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J R DePaulo

Publications and source records attributed to J R DePaulo.

At least 19 recordsLinked to original sources
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

Full-genome scan for linkage in 50 families segregating the bipolar affective disease phenotype.

A genome scan of approximately 12-cM initial resolution was done on 50 of a set of 51 carefully ascertained unilineal multiplex families segregating the bipolar affective disorder phenotype. In addition to standard multipoint linkage analysis methods, a simultaneous-search algorithm was applied in an attempt to surmount the problem of genetic heterogeneity. The results revealed no linkage across the genome. The results exclude monogenic models and make it unlikely that two genes account for the disease in this sample. These results support the conclusion that at least several hundred kindreds will be required in order to establish linkage of susceptibility loci to bipolar disorder in heterogeneous populations.

Bipolar Disorder↗
PubMed1998

Integrating clinical and laboratory data in genetic studies of complex phenotypes: a network-based data management system.

The identification of genes underlying a complex phenotype can be a massive undertaking, and may require a much larger sample size than thought previously. The integration of such large volumes of clinical and laboratory data has become a major challenge. In this paper we describe a network-based data management system designed to address this challenge. Our system offers several advantages. Since the system uses commercial software, it obviates the acquisition, installation, and debugging of privately-available software, and is fully compatible with Windows and other commercial software. The system uses relational database architecture, which offers exceptional flexibility, facilitates complex data queries, and expedites extensive data quality control. The system is particularly designed to integrate clinical and laboratory data efficiently, producing summary reports, pedigrees, and exported files containing both phenotype and genotype data in a virtually unlimited range of formats. We describe a comprehensive system that manages clinical, DNA, cell line, and genotype data, but since the system is modular, researchers can set up only those elements which they need immediately, expanding later as needed.

Clinical Laboratory Information Systems↗
PubMed1998

Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data.

OBJECTIVE: The authors performed an analysis of their published chromosome 18 linkage data on 28 families in which there was bipolar disorder to test the potential of comorbid panic disorder to define a genetic subtype of bipolar disorder. METHOD: Families ascertained through probands with bipolar I disorder were stratified into three groups based on a history of panic disorder, panic attacks, or no panic attacks in the probands. Multipoint nonparametric linkage analysis was performed on data from bipolar I and II family members in each group. RESULTS: Linkage scores for five consecutive 18q marker loci were highest in the families of the probands with panic disorder and lowest for the families of the probands without panic attacks. CONCLUSIONS: This study supports the authors' previously reported clinical hypothesis of a genetic subtype of bipolar disorder identified by comorbid panic disorder. The hypothesis merits prospective testing.

Adult↗
PubMed1998

Pilot study on patients' and spouses' attitudes toward potential genetic testing for bipolar disorder.

OBJECTIVE: The purpose of this pilot study was to gain information about attitudes of individuals with bipolar disorder and their spouses toward some of the ethical and social issues arising from rapidly advancing genetic research on bipolar disorder. METHOD: Patients with bipolar disorder and their unaffected spouses were asked to answer questionnaires assessing their knowledge and attitudes about treatment response rates for bipolar disorder, probability of inheritance, genetic testing, disclosure of genetic information, abortion, marriage, and child-bearing. RESULTS: The overwhelming majority of the patients and spouses said that they would take advantage of genetic tests for bipolar disorder if such tests were to become available. Most patients and spouses agreed that the benefits of knowing whether one carries a gene for bipolar disorder would outweigh the risks. The decisive majority of respondents also felt that they would not abort a fetus that carried a gene for bipolar disorder. Furthermore, most patients and spouses agreed that the knowledge that one of them carried a gene for bipolar disorder would not have deterred them from marriage or childbearing. CONCLUSIONS: The results of this study suggest that most individuals believe that they would benefit from the use of genetic testing for bipolar disorder if it were to become available. Follow-up studies using a broader patient sample and nonclinical control groups would be useful in further evaluating the issues addressed in this pilot study.

Abortion, Eugenic↗
PubMed1998

Women with bipolar disorder: findings from the NIMH Genetics Initiative sample.

