Multiple threshold models for the affective disorders: The Yale-NIMH collaborative family study

From the Yale-NIMH collaborative family study, the 1482 first degree relatives of 90 bipolar 1, and 163 major depression probands were examined to test the hypothesis that bipolar 1 and major depression are due to a single underlying genetic liability. We attempted to fit multifactorial-polygenic and single-major-locus multiple threshold models for sex and severity to the relatives in the major depression and bipolar 1 families. With relatives classified as affected only if they met criteria for major depression or bipolar 1, there was at best only marginal support for these models. Differences between these and previously reported results were examined in relation to differences in underlying assumptions. Additional analyses of these and other data from families of NIMH bipolar 2 and schizoaffective probands suggest that different methods of age adjustment, the relative placement of bipolar 2 and schizoaffective disorders in a hypothesized liability continuum and the inclusion or exclusion of sex thresholds were not primarily responsible for differences in the fit of genetic threshold models. Factors which do appear to be important are variability in rates between samples, the possibility of genetic heterogeneity, and the presence of a large secular increase in affective illness over the past three generations; the secular trend cannot be accommodated in the models of genetic transmission examined.     

Clinical evidence for genomic imprinting in bipolar I disorder

The phenotypic indicators of the genomic imprinting model were applied to clinical psychopathology data on 100 bipolar (BP) I probands and their families. The paternal transmission was associated with a significantly younger age of onset of the BP illness in probands and a higher rate of affective disorders in first- and second-degree relatives. The effect of the sex of the transmitting parent on age of onset in probands decreased but remained significant when controlling for the effect of the probands' age at investigation. Probands' sex had no significant influence on their age of onset. The severity of the BP illness in probands in terms of number of illness episodes and annual frequency was not influenced by the sex of the transmitting parent.     

Family-based association study of the serotonin-2A receptor gene (5-HT2A) and bipolar disorder

Objectives: The serotonin 2A receptor gene (5-HT2A) is of great interest for research in neuropsychiatric disorders based on the observation that various neuroleptic agents and antidepressants bind with relatively high affinity at 5-HT2A receptors, and the fact that the receptor density in platelets tends to increase in depression. To test for the presence of association between 5-HT2A and bipolar disorder (BP), we studied a large number of triad families having probands affected with DSM-IV bipolar I (BPI), bipolar II (BPII) or schizoaffective disorder, bipolar type. Methods: Two polymorphisms of 5-HT2A, 102T/C, and His452Tyr were analyzed in the 274 bipolar triad families. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data. We also calculated the maternal transmission and paternal transmission for each allele and compared the mean ages of onset across probands grouped by genotype at each of the two markers. Results: No significant transmission disequilibrium between the alleles of 5-HT2A and BP was found. Separate studies of the sub-phenotypes also failed to demonstrate significant association. However, we found a trend towards transmission disequilibrium with the haplotype 102C.His452 (p=0.0504). This trend may become more significant with a larger sample size. Significance: At present, results of this study suggest that the 5-HT2A is unlikely to play a major role in the genetic susceptibility to BP. Future studies will be directed towards increasing sample size, focusing on subtypes of BP or biochemical measures as phenotypes, and investigating other polymorphisms of 5-HT2A to provide more information at the DNA level.     

Color blindness linkage to bipolar manic-depressive illness. New evidence.

Linkage between protanopia and deuteranopia and bipolar manic-depressive illness is demonstrated in a sample of eight informative families ascertained in Brussels. Genetic heterogeneity of bipolar affective disorders is also shown in the present study. These results add new evidence to the hypothesis of X-linked dominant genetic transmission of affective liability in a subgroup of patients with bipolar affective disorders.     

Phenotypic spectra of bipolar disorder in responders to lithium versus lamotrigine

Objective:  We conducted a study of clinical presentation and family history in patients responsive to either of two commonly used mood stabilizers, lithium and lamotrigine.
Methods:  The sample included 164 subjects from 21 families of bipolar probands, 14 responders to lithium and seven to lamotrigine. Diagnostic information on first-degree relatives was obtained in a blind fashion through a combination of direct interviews (SADS-L) and family history assessments (FH-RDC).
Results:  The probands differed with respect to clinical course (episodic in the lithium group, rapid cycling in the lamotrigine group), and comorbidity (panic attacks and substance abuse in the lamotrigine group). The relatives of lithium responders had significantly higher risk of bipolar disorder while relatives of lamotrigine responders had higher prevalence of schizoaffective disorder, major depression and panic attacks.
Conclusions:  These findings suggest that lithium- and lamotrigine-responsive patients differ with respect to course of illness, comorbidity and family history and may represent distinct subtypes of bipolar disorder.     

