A genome-wide scan of symptom dimensions in bipolar disorder pedigrees of adult probands (original) (raw)
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Familiality of temperament in bipolar disorder: support for a genetic spectrum
Journal of Affective Disorders, 2005
Background: The array of different diagnoses and clinical presentations seen in the family members of bipolar probands suggests a quantitative or spectrum phenotype. Consistent with this idea, it has been proposed that an underlying quantitative variation in temperament may be the primary phenotype that is genetically transmitted and that it in turn predisposes to bipolar disorder (BP). Choosing the appropriate phenotypic model for BP is crucial for success in genetic mapping studies. To test this theory, various measures of temperament were examined in the family members of bipolar probands. We predicted that a gradient of scores would be observed from those with BP to those with major depression to Unaffected relatives to controls. Methods: Members of 85 bipolar families and 63 control subjects were administered clinical interviews for diagnosis (SCID) and two temperament assessments, the TEMPS-A and TCI-125. Subjects with BP, major depressive disorder. unaffected relatives, and controls were compared on each temperament scale and on eight factors extracted from a joint factor analysis of the TEMPS-A and TCI-125. Results: The four groups were found to be significantly different and with the expected order of average group scores for four of the TEMPS-A scales, three of the TCI-125 scales, and eScholarship provides open access, scholarly publishing services to the University of California and delivers a dynamic research platform to scholars worldwide. one of the extracted factors. On the fifth TEMPS-A scale, hyperthymic, controls scored higher than the other three subject groups contrary to expectations. Significant differences were seen between unaffected relatives and controls on the hyperthymic scale and on the first extracted factor, anxious/reactive. Limitations: Controls were mainly recruited through advertisements, which may have introduced an ascertainment bias. It is also possible that mood state at the time of completing the questionnaire influenced subject's rating of their temperament. Additionally, bipolar I and bipolar II subjects were placed in the same group even though they had some differing clinical features. Conclusions: Our data support the theory that some dimensions of temperament are transmitted in families as quantitative traits that are part of a broader bipolar spectrum. In particular, the hyperthymic scale of the TEMPS-A and the anxious/reactive extracted factor distinguished unaffected relatives from controls. The hyperthymic scale yielded results opposite to expectation with controls higher than any family group. This may be an artifact of the self-rated form of the questionnaire, a consequence of our grouping bipolar I and II subjects together, or the result of a "protective" factor and bears further study. Nevertheless, both of these scales may be useful quantitative traits for genetic mapping studies. (c)
Bipolar Disorders, 2004
Epidemiologic studies have demonstrated that bipolar disorder (BPD) is substantially heritable. Concordance of BPD for monozygotic twins is between 0.67 and 0.85, more than three times greater than the concordance for dizygotic twins or siblings (1, 2). Family studies employing currently accepted diagnostic criteria have repeatedly demonstrated a 10-to 20-fold increase in risk for BPD among first-degree relatives of index cases when compared with relatives of controls (3-5). Adoption studies have further indicated that increased familial aggregation is not simply the result of environmental factors (6, 7). Despite the substantial evidence that risk for BPD is inherited, the disorder's genetic basis remains elusive. The search for the genetic loci Glahn DC, Bearden CE, Niendam TA, Escamilla MA. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder.
Bipolar disorder: from families to genes
Canadian journal of psychiatry. Revue canadienne de psychiatrie, 1997
Genetic factors are known to contribute to the etiology of bipolar illness, but the actual genetic mechanisms remain to be clarified. This paper reviews the research undertaken to establish the genetic basis of bipolar illness and to elucidate the nature of its genetic predisposition. The presented findings suggest that bipolar affective disorder is a heterogeneous condition characterized by a complex relationship between the genetic susceptibility and the clinical presentation. Linkage studies have generated promising and replicated findings on chromosomes 18 and 21. In spite of the methodological difficulties inherent in the genetic study of psychiatric disorders recent investigations have made important advances and promise to identify specific susceptibility genes.
Heritability and genome-wide SNP linkage analysis of temperament in bipolar disorder
Journal of Affective Disorders, 2013
Background: The many attempts to identify genes for bipolar disorder (BD) have met with limited success, which has generally been attributed to genetic heterogeneity and small gene effects. However, it is also possible that the categorical phenotypes used in genetic studies of BD are not the most informative or biologically relevant. We have explored aspects of temperament as quantitative phenotypes for BD through the use of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A), which is designed to assess lifelong, milder aspects of bipolar symptomatology and defines five temperaments: hyperthymic, dysthymic, cyclothymic, irritable, and anxious. Methods: We compared temperament scores between diagnostic groups and assessed heritability in a sample of 101 families collected for genetic studies of BD. A genome-wide SNP linkage study was then performed in the subset of 51 families for which genetic data was available. Results: Significant group differences were observed between BD subjects, their first-degree relatives, and independent controls, and all five temperaments were found to be significantly heritable, with heritabilities ranging from 21% for the hyperthymic to 52% for the irritable temperaments. Suggestive evidence for linkage was observed for the hyperthymic (chromosomes 1q44, 2p16, 6q16, and 14q23), dysthymic (chromosomes 3p21 and 13q34), and irritable (chromosome 6q24) temperaments. Limitations: The relatively small size of our linkage sample likely limited our ability to reach genomewide significance in this study. Conclusions: While not genome-wide significant, these results suggest that aspects of temperament may prove useful in the identification of genes underlying BD susceptibility.