Bipolar I (BPI) mood disorder is a severe recurrent mental Illness with a population prevalence of 1 percent. Evidence is strong for genetic risk factors in onset. However, unlike unipolar mood disorders, in which women outnumber men by 2 to 1, for BPI disorder, the male:female ratio is equal. Perhaps for this reason, relatively little research has examined gender-related risks in BPI course. This article presents data from 186 BPI women and 141 BPI men ascertained as part of the NIMH Genetics Initiative, a multisite collaborative molecular genetic study. Subjects were interviewed using the Diagnostic Interview for Genetic Studies (DIGS). DIGS items included a medical history, and for women, questions concerning psychiatric disorders in relation to childbearing, the menstrual cycle, and menopause. Almost half of BPI women who had been pregnant reported having experienced severe emotional disturbances in relation to childbearing, with close to one-third reporting episode onset during pregnancy. Two-thirds of BPI women reported frequent premenstrual mood disturbances and almost 20 percent of postmenopausal BPI women reported severe emotional disturbances during the menopausal transition. More BPI women than men reported thyroid disorder and migraine headaches. Findings are discussed in relation to gender differences in population and other clinical samples, and in terms of their implications for the development of new treatments and preventive interventions.

Adult↗
PubMed1997

Quantitative analysis of leukocyte mitochondrial DNA deletion in affective disorders.

Mutations in mitochondrial DNA (mtDNA) are implicated in the pathophysiology of affective disorders. To determine whether the 4977-base-pair deletion in mtDNA is more frequent in affective disorders, we quantitated the concentration of this deletion in leukocyte mtDNA in 34 probands with affective disorders (20 bipolar and 14 unipolar) and 20 controls. We found no significant difference in the quantitative ratio of deletion to wild-type mtDNA between patients and controls. One patient with unipolar depression and 1 of 2 patients previously reported as having a large quantity of the deleted mtDNA did have a markedly high ratio; however, the deletion did not segregate with the disease in these two families. These results do not support a hypothesis that the 4977-base-pair deletion plays an important role in the pathophysiology of affective disorders.

Adult↗
PubMed1997

Panic disorder with familial bipolar disorder.

If bipolar disorder is genetically heterogeneous, it may be possible to discern clinically heterogeneous familial subtypes based on differential risk for psychiatric comorbidity, for example panic disorder. We evaluated 528 members of 57 families ascertained for a genetic linkage study of bipolar disorder. Families were assorted according to the panic disorder diagnosis of the bipolar proband; the rates of panic and other disorders in relatives were compared. Eighty-eight percent of the 41 subjects with panic disorder had bipolar disorder. Panic disorder was diagnosed in 18% of family members with bipolar disorder. Ten of 57 bipolar probands had panic disorder. Their bipolar first-degree relatives had a significantly higher prevalence of panic disorder, bipolar II, cyclothymia, and dysthymia, but had lower prevalence of substance abuse than the relatives of the bipolar probands without panic disorder. These findings suggest the testable hypothesis that comorbid panic disorder is a marker of genetic heterogeneity in bipolar disorder.

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↗
PubMed1997

Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 4, 7, 9, 18, 19, 20, and 21q.

An initial genome scan was performed on 540 individuals from 97 families segregating bipolar disorder, collected through the National Institutes of Mental Health Genetics Initiative. We report here affected-sib-pair (ASP) data on 126 marker loci (approximately 68,000 genotypes) mapping to chromosomes 4, 7, 9, 18, 19, 20, and 21q, under three affection status models. Modest increases in identical-by-descent (IBD) allele sharing were found at the following loci: D4S2397 and D4S391 (P < 0.05) on 4p, D4S1647 (P < 0.05) on 4q, D7S1802 and D7S1869 (low P = 0.01) on 7p, D9S302 (P = 0.004) on 9q, and D20S604 on 20p and D20S173 on 20q (P < 0.05). In addition, five markers on 7q displayed increased IBD sharing (P = 0.046-0.002). Additional ASP analyses on chromosomes 18 and 21q marker data were performed using disease phenotype models defined previously. On chromosome 18, only D18S40 on 18p and D18S70 on 18q yielded a slight elevation in allele sharing (P = 0.02), implying that the reported linkages in these regions were not confirmed. On chromosome 21q, a cluster of markers within an approximately 9 cM interval: D21S1254, D21S65, D21S1440, and D21S1255 exhibited excess allele sharing (P = 0.041-0.008). Multilocus data on overlapping marker quartets, from D21S1265 to D21S1255, which were consistent with increased IBD sharing (P < 0.01, with a low of 0.0009), overlapped a broad interval of excess allele sharing reported previously, increasing support for a susceptibility locus for bipolar disorder on 21q.