The familial aggregation of psychotic symptoms in bipolar disorder pedigrees

OBJECTIVE: Symptomatic overlap between affective disorders and schizophrenia has long been noted. More recently, family and linkage studies have provided some evidence for overlapping genetic susceptibility between bipolar disorder and schizophrenia. If shared genes are responsible for the psychotic manifestations of both disorders, these genes may result in clustering of psychotic symptoms in some bipolar disorder pedigrees. The authors tested this hypothesis in families ascertained for a genetic study of bipolar disorder. METHOD: Rates of psychotic symptoms-defined as hallucinations or delusions-during affective episodes were compared in families of 47 psychotic and 18 nonpsychotic probands with bipolar I disorder. The analysis included 202 first-degree relatives with major affective disorder. RESULTS: Significantly more families of psychotic probands than families of nonpsychotic probands (64% versus 28%) contained at least one relative who had affective disorder with psychotic symptoms. Significantly more affectively ill relatives of psychotic probands than of nonpsychotic probands (34% versus 11%) had psychotic symptoms. An analysis of clustering of psychotic subjects across all families revealed significant familial aggregation. Clustering of psychosis was also apparent when only bipolar I disorder was considered the affected phenotype. CONCLUSIONS: Psychotic bipolar disorder may delineate a subtype of value for genetic and biological investigations. Families with this subtype should be used to search for linkage in chromosomal regions 10p12-13, 13q32, 18p11.2, and 22q11-13, where susceptibility genes common to bipolar disorder and schizophrenia may reside. Putative schizophrenia-associated biological markers, such as abnormal evoked response, oculomotor, and neuroimaging measures, could similarly be explored in such families.     

Age-of-onset and genetic transmission in affective disorders

Age-of-onset data were gathered on first-degree relatives of 252 probands with bipolar and unipolar affective disorders. Early onset probands (younger than 40 at onset) had more early onset relatives and a greater risk for affective disorder among their relatives than late onset probands (40 or older). This indicates that age-of-onset is a familial factor correlated with the liability to affective illness. Multiple threshold models of inheritance were applied to the data using age-of-onset as a liability-threshold determinant. The hypothesis of autosomal single-major locus was ruled out. Multi-factorial-polygenic inheritance provided a better fit to the data. The data suggest that early and late onset affective disorders can be placed at different thresholds on a genetic environmental continuum and that the early onset form is more deviant genetically than the late onset type. The implications for genetic research in affective disorder are discussed.     

Bipolar-panic disorder comorbidity within bipolar disorder families: a study of siblings

Objectives:  Although anxiety disorders often co-occur with bipolar disorder in clinical settings, relatively few studies of bipolar disorder have looked specifically at panic comorbidity. This report examines lifetime panic comorbidity within a sample of families with a history of bipolar disorder.
Methods:  One hundred and nine probands with bipolar disorder and their 226 siblings were interviewed as part of a family-genetic study. Logistic regression was used to model bipolar disorder as a predictor of comorbid panic in those with affective disorder, with age at interview and gender included as covariates.
Results:  The percentage with panic attacks was low in those without affective disorder (3%) compared with those with unipolar depression (22%) or bipolar disorder (32%). Panic disorder was found only in those with affective disorder (6% for unipolar, 16% for bipolar). When bipolar disorder and unipolar disorder were compared, controlling for age and sex, having bipolar disorder was associated with panic disorder (OR = 3.0, 95% CI = 1.1, 7.8) and any panic symptoms (OR = 2.0, CI = 1.0,3.8) and more weakly with the combination of panic disorder and recurrent attacks (OR = 1.8, CI = 0.9, 3.5).
Conclusions:  The absence of panic disorder and the low prevalence of any panic symptoms in those without bipolar or unipolar disorder suggest that panic is associated primarily with affective disorder within families with a history of bipolar disorder. Furthermore, panic disorder and symptoms are more common in bipolar disorder than in unipolar disorder in these families.     

