Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.

Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder.

In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 5'-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2)=9.6, one-sided P value=0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.

Linkage of a bipolar disorder susceptibility locus to human chromosome 13q32 in a new pedigree series.

Bipolar (BP) disorder or manic depressive illness is a major psychiatric disorder for which numerous family, twin and adoption studies support a substantial genetic contribution. Recently, we reported the results of a genome-wide search for BP disorder susceptibility loci in 20 pedigrees. Suggestive evidence for linkage was found in this study at three markers on 13q, representing possibly two peaks separated by 18 cM. We have now collected a second set of 32 pedigrees segregating BP disorder and have tested for evidence of linkage to markers on human chromosome 13q. In this sample, we have replicated the linkage result in 13q32 at D13S154 (lod=2.29), the more proximal of the two original peaks. When all 52 pedigrees were combined, the multipoint maximum lod score peaked approximately 7 cM proximal to D13S154 (lod=3.40), with a second peak occurring between D13S225 and D13S796 (lod=2.58). There have been several other reports of significant linkage to both BP disorder and schizophrenia in this region of chromosome 13. These pedigrees provide additional evidence for at least one locus for BP disorder in 13q32, and are consistent with other reports of a possible genetic overlap between these disorders.

Segmental linkage disequilibrium within the dopamine transporter gene.

The dopamine transporter gene (DAT) has been implicated in a variety of disorders, including bipolar disorder, attention-deficit hyperactivity disorder, cocaine-induced paranoia, Tourette's syndrome, and Parkinson's disease. As no clear functional polymorphism has been identified to date, studies rely on linkage disequilibrium (LD) to assess the possible genetic contribution of DAT to the various disorders. A better understanding of the complex structure of LD across the gene is thus critical for an accurate interpretation of the results of such studies, and may facilitate the mapping of the actual functional variants. In the process of characterizing the extent of variation within the DAT gene, we have identified a number of single nucleotide polymorphisms (SNPs) suitable for LD studies, 14 of which have been analyzed, along with a 3' repeat polymorphism, in a sample of 120 parent-proband triads. Calculations of pairwise LD between the SNPs in the parental haplotypes revealed a high degree of LD (P < 0.00001) in the 5' (distal promoter through intron 6) and 3' (exon 9 through exon 15) regions of DAT. This segmental LD pattern is maintained over approximately 27 kb and 20 kb in these two regions, respectively, with very little significant LD between them, possibly due to the presence of a recombination hotspot located near the middle of the gene. These analyses of the DAT gene thus reveal a complex structure resulting from both recombination and mutation, knowledge of which may be invaluable to the design of future studies.

Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder.

A role for the dopamine transporter (DAT) in bipolar disorder is implicated by several lines of pharmacological evidence, as well as suggestive evidence of linkage at this locus, which we have reported previously. In an attempt to identify functional mutations within DAT contributing a susceptibility to bipolar disorder, we have screened the entire coding region, as well as significant portions of the adjacent non-coding sequence. Though we have not found a definitive functional mutation, we have identified a number of single nucleotide polymorphisms (SNPs) that span the gene from the distal promoter through exon 15. Of the 39 SNPs that are suitable for linkage disequilibrium (LD) studies, 14 have been analyzed by allele-specific PCR in a sample of 50 parent-proband triads with bipolar disorder. A haplotyped marker comprised of five SNPs, spanning the region between exon 9 and exon 15, was constructed for each individual, and transmission/disequilibrium test (TDT) analysis revealed this haplotype to be in linkage disequilibrium with bipolar disorder (allele-wise TDT p = 0.001, genotype-wise TDT p = 0.0004). These data replicate our previous finding of linkage to markers within and near DAT in a largely different family set, and provide further evidence for a role of DAT in bipolar disorder. Published 2001 Wiley-Liss. Inc.

A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22.

Bipolar disorder or manic depressive illness is a major psychiatric disorder that is characterized by fluctuation between two abnormal mood states. Mania is accompanied by symptoms of euphoria, irritability, or excitation, whereas depression is associated with low mood and decreased motivation and energy. The etiology is currently unknown; however, numerous family, twin, and adoption studies have argued for a substantial genetic contribution. We have conducted a genome survey of bipolar disorder using 443 microsatellite markers in a set of 20 families from the general North American population to identify possible susceptibility loci. A maximum logarithm of odds score of 3.8 was obtained at D22S278 on 22q. Positive scores were found spanning a region of nearly 32 centimorgans (cM) on 22q, with a possible secondary peak at D22S419. Six other chromosomal regions yielded suggestive evidence for linkage: 3p21, 3q27, 5p15, 10q, 13q31-q34, and 21q22. The regions on 22q, 13q, and 10q have been implicated in studies of schizophrenia, suggesting the possible presence of susceptibility genes common to both disorders.

