Association study of Wnt signaling pathway genes in bipolar disorder.

CONTEXT: The Wnt signaling pathways promote cell growth and are best known for their role in embryogenesis and cancer. Several lines of evidence suggest that these pathways might also be involved in bipolar disorder. OBJECTIVE: To test for an association between candidate genes in the Wnt signaling pathways and disease susceptibility in a family-based bipolar disorder study. DESIGN: Two hundred twenty-seven tagging single- nucleotide polymorphisms (SNPs) from 34 genes were successfully genotyped. Initial results led us to focus on the gene PPARD, in which we genotyped an additional 13 SNPs for follow-up. SETTING: Nine academic medical centers in the United States. PARTICIPANTS: Five hundred fifty-four offspring with bipolar disorder and their parents from 317 families. MAIN OUTCOME MEASURES: Family-based association using FBAT and HBAT (http://www.biostat.harvard.edu/~fbat/default.html; Harvard School of Public Health, Boston, Massachusetts). Exploratory analyses testing for interactions of PPARD SNPs with clinical covariates and with other Wnt genes were conducted with GENASSOC (Stata Corp, College Station, Texas). RESULTS: In the initial analysis, the most significantly associated SNP was rs2267665 in PPARD (nominal P < .001). This remained significant at P = .05 by permutation after accounting for all SNPs tested. Additional genotyping in PPARD yielded 4 SNPs in 1 haplotype block that were significantly associated with bipolar disorder (P < .01), the most significant being rs9462082 (P < .001). Exploratory analyses revealed significant evidence (P < .01) for interactions of rs9462082 with poor functioning on the Global Assessment Scale (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.85-6.08) and with SNPs in WNT2B (rs3790606: OR, 2.56; 95% CI, 1.67-4.00) and WNT7A (rs4685048: OR, 1.79; 95% CI, 1.23-2.63). CONCLUSIONS: We found evidence for association of bipolar disorder with PPARD, a gene in the Wnt signaling pathway. The consistency of this result with one from the Wellcome Trust Case-Control Consortium encourages further study. If the finding can be confirmed in additional samples, it may illuminate a new avenue for understanding the pathogenesis of severe bipolar disorder and developing more effective treatments.

The bipolar disorder phenome database: a resource for genetic studies.

OBJECTIVE: 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.

Rapid mood switching and suicidality in familial bipolar disorder.

OBJECTIVES: Rapidly alternating or mixed mood states in bipolar disorder are associated with a particularly high risk for suicidal behavior. Are individuals with these patterns of illness more likely to develop suicidal intentions, or are they less able to resist them? This analysis examines the specific contribution of rapid switching and other variables to the relative likelihood of having or acting on self-reported suicidal thought and action, in a large group of individuals with bipolar disorder. METHODS: The analysis included 1574 family members with bipolar disorder interviewed for a multi-site bipolar disorder genetic linkage study. Two models were tested, using the same set of demographic and clinical data points as independent variables. One model tested the influence of rapid switching and other variables on self-reported suicidal thought or action (i.e., suicidality), while the other tested the influences on suicidal action only among those who reported a history of suicidality. RESULTS: Over 75% of subjects had contemplated suicide and 38% reported a history of suicidal behavior. A history of rapid switching was associated with higher likelihood of a history of suicidality, as was panic disorder. Familial suicidal behavior, as well as drug abuse, increased the likelihood of suicidal action among suicidal individuals, but did not increase the likelihood of becoming suicidal. Female sex, early age at onset, and several demographic factors were associated with both facets of suicidality. CONCLUSIONS: Factors associated with high acuity of distress, such as panic attacks and unstable moods, appear to enhance the risk of suicidality in general. Factors that affected the threshold for action without increasing suicidality overall can also be seen as markers of impulsive decision-making. Of the two distinct kinds of suicidal risk, the latter - the likelihood of action given intent - appears to be the more familial.

Challenges in operationalizing the DSM-IV clinical significance criterion.