Family-based association of FKBP5 in bipolar disorder

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.     

Familial aggregation of delusional depression: Re-examination in a recent family study

Background: Delusional (D-MDD) and nondelusional depression (ND-MDD) differ in clinical presentation, biological abnormalities, course of illness, and treatment response. Family data, however, have been less consistent regarding differential risk both for any major depression (MDD) and specifically D-MDD in relatives of D-MDD probands. In an earlier family study, we observed a 1.5-fold increase in rates of any MDD, specificity of transmission of D-MDD, and increased rates of bipolar disorders in relatives of D-MDD compared to relatives of ND-MDD probands. In a new family study, we attempted to replicate these findings. Method: A family study of 361 directly interviewed adult first-degree relatives (FDRs) of 163 probands (118 with MDD and 45 screened normal controls) was used to examine familial aggregation of any MDD, D-MDD, and bipolarity by proband delusional status. Results: Compared to FDRs of ND-MDD probands, FDRs of D-MDD probands were at modestly increased risk for any MDD. These results were unaffected by adjustment for proband ascertainment source, comorbidity, or whether probands had chronologically primary MDD. There was a trend toward increased rates of broadly defined bipolarity (bipolar I, bipolar II, or cyclothymia) in FDRs of D-MDD compared to FDRs of ND-MDD probands. Conclusion: Results from the present study were broadly consistent with those from our previous work. While other lines of evidence for D-MDD as a distinct subtype are more compelling than family data, it would be of methodologic interest to identify sources of inconsistency across studies in findings concerning the familial aggregation of delusional depression. Depression and Anxiety 8:160–165, 1998. © 1998 Wiley-Liss, Inc.     

von Willebrand's disease and psychotic disorders: co-segregation and genetic associations

Objectives:  To evaluate co-segregation and genetic associations between von Willebrand's disease (vWD) and psychotic disorders.
Methods:  The study was initiated following ascertainment of a nuclear family in which four members were diagnosed with vWD and psychotic/mood disorders. As co-segregation was uncertain in the extended pedigree, we also investigated population-based linkage and association using polymorphisms of vWF , the gene conferring susceptibility to vWD. Three common vWF polymorphisms were investigated among 194 patients with psychotic disorders (bipolar I disorder, BD I; schizoaffective disorder, SZA and schizophrenia, SZ) and their parents. The cases were also compared with unrelated population-based controls (n = 183).
Results:  The transmission disequilibrium test and related analyses suggested nominally significant transmission distortion of one allele and related haplotypes to the probands from their parents. The most significant results were obtained among patients with BD I, and similar trends were also evident in the SZ sample. Comparisons between the cases and population-based controls did not reveal associations, though marginally significant case–control differences were obtained in the BD I sample.
Conclusions:  These studies are consistent with association and linkage between vWF and BD I. However, given the relatively small sample, stochastic variation is an alternative explanation.     

Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity

The aim of the present study was to test a possible effect of the A218C tryptophan hydroxylase (TPH) gene variant on the antidepressant activity of fluvoxamine in a sample of major and bipolar depressives, with or without psychotic features. Two hundred and seventeen inpatients were treated with fluvoxamine 300 mg and either placebo or pindolol in a double blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. TPH allelic variants were determined in each subject by using a PCR-based technique. No significant finding was observed in the overall sample as well as in the pindolol group, while TPH*A/A was associated with a slower response to fluvoxamine treatment in subjects not taking pindolol (P = 0.001). This effect was independent from the previously reported influence of 5-HTTLPR polymorphism. If confirmed, these results may shed further light on the genetically determined component of the response to pharmacological treatments, thus helping the clinician to individualize each patient's therapy according to their genetic pattern.     