Alleles↗
PubMed1997

Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 3, 5, 15, 16, 17, and 22.

As part of the four-center NIMH Genetics Initiative on Bipolar Disorder we carried out a genomic scan of chromosomes 3, 5, 15, 16,17, and 22. Genotyping was performed on a set of 540 DNAs from 97 families, enriched for affected relative pairs and parents where available. We report here the results of the initial 74 markers that have been typed on this set of DNAs. The average distance between markers (theta) was 12.3 cM. Nonparametric analysis of excess allele sharing among affected sibling pairs used the SIBPAL program of the S.A.G.E. package to test three hierarchical models of affected status. D16S2619 gave some evidence of linkage to bipolar disorder, with P = 0.006 for Model II (in which bipolar 1, bipolar 2 and schizoaffective-bipolar type individuals are considered affected). Nearby markers also showed increased allele sharing. A second interesting region was toward the telomere of chromosome 5q, where D5S1456 and nearby markers showed increased allele sharing; for D5S1456, P = 0.05, 0.015 and 0.008 as the models of affected status become more broad. MOD score analysis also supported the possible presence of a susceptibility locus in this region of chromosome 5. A pair of adjacent markers on chromosome 3, D3S2405 and D3S3038, showed a modest increased allele sharing in the broad model. Several isolated markers had excess allele sharing at the P < 0.05 level under a single model. D15S217 showed a MOD score of 2.37 (P < 0.025). Multipoint analysis flagged the region of chromosome 22 around D22S533 as the most interesting. Thus, several regions showed modest evidence for linkage to bipolar disorder in this initial genomic scan of these chromosomes, including broad regions near previous reports of possible linkage.

Alleles↗
PubMed1997

Initial genome screen for bipolar disorder in the NIMH genetics initiative pedigrees: chromosomes 2, 11, 13, 14, and X.

We report on an initial genome screen of 540 individuals from 97 families collected as part of the NIMH Genetics Initiative Bipolar Group. Among the individuals studied, 232 were diagnosed with bipolar (BP) I, 72 with BPII, 88 with major depressive disorder-recurrent type (UPR), and 32 with schizoaffective disorder, bipolar type (SA/BP). A total of 53 markers on chromosomes 2, 11, 13, 14, and X (average spacing: 11.5 cM) were studied at Johns Hopkins University. Tests for linkage were performed using nonparametric affected sib-pair and whole pedigree methods with three definitions of affected status. Three regions of interest were identified (13q14-32, Xp22, and Xq26-28). On chromosomes 2, 11, and 14, a disease locus with relative risk lambda(i) = 1.5 could be excluded in <10% of the genetic distance studied, while a locus conferring lambda(i) = 3 or greater could be excluded across at least 96%. The autosomal region that could not be excluded even with lambda(i) = 5 was near 13q14-32. In this region, two-point affected sib-pair analyses revealed a pair of consecutive loci with excess sharing (P < 0.05) and a multipoint affected sib-pair LOD score of 1.12. On the X chromosome, nonparametric multipoint affected sib-pair analyses revealed peak total LOD scores of 0.94 on Xp22 and 1.34 on Xq26-28. A locus linked to the markers in Xp22 would have lambda(i) = 3.6 in affected brother-brother pairs, while a locus linked to the markers in Xq26-28 would have lambda(i) > 1.9 in affected sister-sister pairs. The results on 13q14-32, Xp22, and Xq26-28 suggest areas of interest for further studies.

Bipolar Disorder↗
PubMed1997

Linkage of bipolar affective disorder to chromosome 18 markers in a new pedigree series.