BACKGROUND: An explicit clinical significance (CS) criterion was added to many DSM-IV diagnoses in an attempt to more closely approximate the clinical diagnostic process and reduce the proportion of false positives in epidemiological studies. The American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project (AI-SUPERPFP) offered a unique opportunity to examine the success of this effort. OBJECTIVE: To determine the impact of distress, impairment, and help-seeking reported in a lay structured interview on concordance with a clinical reappraisal. Further, to test the efficacy of 5 operationalizations of CS on the concordance and prevalence of DSM-IV lifetime disorders. DESIGN: Completed between 1997 and 2000, a cross-sectional probability sample survey with clinical reappraisal of approximately 10% of participants. SETTING: General community. PARTICIPANTS: A population-based sample of 3084 members of 2 American Indian tribal groups, who were between the ages of 15 and 54 years and resided on or near their home reservations, were randomly sampled from the tribal rolls and participated in structured psychiatric interviews. Clinical reappraisals were conducted with approximately 10% of the lay-interview participants. The response rate for the lay interview was 75%, and for the clinical reappraisal it was 72%. MAIN OUTCOMES MEASURES: The AI-SUPERPFP Composite International Diagnostic Interview (CIDI), a culturally adapted version of the CIDI, University of Michigan version. Adapted to assess DSM-IV diagnoses, questions assessing the CS criterion were inserted in all diagnostic modules. The Structured Clinical Interview for DSM-III-R (SCID) was used in the clinical reappraisal. RESULTS: Most participants who qualified as having AI-SUPERPFP CIDI lifetime disorders reported at least moderate levels of distress or impairment. Evidence of increased concordance between the CIDI and the SCID was lacking when more restrictive operationalizations of CS were used; indeed, the CIDI was very likely to underdiagnose disorders compared with the SCID (false negatives). Concomitantly, the CS operationalizations affected prevalence rates dramatically. CONCLUSION: The CS criterion, at least as operationalized to date, demonstrates little effectiveness in increasing the validity of diagnoses using lay-administered structured interviews.

Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.

BACKGROUND: In 1989 the National Institute of Mental Health began a collaborative effort to identify genes for bipolar disorder. The first 97 pedigrees showed evidence of linkage to chromosomes 1, 6, 7, 10, 16, and 22 (Nurnberger et al 1997). An additional 56 bipolar families have been genotyped, and the combined sample of 153 pedigrees studied. METHODS: Three hierarchical affection status models were analyzed with 513 simple sequence repeat markers; 298 were common across all pedigrees. The primary analysis was a nonparametric genome-wide scan. We performed conditional analyses based on epistasis or heterogeneity for five regions. RESULTS: One region, on 16p13, was significant at the genome-wide p <.05 level. Four additional chromosomal regions (20p12, 11p15, 6q24, and 10p12) showed nominally significant linkage findings (p

Genome scan of the fifty-six bipolar pedigrees from the NIMH genetics initiative replication sample: chromosomes 4, 7, 9, 18, 19, 20, and 21.

The NIMH genetics initiative on bipolar disorder was established to collect uniformly ascertained bipolar pedigrees for genetic studies. In 1997, the four participating sites published a genome scan on the initial set of 97 bipolar pedigrees. Fifty-six additional bipolar pedigrees have now been ascertained and evaluated. This replication pedigree set contains 354 genotyped subjects, including 139 bipolar I (BPI) subjects, five schizoaffective bipolar type SA/BP subjects, 41 bipolar II (BPII) subjects, and 43 recurrent unipolar (RUP) depression subjects. Our site has recently genotyped the replication study bipolar pedigrees using 107 microsatellite markers from chromosomes 4, 7, 9, 18, 19, 20, and 21. We are now reporting parametric and nonparametric linkage results from this effort. Multipoint nonparametric linkage analysis produced three candidate regions with allele sharing LOD scores >/= 1.0. The linkage signal on 4q35 peaked between markers D4S3335 and D4S2390 with an allele sharing LOD score of 2.49. This finding exceeds standard criteria for suggestive linkage. Two additional loci approach suggestive linkage levels: the 4q32 finding had its maximum near marker D4S1629 with an allele sharing LOD score of 2.16, and the 20p12 finding peaked at D20S162 with an allele sharing LOD score of 1.82. Multipoint parametric linkage analysis produced similar findings. When we combined the genotype data from the original and the replication pedigree sets, 20p12 yielded a nonparametric LOD score of 2.38, which exceeds standard criteria for suggestive linkage, and a corresponding parametric HLOD score of 2.98. The combined analysis did not provide further support for linkage to 4q32 and 4q35.

Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder.

OBJECTIVE: Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions-10p12-14, 13q32, 18p11.2, and 22q12-13. The authors previously demonstrated familial clustering of psychotic symptoms-defined as hallucinations and/or delusions-in some bipolar disorder pedigrees. In this study they used stratified linkage analysis to test the hypothesis that those bipolar disorder pedigrees most enriched for psychotic symptoms would show greater evidence of linkage to the regions of previous bipolar disorder/schizophrenia linkage overlap. METHOD: Nonparametric linkage analyses using GENEHUNTER and ASPEX were performed on 65 bipolar disorder families. Family subsets were defined by the number of family members with psychotic mood disorder. RESULTS: The 10 families in which three or more members had psychotic mood disorder showed suggestive evidence of linkage to 13q31 (nonparametric linkage score=3.56; LOD score=2.52) and 22q12 (nonparametric linkage score=3.32; LOD score=3.06). These results differed significantly from those for the entire study group of 65 families, which showed little or no linkage evidence in the two regions. The 10 families with three or more psychotic members did not show evidence of linkage to 10p12-14 or 18p11.2. The 95% confidence interval on 22q12 spanned 4.3 centimorgans (2.6 megabases) and was congruent with previous findings. CONCLUSIONS: Bipolar disorder families in which psychotic symptoms cluster may carry susceptibility genes on chromosomal regions 13q31 and 22q12. Replication should be attempted in similar families and perhaps in schizophrenia families in which mood symptoms cluster because these overlapping phenotypes may correlate most closely with the putative susceptibility genes. The localization of the 22q12 finding particularly encourages further study of this region.

Genome scan of a second wave of NIMH genetics initiative bipolar pedigrees: chromosomes 2, 11, 13, 14, and X.

As part of the on-going NIMH Genetics Initiative on Bipolar Disorder, we have ascertained 153 multiplex bipolar pedigrees and genotyped them in two waves. We report here the genome scan results for chromosomes 2, 11, 13, 14, and X in the second wave of 56 families. A total of 354 individuals were genotyped and included in the current analyses, including 5 with schizoaffective/bipolar (SA/BP), 139 with bipolar I disorder (BPI), 41 with bipolar II disorder (BPII), and 43 with recurrent unipolar depression (RUP). Linkage analyses were carried out with multi-point parametric and non-parametric affected relative pair methods using three different definitions of the affected phenotype: (model 1) SA/BP and BPI; (model 2) SA/BP, BPI, and BPII; and (model 3) SA/BP, BPI, BPII, and RUP. The best findings were on 11p15.5 (NPL = 2.96, P = 0.002) and Xp11.3 (NPL = 2.19, P = 0.01). These findings did not reach conventional criteria for significance, but they were located near regions that have been identified in previous genetic studies of bipolar disorder. The relatively modest but consistent findings across studies may suggest that these loci harbor susceptibility genes of modest effect in a subset of families. Large samples such as that being collected by the NIMH Initiative will be necessary to examine the heterogeneity and identify these susceptibility genes.

Familial aggregation of psychotic symptoms in a replication set of 69 bipolar disorder pedigrees.