Mitochondrial DNA sequence diversity in bipolar affective disorder

OBJECTIVE: Point mutations in mitochondrial DNA (mtDNA) are one mechanism that could explain the apparent excess maternal transmission of bipolar affective disorder observed in some families. The authors sequenced the mtDNA from probands with bipolar disorder and tested nucleotide variants for association with the disorder. METHOD: The entire 16.5 kilobase mitochondrial genome was sequenced in nine unrelated probands selected from large pedigrees with exclusively maternal transmission of bipolar affective disorder. Compared to a reference sequence, variants were detected at 107 nucleotide positions. Fifteen variants of possible pathogenic significance were selected for further study. These variants were assayed in 93 unrelated probands with bipolar I, bipolar II, or schizoaffective-manic disorder and 63 comparison subjects, all of whom were classified into the major groups comprising the European mtDNA haplotype structure (haplogroups).RESULTS: The major European haplogroups were represented at the expected frequencies among both probands and comparison subjects. There was no significant difference between probands and comparison subjects in the frequency of any variant, although odds ratios >2 or <0.5 were observed for four variants. Frequencies of these four variants were similar in probands and haplogroup-matched comparison subjects. The results of all comparisons were essentially unchanged when probands from families with an apparently paternal transmission pattern were excluded.CONCLUSIONS: The results demonstrate that bipolar affective disorder occurs across all of the major European mtDNA haplogroups but do not reveal any point mutations that explain excess maternal transmission of the disorder.     

Affective disorders in the first-degree relatives of bipolar probands: results from the South Island Bipolar Study

The current study was performed to document observed rates of affective disorders in the first degree relatives of probands with bipolar I or II disorder; to determine whether bipolar II probands have an excess of bipolar II relatives; and to determine whether bipolar probands with a history of one or more suicide attempts have more relatives who have also made suicide attempts. Bipolar probands with positive family histories of affective disorder were recruited from a variety of sources for a study on the molecular genetics of bipolar disorder. Probands and relatives were interviewed with the Diagnostic Interview for Genetic Studies (DIGS) and blood was obtained for DNA extraction and genetic analyses. Among 423 first-degree adult relatives of 153 bipolar probands, 7% (29) had bipolar I disorder, 7% had bipolar II disorder, and 7% had bipolar not otherwise specified (NOS) disorder, making 21% of relatives with any bipolar disorder. A further 42% of relatives had a depressive disorder and only 38% had no affective disorder. A suicide attempt by a proband was not associated with any increase in suicide attempts by relatives. We conclude that while unipolar depressive disorders are the most common affective disorders in the first-degree relatives of bipolar probands, extension of the bipolar phenotype to include bipolar spectrum disorders results in 21% of relatives having any bipolar disorder.     

A segregation study of panic disorder in families of panic patients responsive to the 35% CO2 challenge.

BACKGROUND: A genetic component has a role in the etiology of Panic Disorder (PD) and a familial association between PD and CO2 hypersensitivity have been repeatedly described. METHODS: Complex segregation analysis was performed on a sample of 165 families of PD probands and on the subgroup homogeneous for CO2 hypersensitivity, using Regressive Logistic Models. The only relatives considered to be affected were those with PD. Relatives have been diagnosed according to Family History Method. RESULTS: A Mendelian hypothesis was compatible with our data, without distinction between different models of transmission. The Akaike's Information Criterion values indicated that the Additive model was the most parsimonious, with a gene frequency of .0005, incomplete penetrance and a phenocopy rate of .00029. By subdividing the families according to the probands' responses to CO2 inhalations, probands of 134 families were hypersensitive to CO2. The analysis performed on this subgroup supported the existence of a SML with a best fit for a Dominant model. CONCLUSIONS: A SML account for genetic transmission in PD families and 35% CO2 challenge test may individuate a genetically homogeneous subgroup of patients with PD.     

Psychiatric morbidity in the relatives of patients with DSM-III schizophreniform disorder: comparisons with the relatives of schizophrenic and bipolar disorder patients

Risks for psychiatric disorders (RDC) among first degree relatives of DSM-III schizophreniform, bipolar, and schizophrenic probands obtained from an epidemiologic sample using family history methods were examined. The relatives of the schizophreniform probands differed from the relatives of the schizophrenic and bipolar probands. The relatives of schizophreniform probands had significantly higher rates of affective illnesses (with the exception of bipolar illness) than the relatives of schizophrenic probands, and they had a significantly higher rate of psychotic affective disorders than the relatives of the bipolar probands.     