Comparison of shoplifting behaviours in patients with eating disorders, psychiatric control subjects, and undergraduate control subjects.

Shoplifting behaviours were examined in an eating disorder group (EDG, n = 48), a psychiatric control group (PCG, n = 46), and an undergraduate control group (UCG, n = 82). They were examined in relation to self-esteem, depression, and eating disorder symptomatology. The 3 groups did not differ in overall history of shoplifting, but EDG women were more likely to have shoplifted in the past 6 months (current shoplifting) and to have shoplifted often than were women from the PCG or UCG. Across all 3 groups, current shoplifting was associated with low self-esteem, elevated depression, and purging behaviours at the time of the assessment. The implications of these findings with regard to the relationship between shoplifting and eating disorder symptomatology will be addressed.

Evaluating the parent-of-origin effect in bipolar affective disorder. Is a more penetrant subtype transmitted paternally?

BACKGROUND: Numerous genetic mechanisms and modes of transmission underlying bipolar affective disorder (BPAD) have been postulated. Recently, the discovery of genomic imprinting and mitochondrial transmission of illness in humans has stimulated study of parent-of-origin effects in the transmission of BPAD. METHODS: We examined a large sample of families from an associated linkage study to search for a possible parent-of-origin effect. Selecting for unilineal families with at least one offspring and/or parent diagnosed with BPAD after structured interview, we conducted three analyses: (1) the rates of illness among mothers and fathers of offspring affected with BPAD; (2) the observed frequency of transmission and rates of illness among maternal and paternal lineages; and (3) the rates of affective illness among offspring of parents affected with BPAD. RESULTS: Our results indicate no significant differences in the rates of illness among mothers and fathers of offspring affected with BPAD. Also, the frequency of transmission and rates of illness among maternal and paternal lineages did not differ significantly. However, the rate of BPAD among the offspring of fathers affected with BPAD was significantly higher than for mothers with the illness. LIMITATIONS: Substantially more women than men, and maternal than paternal relatives were studied - introducing possible gender biases. CONCLUSIONS: These results suggest a possible paternal parent-of-origin effect.

A Canadian multicenter, double-blind study of paroxetine and fluoxetine in major depressive disorder.

BACKGROUND: Recent studies have suggested clinical differences among selective serotonin reuptake inhibitors. In a 12-week randomized, multicenter, double-blind trial, the antidepressant and anxiolytic efficacy of the selective serotonin reuptake inhibitors paroxetine and fluoxetine was compared in patients with moderate to severe depression. METHODS: A total of 203 patients were randomized to fixed doses (20 mg/day) of paroxetine or fluoxetine for the first six weeks of therapy. From week 7-12, dosing could be adjusted biweekly, as required (paroxetine 20-50 mg/day, and fluoxetine 20-80 mg/day). The mean prescribed doses were paroxetine 25.5 mg/day (range 20.0-40.2 mg/day), and fluoxetine 27.5 mg/day (range 20.0-59.5 mg/day). Emergence of motor nervousness or restlessness was assessed using the ESRS scale for akathisia. RESULTS: Both active treatments demonstrated comparable antidepressant efficacy (HAM-D, CGI). Anxiolytic activity of the two drugs (COVI, STAI, HAM-D) was also comparable. However, paroxetine was found to be superior to fluoxetine on two subscore measures at week 1 of therapy (HAM-D Agitation item, p < 0.05; Psychic Anxiety item, p < 0.05), with no differences detected after week 2. The overall incidence of adverse effects was comparable in the two treatment groups. Constipation, dyspepsia, tremor, sweating and abnormal ejaculation were more common in paroxetine-treated subjects, whereas nausea and nervousness were more frequent in fluoxetine-treated patients. Weight loss was more common in the fluoxetine versus paroxetine group (11.88% versus 2.94%, respectively). ESRS scores for akathisia were low throughout the study and showed little change. LIMITATIONS: Differences observed between the two drugs in antianxiety effects were limited to two measures of anxiety among several others. DISCUSSION: The data indicate that paroxetine and fluoxetine have comparable antidepressant and anxiolytic efficacy. Paroxetine appears to produce an earlier improvement in agitation and psychic anxiety symptoms compared with fluoxetine.

Olfactory identification and psychosis.