We found evidence previously of familial aggregation of psychotic symptoms in 65 bipolar disorder pedigrees. This finding, together with prior evidence from clinical, family, neurobiological, and linkage studies, suggested that psychotic bipolar disorder may delineate a valid subtype. We sought to replicate this finding in 69 new bipolar disorder pedigrees. The presence of psychotic symptoms, defined as hallucinations or delusions, during an affective episode was compared in families of 46 psychotic and 23 non-psychotic bipolar I probands ascertained at Johns Hopkins for the NIMH Bipolar Disorder Genetics Initiative. There were 198 first-degree relatives with major affective disorder including 90 with bipolar I disorder. Significantly more psychotic proband families than non-psychotic proband families (76% vs. 48%) contained at least one affected relative with psychotic symptoms. Psychotic symptoms occurred in 35% of relatives of psychotic probands and in 22% of relatives of non-psychotic probands (P = 0.10). Both psychotic affective disorder generally and psychotic bipolar I disorder clustered significantly in families. These results are consistent with our prior report although the magnitude of the predictive effect of a psychotic proband is less in the replication families. Our findings provide modest support for the validity of psychotic bipolar disorder as a subtype of bipolar disorder. This clinically defined subtype may prove more homogeneous than the disorder as a whole at the level of genetic etiology and of neuropathology/pathophysiology. Families with this subtype should be used to search for susceptibility genes common to bipolar disorder and schizophrenia, and for biological markers that may be shared with schizophrenia.

Diagnostic reliability of bipolar II disorder.

BACKGROUND: Although the diagnostic reliability of major depression and mania has been well established, that of hypomania and bipolar II (BPII) disorder has not. This remains an important issue for clinicians, especially for those undertaking genetic studies of BP disorder since bipolar I (BPI) and BPII disorders often cluster in the same families. We have assessed our diagnostic reliability of BP disorders, recurrent unipolar disorder, and their constituent episodes (major depression, mania, and hypomania) using interview and best-estimate diagnostic procedures used in a genetic study of families with BPI disorder. METHODS: Reliability was assessed for (1) co-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews of 37 subjects including 15 with BP disorders; (2) test-retest Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews of 26 subjects including 13 with BP disorders; and (3) best-estimate diagnoses made by 2 noninterviewing psychiatrists on 524 subjects in a genetic linkage study of BPI disorder. Diagnoses were based on Research Diagnostic Criteria for a Selected Group of Functional Disorders, except that recurrent major depression as well as hypomania was required for a diagnosis of BPII disorder. RESULTS: On co-rated interviews, we observed complete agreement between interviewers for diagnosing major depressive, manic, and hypomanic episodes. For test-retest interviews, the Cohen kappa coefficients were 0.83 for manic, 0.72 for hypomanic, and 1.0 for major depressive episodes. At the best-estimate level, the Cohen kappa coefficients were 0.99 for BPI, 0.99 for BPII, and 0.98 for recurrent unipolar disorder. CONCLUSION: Good interrater reliability for BPII can be achieved when the interviews and best-estimate diagnoses are done by experienced psychiatrists.

Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder.

OBJECTIVE: Panic attacks are a common complication of affective disorder, although the etiologic relationship of panic and affective symptoms has not been determined. Evidence from a family study suggests that panic attacks and panic disorder may be related genetically to bipolar disorder. This study used diagnostic data from the NIMH Bipolar Disorder Genetics Initiative to assess in a separate, larger family set the familiality of panic combined with bipolar disorder. METHOD: First-degree relatives (N=966) of probands with bipolar I disorder (N=192) and schizoaffective disorder, bipolar type, (N=11) were included in the study. All subjects were interviewed directly and were assigned best-estimate diagnoses for major affective and other psychiatric disorders. The risk of a family member being diagnosed with panic disorder if the proband with bipolar disorder had panic attacks or panic disorder was calculated with logistic regression analysis with generalized estimating equations that controlled for sex and affective disorder subdiagnosis. RESULTS: More than 90% of the probands and first-degree relatives with panic disorder also had an affective disorder diagnosis. Panic disorder was present in 17% of the relatives with recurrent major affective disorder and in 3% of the relatives without recurrent major affective disorder. Risk of panic disorder in relatives with bipolar disorder was increased significantly if the proband had panic attacks or panic disorder. CONCLUSIONS: Risk for panic disorder with familial bipolar disorder appears to be inherited. Inherited risk for panic disorder with bipolar disorder may indicate a shared genetic etiology for both disorders in some families. The patterns of bipolar disorder and panic disorder comorbidity observed in families imply a complex genetic etiology, which may be elucidated by using endophenotypes.