Several groups have reported evidence suggesting linkage of bipolar affective disorder (BPAD) to chromosome 18. We have reported data from 28 pedigrees that showed linkage to marker loci on 18p and to loci 40 cM distant on 18q. Most of the linkage evidence derived from families with affected phenotypes in only the paternal lineage and from marker alleles transmitted on the paternal chromosome. We now report results from a series of 30 new pedigrees (259 individuals) genotyped for 13 polymorphic markers spanning chromosome 18. Subjects were interviewed by a psychiatrist and were diagnosed by highly reliable methods. Genotypes were generated with automated technology and were scored blind to phenotype. Affected sib pairs showed excess allele sharing at the 18q markers D18S541 and D18S38. A parent-of-origin effect was observed, but it was not consistently paternal. No robust evidence of linkage was detected for markers elsewhere on chromosome 18. Multipoint nonparametric linkage analysis in the new sample combined with the original sample of families supports linkage on chromosome 18q, but the susceptibility gene is not well localized.

Baltimore↗
PubMed1997

A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1.

There are currently 13 diseases known to be caused by unstable triplet repeat mutations; however, there are some instances (as with FRAXF and FRA16) when these mutations appear to be asymptomatic. In a search for polymorphic CTG repeats as candidate genes for bipolar disorder, we screened a genomic human chromosome 18-specific library and identified a 1.6 kb clone (7,6A) with a CTG24 repeat that maps to 18q21.1. The CTG repeat locus, termed CTG18.1, is located within an intron of human SEF2-1, a gene encoding a basic hellx-loop-hellx DNA binding protein involved in transcriptional regulation. The CTGn repeat is highly polymorphic and very enlarged alleles, consistent with expansions of up to CTG2100, were identified. PCR and Southern blot analysis in pedigrees ascertained for a Johns Hopkins University bipolar disorder linkage study and in CEPH reference pedigrees revealed a tripartite distribution of CTG18.1 alleles with stable alleles (CTG10-CTG37), moderately enlarged and unstable alleles (CTG53-CTG250), and very enlarged, unstable alleles (CTG800-CTG2100). Moderately enlarged alleles were not associated with an abnormal phenotype and have a combined enlarged allele frequency of 3% in the CEPH and bipolar populations. Very enlarged alleles, detectable only by Southern blot analysis of genomic digests, have thus far been found in only three individuals from our bipolar pedigrees, and to date, have not been found in any of the CEPH reference pedigrees. These enlarged alleles may arise, at least in part, via somatic mutation.

Alleles↗
PubMed1997

Genetics of manic depressive illness.

Manic depressive illness is a common and frequently debilitating familial psychiatric disorder. Efforts to understand the mechanisms of inheritance have been hindered by the complexity of the phenotype, which may range from benign mood swings to chronic psychosis, and by apparently nonmendelian modes of transmission. Early reports of linkage to chromosomal loci have fallen into doubt; however they have helped encourage the development of more sophisticated methods for analyzing complex phenotypes. Using such methods, linkage of manic depressive illness to loci on chromosome 18 has been reported and apparently replicated, and work is proceeding to identify genes associated with what is probably a genetically heterogeneous set of disorders. As molecular mechanisms of inheritance are elucidated, it will be important to consider the ethical implications of genetic testing in a clinically and genetically complex disorder such as manic depressive illness.

Bipolar Disorder↗
PubMed1996

Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies.

The dominant, contemporary paradigm for developing and refining diagnoses relies heavily on assessing reliability with kappa coefficients and virtually ignores a core component of psychometric practice: the theory of latent structures. This article describes a psychometric approach to psychiatric nosology that emphasizes the diagnostic accuracy and confusability of diagnostic categories. We apply these methods to the Diagnostic Interview for Genetic Studies (DIGS), a structured psychiatric interview designed by the NIMH Genetics Initiative for genetic studies of schizophrenia and bipolar disorder. Our results show that sensitivity and specificity were excellent for both DSM-III-R and RDC diagnoses of major depression, bipolar disorder, and schizophrenia. In contrast, diagnostic accuracy was substantially lower for subtypes of schizoaffective disorder-especially for the DSM-III-R definitions. Both the bipolar and depressed subtypes of DSM-III-R schizoaffective disorder had excellent specificity but poor sensitivity. The RDC definitions also had excellent specificity but were more sensitive than the DSM-III-R schizoaffective diagnoses. The source of low sensitivity for schizoaffective subtypes differed for the two diagnostic systems. For RDC criteria, the schizoaffective subtypes were frequently confused with one another; they were less frequently confused with other diagnoses. In contrast, the DSM-III-R subtypes were often confused with schizophrenia, but not with each other.

Bipolar Disorder↗