BACKGROUND: Olfactory identification performance has been investigated in several psychiatric populations, with deficits most commonly reported in patients with schizophrenia. In this study, olfactory identification performance was investigated in a more homogenous group of treatment-refractory patients with schizophrenia (T-RS) and in two additional psychiatric groups who demonstrate some similarities to the patients with schizophrenia in terms of symptomotology and medication regime. METHODS: The olfactory identification performance of 16 T-RS patients was assessed using the University of Pennsylvania Smell Identification Test (UPSIT) and compared to that of 16 normal control subjects and two other psychiatric patient groups: 19 affective disorder patients requiring maintenance antipsychotic medication and 20 affective disorder patients not receiving antipsychotic medication. RESULTS: The olfactory identification performance of T-RS patients was significantly lower than that of normal controls but not significantly different from either affective disorder group. The olfactory identification performance of affective disorder patients receiving antipsychotic medication was significantly lower than that of affective disorder patients not receiving antipsychotic medication. DISCUSSION: Results are discussed in the context of a possible link between psychotic symptomotology and olfactory identification performance.

Shape- and weight-based self-esteem and the eating disorders.

OBJECTIVES: To determine the psychometric properties of the Shape- and Weight-Based Self-Esteem (SAWBS) Inventory in women with eating disorders, and to compare SAWBS scores in women who have eating disorders with women from psychiatric and normal control groups. METHOD: Women with eating disorders (n = 48), women with other psychiatric disorders (n = 44), and undergraduate control women (n = 82) completed the SAWBS Inventory and measures of depression, self-esteem, and eating disorder symptomatology. Twenty women from the eating disorder group completed the SAWBS Inventory a second time 1 week later. RESULTS: Similar to previous work in undergraduate samples, SAWBS scores were stable over 1 week, and demonstrated concurrent and discriminant validity in women with eating disorders. In between-group comparisons, SAWBS scores were higher among women with eating disorders than in either control group, even after controlling for age, socioeconomic status, body mass index, and self-esteem. A differing relationship between depression and SAWBS emerged as a function of group; SAWBS scores differed significantly among depressed, but not nondepressed women from the three groups. CONCLUSION: The psychometric properties of the SAWBS Inventory were established in women with eating disorders. As expected, SAWBS scores were higher in women with eating disorders than in the control groups. Clinical implications of these findings are discussed.

A Canadian multicenter study of three fixed doses of controlled-release ipsapirone in outpatients with moderate to severe major depression.

Ipsapirone, an azapirone with 5-hydroxytryptamine (5-HT1A) partial agonist activity, has been shown in preliminary studies to be effective in the treatment of major depressive disorder. This 8-week, randomized, double-blind study compared the efficacy, safety, and tolerability of three fixed doses of controlled-release ipsapirone (10-, 30-, and 50-mg dose once daily) with placebo in 410 patients with moderate to severe major depression (Hamilton Rating Scale for Depression [HAM-D] score > or = 20). The 10-mg ipsapirone treatment arm was discontinued early in the study. A total of 390 patients were eligible for evaluation in the intent-to-treat sample. The primary efficacy variable was the change in HAM-D total score from baseline to visit 8. There was no significant difference in efficacy in the two treatment groups versus the placebo group. The overall treatment response, defined as a 50% decrease in the HAM-D total score from baseline, was 43% with ipsapirone 50 mg given once daily, 34% with ipsapirone 30 mg given once daily, and 35% with placebo. In subanalyses, ipsapirone 50 mg given once daily was superior to placebo according to the HAM-D Core Depression (mood, guilt, interest, psychomotor activity) subtotal (p = 0.0453) and Melancholic item (p = 0.0225). Ipsapirone 30 mg given once daily was superior to placebo only in patients with moderate depression (baseline HAM-D total score < or = 25; p = 0.0100). The most common adverse effect in all groups was headache. The only dose-dependent adverse effects were dizziness and nausea.

Linkage studies suggest a possible locus for bipolar disorder near the velo-cardio-facial syndrome region on chromosome 22.

Velo-cardio-facial syndrome (VCFS) is a congenital anomaly characterized by multiple dysmorphisms, cleft palate, cardiac anomalies, and learning disabilities, that results from a microdeletion of chromosome 22q11. An increased prevalence of psychiatric illness has been observed, with both schizophrenia and bipolar disorder commonly being diagnosed. For these reasons, the VCFS region is an interesting candidate region for bipolar disorder. We examined this region in 17 bipolar families from three populations: 13 families from the general North American population (University of California, San Diego/University of British Columbia, UCSD/UBC), three larger families from New York, and a portion of Old Order Amish pedigree 110. Three microsatellite markers spanning 13 cM around the VCFS region were genotyped in all the families. A maximum lod score of 2.51 was obtained in the UCSD/UBC families under a dominant model at D22S303. In the combined family set, maximum lod scores of 1.68 and 1.28 were obtained at this marker under dominant and recessive models, respectively. Four additional markers were subsequently typed in selected positive families, and yielded positive lods at 6 of 7 markers spanning 18 cM in this region. Nonparametric, multipoint analyses using the affected pedigree member (APM) method also yielded suggestive evidence for linkage in both the UCSD/UBC family set (P = 0.0024) and in the combined families (P = 0.017). Affected sibpair analyses were similarly positive in the UCSD/UBC families (P = 0.017), and in the combined families (P = 0.004). These results are suggestive of a possible locus for bipolar disorder near the VCFS region on chromosome 22.

Effects of chronic lithium treatment on retinal electrophysiologic function.

Some hypotheses suggest that lithium produces its therapeutic effect by reducing sensitivity to light at the level of the retina. In humans, acute administration of lithium is associated with a reduction in retinal light sensitivity. To determine whether similar retinal light sensitivity changes occur with chronic use, we studied 24 euthymic bipolar patients on chronic lithium treatment and 21 age- and sex-matched normal comparison subjects using electroretinography (ERG) and electro-oculography (EOG). No significant differences were found in ERG b-wave amplitudes or implicit times, or in EOG ratios, between the two groups. We conclude that chronic lithium use is not associated with differences in retinal light sensitivity when bipolar patients are compared to normal comparison subjects, and that there is no evidence for retinal toxicity with long-term lithium treatment.

Possible locus for bipolar disorder near the dopamine transporter on chromosome 5.

The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission by mediating the active reuptake of synaptic dopamine. It is an important candidate gene for bipolar disorder because of data implicating dopamine abnormalities in mania, and because it is the site of action of amphetamine, which has activating and psychotogenic properties. DAT has recently been cloned by its homology to a family of transporters, and mapped to chromosome 5p15.3. We tested DAT for linkage to bipolar disorder in a collection of 21 families from the general North American population (University of California, San Diego/University of British Columbia [UCSD/UBC] families), three Icelandic pedigrees, and Old Order Amish pedigree 110. We examined three markers at DAT, including a 5' TaqI RFLP (HDAT-TaqI), a highly polymorphic variable number of tandem repeats marker (VNTR) (HDAT-VNTR1), and a 3' 40-bp repeat marker (HDAT-PCR1), as well as two nearby microsatellite markers, D5S392 and D5S406. A maximum lod score of 2.38 was obtained at D5S392 in one of the UCSD/UBC families under an autosomal-dominant model. A lod score of 1.09 was also obtained under the same dominant model in the Amish at HDAT-PCR1. In the combined set of families, a maximum lod score of 1.76 was obtained under an autosomal-recessive model at HDAT-TaqI. Positive results were also obtained at several markers, using three nonparametric methods in the UCSD/UBC family set: the affected pedigree member method (P = 0.001), an affected sib pair method (ESPA, P = 0.0008), and the transmission disequilibrium test (P = 0.024). These results suggest the presence of a susceptibility locus for bipolar disorder near the DAT locus on chromosome 5.

Major depression, minor depression, and double depression: are they distinct clinical entities?

The clinical concept of "double depression," i.e., the superimposition of a major depressive disorder in a patient with dysthymic disorder, implies that there are at least some differences between dysthymia, major depression, and double depression. However, the relationship between these two syndromes remains unclear. The present study uses genetic methodology to explore any possible relationship between minor depression, double depression, and major depression. From 1988-1990, all consecutive unrelated inpatients and outpatients (index cases) presenting to a university-based mood disorders service had detailed family histories taken, using modification of the "family history method." Diagnoses for index cases and their first-degree relatives were made according to Research Diagnostic Criteria. For all index cases with a diagnosis of minor or intermittent depression, and minor/intermittent depression plus either single or recurrent depression ("double depression"), morbidity risks for mood disorders were calculated for first-degree relatives (parents, siblings, and children) using the maximum likelihood approach. Results showed no significant differences in morbidity risk calculations to first-degree relatives of index cases with minor/intermittent depression, major depression, or double depression. The data from this genetic perspective suggest that single depression, recurrent depression, minor depression, and double depression are indistinguishable.