loci related to the generation of the P3 component of the ERP, which are possible candidate loci underlying the functional organization of human neuroelectric activity.

Alcoholism↗

PubMed1998

A family-based analysis of whether the functional promoter alleles of the serotonin transporter gene HTT affect the risk for alcohol dependence.

A population association between a regulatory variation in the promoter of the serotonin transporter gene (HTT) and severe alcohol dependence was recently reported. We analyzed this potential association in a large number of systematically ascertained families in the United States; these families had at least three first-degree relatives who were alcohol-dependent. Analyses focused on individuals defined as alcohol-dependent by criteria from ICD-10 and on subsets of these individuals reporting withdrawal-related symptoms. Application of the transmission disequilibrium test did not provide support for either linkage or association between this functional polymorphism and alcohol dependence; there was no significant bias in the transmission of either allele to the alcohol-dependent offspring. We also report that African Americans differ from Caucasians in allele frequencies for this polymorphism.

Adult↗

PubMed1997

Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12.

A report on an initial genome screen on 540 individuals in 97 families was collected as part of the NIMH Genetics Initiative on Bipolar Disorder. Families were ascertained to be informative for genetic linkage and underwent a common ascertainment and assessment protocol at four clinical sites. The sample was genotyped for 65 highly polymorphic markers from chromosomes 1, 6, 8, 10, and 12. The average intermarker interval was 16 cM. Genotypic data was analyzed using affected sib pair, multipoint affected sib pair, and pedigree analysis methods. Multipoint methods gave lod scores of approximately two on chromosomes 1, 6, and 10. The peak lod score on chromosome 6 occurred at the end of the q-arm, at some distance from the 6p24-22 area previously implicated for schizophrenia. We are currently genotyping additional markers to reduce the intermarker interval around the signals. The interpretation of results from a genome screen of a complex disorder and the problem of achieving a balance between detecting false positive results and the ability to detect genes of modest effect are discussed.

Bipolar Disorder↗