Treatment‐emergent mania/hypomania during antidepressant monotherapy in patients with rapid cycling bipolar disorder

Objective: To study treatment‐emergent mania/hypomania (TEM) associated with second‐generation antidepressant monotherapy in patients with rapid cycling bipolar disorder (RCBD). Methods: Data of patients with RCBD (n = 180) enrolled into two clinical trials were used to study the risk for TEM during second‐generation antidepressant monotherapy. History of TEM was retrospectively determined at the initial assessment by asking patients whether they were exposed to second‐generation antidepressants and if a hypomania/mania episode emerged during the first four weeks of treatment. Data were analyzed using t‐test, chi‐square, and logistic regression. Results: Of the 180 patients (bipolar I disorder, n = 128; bipolar II disorder, n = 52) with RCBD, 85% (n = 153) had at least one antidepressant treatment. Among these patients, 94.1% (144/153) had at least one antidepressant monotherapy treatment. Overall, 49.3% of patients had at least one TEM and 29.1% (116/399) of treatment trials were associated with TEM. In regression analysis, an inverse association between the number of mood episodes in the last 12 months and TEM was observed with an odds ratio of 0.9. However, gender, bipolar subtype, a lifetime history of comorbid anxiety disorder, substance use disorder, or psychosis, and age of mood disorder onset were not associated with TEM. For individual antidepressants, the rates of TEM varied from 42.1% for fluoxetine to 0% for fluvoxamine and mirtazapine. As a group, there was no difference between selective serotonin reuptake inhibitors and venlafaxine or bupropion in the incidence of TEM. Conclusions: Use of second‐generation antidepressants as monotherapy in RCBD is accompanied by clinically relevant rates of TEM. Even in patients with RCBD, differential vulnerabilities to antidepressant TEM may exist.     

A genetic study of affective disorders

First and second degree relatives of 99 probands with affective disorders (49 unipolar and 50 bipolar subjects) were studied. The high risk values obtained for affective disorders were shown to be compatible with those found by other authors, although the prevalence of the illness in the population of Lombardy appears to be much lower than in other countries. Very low rates of suicide and alcoholism were found in our sample. Data obtained by analysis of the affected pairs of relatives rule out the hypothesis of a dominant X-linked gene if the bipolar and the unipolar forms are considered genetically separated entities. Results compatible with a polygenic condition, partially shared by bipolar patients, were found using Slater's and Smith & Falconer's methods. Our data, however, cannot rule out the dominant hypothesis.     

Neuregulin 1 and age of onset in the major psychoses

Genetic vulnerability to psychiatric illness extends across major psychiatric illness. Neuregulin 1 (NRG1) is a large gene on chromosome 8p, that has been identified as a susceptibility factor in bipolar disorder and schizophrenia. In particular, a core at risk haplotype has received considerable attention for a putative role in the pathophysiology of the major psychoses (schizophrenia and bipolar disorder). This core haplotype can be represented by three markers 478B14-848, 420M9-1395, and SNP8NRG221533. We genotyped 312 families with bipolar probands, and 120 families with schizophrenia probands. Association of the core haplotype was tested for with age-at-onset and with three phenotypes: major psychosis, schizophrenia, and bipolar disorder. Neither age of onset (P = 0.893) nor the major psychosis phenotype (P = 0.374) was associated with the core haplotype in the overall sample. Ours was the first study to investigate the NRG1 core haplotype with age of onset of major psychoses, and despite our preliminary negative findings, this area deserves further investigation.     

Pharmacogenetics of lithium response in bipolar disorder

Lithium is the first-line treatment for bipolar disorder. In the past, genetic studies have attempted to identify factors associated with positive treatment response or side effects. Several research groups have shown that familial factors, family history of primary bipolar disorder, and negative family history of schizophrenia in particular, correlate well with prophylactic lithium response. Conversely, studies of lithium responsive patients and their families can assist genetic research of bipolar disorder. Lithium responders appear to suffer from a form of bipolar disorder that is more genetically based and more homogeneous. In a series of family studies, the author and his colleagues have confirmed the differences in family histories of lithium responders and nonresponders and shown that the mode of inheritance in lithium responders is compatible with a major-gene model. Subsequently, they initiated an international collaborative study to map the gene(s) predisposing to the illness or treatment response, or both, using both linkage and association strategies. To date, a sample of 32 families, 138 unrelated patients and 163 control subjects has been studied. In these studies, they found support for the role of phospholipase C in lithium responsive bipolar disorder.