The Bipolar Disorder Phenome Database: A Resource for Genetic Studies
American Journal of Psychiatry, 2007
The purpose of this study was to assemble and validate a database of phenotypic variables that were collected from families with bipolar disorder as a resource for genetic and other biological studies. Method: Participants were ascertained for two bipolar disorder genetic linkage studies: the University of Chicago, Johns Hopkins, and National Institute of Mental Health (NIMH) Intramural Program (CHIP) Collaboration and the NIMH Genetics Initiative project. All participants underwent detailed, phenotypic assessment with either the Schedule for Affective Disorders and Schizophrenia-Lifetime Version or one of four versions of the Diagnostic Interview for Genetic Studies. Clinicians reviewed the interview items and derived variable definitions that were used to extract data from the original datasets. The combined data were subjected to range and logic assessments, and a subset was re-verified against the original data. Inconsistent data and variables that were deemed unreliable were excluded. Several of the resulting variables were characterized in the total cohort and tested for familial clustering, heritability, and statistical power in genetic linkage and association studies. Results: The combined database of phenotypic variables contained 197 variables on 5,721 subjects in 1,177 families. Deoxyribonucleic acid (DNA) samples are available for 5,373 of these subjects. The clinical presentation of bipolar disorder varied markedly. Most subjects suffered from serious and often disabling illness. Many phenotypic variables are strongly familial, and some quantitative variables are highly heritable. The cohort assembled in this study offers substantial power to carry out genetic linkage and association studies that use specific clinical features as covariates or as primary phenotypes. Conclusions: This is the largest database of phenotypic variables yet assembled for bipolar disorder, and it is now available to the research community. Researchers and clinicians can use this database to explore the connections between phenomenology and genetics in a cohort that is adequately powered to detect even modest genetic effects in bipolar disorder.
Bipolar manic-depressive psychoses: Results of a genetic investigation
Human Genetics, 1980
Ninety-five patients with bipolar manicdepressive disorders were followed from 1959 to 1975, and their first-degree relatives (N=617) were studied. In the search for heterogeneity of bipolar illness the patients were subclassified according to various criteria: sex, age at onset, number of episodes, and longitudinal syndrome subtypes (Dm, MD, Md), and the genetic findings were used as an external criterion. The first-degree relatives of female probands showed a higher morbidity risk for psychiatric disorders than the relatives of male probands, and the highest morbidity risk was found in the female relatives of female probands. Early onset and late-onset patients did not differ from a genetic point of view. Patients with ten episodes or more showed slightly higher family morbidity than those with less than ten episodes. The three subtypes of bipolar disorders preponderantly depressed (Dm), nuclear type (MD), and preponderantly manic (Md), showed significant genetic differences. The families of type Dm had the highest morbidity, and families of type Md, the lowest! The type MD took an intermediate position. The results are surprising and not compatible with current hypotheses of multifactorial heredity assuming a continuum from depression to mania with distinct thresholds for the manifestation of unipolar depression, bipolar psychosis, and pure mania. The findings also do not suggest the existence of a drug-induced hypomania. Father-son transmission was frequent, and this fact excludes a substantial amount of X-chromosomal inheritance. Parents, siblings, and children exhibited roughly the same morbidity risk. If a proband had an affected parent, the morbidity risk for his siblings and children was nearly twice as high as without such a parent (38% vs 21%). The analysis of the intrafamilial distribution of diagnoses supported the assumption that “neurotic depression” belongs to the true spectrum of affective psychoses.
The current status and prospects for genetic studies of bipolar disorder
Clinical Neuroscience Research, 2001
Family, twin, and adoption studies provide strong evidence for a genetic etiology in bipolar disorder (BPD). Early studies seeking to locate genes reported statistical evidence for linkage of BPD to DNA markers at several chromosomal sites. The earliest of these have not proven robust while several more powerful genome scans have had largely negative ®ndings. Recurring, suggestively positive linkage ®ndings on chromosomes 4p, 12q, 18p, 18q, and 21q have emerged as attractive candidate regions for further study. However, it is clear now that single gene forms of BPD, if they exist, must be uncommon. Clinical strategies for increasing the power of linkage and association studies include: