Circadian phase variation in bipolar I disorder

Abnormalities in circadian rhythms are prominent features of bipolar I disorder (BD1). To investigate circadian variation in BD1, we evaluated morningness-eveningness (M/E), a stable trait reflecting circadian phase, using the composite scale (CS) among BD1 patients (DSM IV criteria; n=75), unscreened controls (n=349), and patients with schizophrenia (SZ) or schizoaffective disorder (SZA) (n=81). Our analyses showed that CS scores correlated significantly with age but did not differ by gender among the controls. BD1 patients differed significantly from controls and from SZ/SZA patients when age was considered. CS scores were distributed bi-modally among BD1 cases. There are several possible reasons for the observed heterogeneity. Younger BD1 patients, and those with rapid mood swings, were significantly more likely to have lower CS scores (i.e., to score in the 'evening' range and to have later circadian phase). CS scores were also positively correlated with the age at onset and the duration of the most severe depressive episodes. These relationships were not observed among the SZ/SZA groups. Thus, distinct patterns of M/E were noted among BD1 patients and among BD1 subgroups. The impact of medication, mood state, and chronicity on CS scores needs to be considered.     

Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia

We hypothesize that circadian dysfunction could underlie, at least partially, the liability for bipolar 1 disorder (BD1). Our hypothesis motivated tests for the association between the polymorphisms of genes that mediate circadian function and liability for BD1. The US Caucasian patients with BD1 (DSM-IV criteria) and available parents were recruited from Pittsburgh and surrounding areas (n = 138 cases, 196 parents) and also selected from the NIMH Genetics Collaborative Initiative (n = 96 cases, 192 parents). We assayed 44 informative single-nucleotide polymorphisms (SNPs) from eight circadian genes in the BD1 samples. A population-based sample, specifically cord blood samples from local live births, served as community-based controls (n = 180). It was used as a contrast for genotype and haplotype distributions with those of patients. US patients with schizophrenia/schizoaffective disorder (SZ/SZA, n = 331) and available parents from Pittsburgh (n = 344) were assayed for a smaller set of SNPs based on the results from the BD1 samples. Modest associations with SNPs at ARNTL (BmaL1) and TIMELESS genes were observed in the BD1 samples. The associations were detected using family-based and case-control analyses, albeit with different SNPs. Associations with TIMELESS and PERIOD3 were also detected in the Pittsburgh SZ/SZA group. Thus far, evidence for association between specific SNPs at the circadian gene loci and BD1 is tentative. Additional studies using larger samples are required to evaluate the associations reported here.     

Chronotypes of Bipolar Patients in Remission: Validation of the French Version of the Circadian Type Inventory in the FACE-BD Sample

Circadian rhythm disturbances have been associated with bipolar disorder (BD) during both the mood episodes and the periods of remission. Circadian phase preferences for the evening have been reported for remitted patients, whereas the amplitude and stability of their rhythms have never been assessed using questionnaires. The primary aim of our study was the validation of a French version of the Circadian Type Inventory (CTI), whereas its secondary aim was the comparison between remitted patients with BD and healthy controls for rhythm stability and amplitude and for phase preference. For this purpose, we used the CTI and the Composite Scale of Morningness (CSM) that assesses phase preference (“morning” or “evening” type). First, we report here on the validation of the French version of the 11-item Circadian Type Inventory in a sample of 140 remitted patients with BD and 156 healthy controls. Principal components analysis revealed a two-factor structure (FR: flexibility/rigidity scale corresponding to rhythm stability; LV: languid/vigorous scale corresponding to rhythm amplitude) explaining 52% of the variance in the control group and 47% in the bipolar group. Cronbach’s alpha was 0.75 for FR and 0.73 for LV. The test-retest reliability was 0.74 for FR and 0.86 for LV (3 wks) and 0.62 for FR and 0.72 for LV (6 mos). LV and FR scores correlated with the Composite Scale of Morningness score (p?<?0.00001 and p?=?0.0002, respectively). Second, as compared with controls, patients with BD were more languid (p?<?0.00001) and showed an evening preference (p?=?0.0003), but they did not differ from the controls with regard to flexibility/rigidity. The French version of the CTI appeared to have satisfactory psychometrics characteristics. Bipolar patients exhibited not only abnormalities in phase preference but also in amplitude as measured by languidity. Since circadian rhythm dysfunction has been shown to predict poor functioning and mood relapses in interepisodic patients with BD, this tool would appear to be a promising, easy-to-use, measure of the amplitude and flexibility of circadian rhythms that could enrich the arsenal of assessments used in clinical settings.     

CACNA1C Risk Variant and Amygdala Activity in Bipolar Disorder,Schizophrenia and Healthy Controls

Objectives

Several genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups.

Methods

Rs1006737 was genotyped in 250 individuals (N = 66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group.

Results

In the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups.

Conclusions

These results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ.     

Analysis of genetic association and epistasis interactions between circadian clock genes and symptom dimensions of bipolar affective disorder

Bipolar affective disorder (BD) is a severe psychiatric disorder characterized by periodic changes in mood from depression to mania. Disruptions of biological rhythms increase risk of mood disorders. Because clinical representation of disease is heterogeneous, homogenous sets of patients are suggested to use in the association analyses. In our study, we aimed to apply previously computed structure of bipolar disorder symptom dimension for analyses of genetic association. We based quantitative trait on: main depression, sleep disturbances, appetite disturbances, excitement and psychotic dimensions consisted of OPCRIT checklist items. We genotyped 42 polymorphisms from circadian clock genes: PER3, ARNTL, CLOCK and TIMELSSS from 511 patients BD (n?=?292 women and n?=?219 men). As quantitative trait we used clinical dimensions, described above. Genetic associations between alleles and quantitative trait were performed using applied regression models applied in PLINK. In addition, we used the Kruskal–Wallis test to look for associations between genotypes and quantitative trait. During second stage of our analyses, we used multidimensional scaling (multifactor dimensionality reduction) for quantitative trait to compute pairwise epistatic interactions between circadian gene variants. We found association between ARNTL variant rs11022778 main depression (p?=?0.00047) and appetite disturbances (p?=?0.004). In epistatic interaction analyses, we observed two locus interactions between sleep disturbances (p?=?0.007; rs11824092 of ARNTL and rs11932595 of CLOCK) as well as interactions of subdimension in main depression and ARNTL variants (p?=?0.0011; rs3789327, rs10766075) and appetite disturbances in depression and ARNTL polymorphism (p?=?7?×?10^?4; rs11022778, rs156243).     

A haplotype of glycogen synthase kinase 3β is associated with early onset of unipolar major depression

Recent findings suggest that glycogen synthase kinase 3β (GSK3β) may play a role in the pathophysiology and treatment of mood disorders. Various genetic studies have shown the association of GSK3β polymorphisms with different mood disorder phenotypes. We hypothesized that genetic variants in the GSK3β gene could partially underlie the susceptibility to mood disorders. We performed a genetic case–control study of 440 psychiatrically screened control subjects and 445 mood disorder patients [256 unipolar major depressive disorder (MDD) and 189 bipolar disorder (BD)]. We genotyped a set of 11 single nucleotide polymorphisms (SNPs) and determined the relative frequency of a known copy number variant (CNV) overlapping the GSK3β by quantitative real‐time polymerase chain reaction (PCR). We found no evidence of association with MDD or BD diagnosis, and we further investigated the age at onset (AAO) of the disorder and severity of depressive index episode. We found that rs334555, located in intron 1 of GSK3β, was nominally associated with an earlier AAO of the disease in MDD (P = 0.001). We also identified a haplotype containing three SNPs (rs334555, rs119258668 and rs11927974) associated with AAO of the disorder (permutated P = 0.0025). We detected variability for the CNV, but we could not detect differences between patients and controls for any of the explored phenotypes. This study presents further evidence of the contribution of GSK3β to mood disorders, implicating a specific SNP and a haplotype with an earlier onset of the disorder in a group of well‐characterized patients with unipolar MDD. Further replication studies in patients with the same phenotypic characteristics should confirm the results reported here.     

Association between circadian genes,bipolar disorders and chronotypes

Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR?=?1.49 95%CI[1.18–1.88]; p?=?0.0008) and rs782931 in RORA (OR?=?1.31 95%CI[1.12–1.54]; p?=?0.0006) and BD. Then we used a “reverse phenotyping approach” to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p?=?0.04) and languid circadian type (p?=?0.01), whereas rs782931 was associated with rigid circadian type (p?=?0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.     

Altered Cortico-Striatal Connectivity in Offspring of Schizophrenia Patients Relative to Offspring of Bipolar Patients and Controls

Schizophrenia (SZ) and bipolar disorder (BD) share clinical features, genetic risk factors and neuroimaging abnormalities. There is evidence of disrupted connectivity in resting state networks in patients with SZ and BD and their unaffected relatives. Resting state networks are known to undergo reorganization during youth coinciding with the period of increased incidence for both disorders. We therefore focused on characterizing resting state network connectivity in youth at familial risk for SZ or BD to identify alterations arising during this period. We measured resting-state functional connectivity in a sample of 106 youth, aged 7–19 years, comprising offspring of patients with SZ (N = 27), offspring of patients with BD (N = 39) and offspring of community control parents (N = 40). We used Independent Component Analysis to assess functional connectivity within the default mode, executive control, salience and basal ganglia networks and define their relationship to grey matter volume, clinical and cognitive measures. There was no difference in connectivity within any of the networks examined between offspring of patients with BD and offspring of community controls. In contrast, offspring of patients with SZ showed reduced connectivity within the left basal ganglia network compared to control offspring, and they showed a positive correlation between connectivity in this network and grey matter volume in the left caudate. Our findings suggest that dysconnectivity in the basal ganglia network is a robust correlate of familial risk for SZ and can be detected during childhood and adolescence.     

Novel urinary biomarkers for diagnosing bipolar disorder

Bipolar disorder (BD) is a debilitating mental disorder. However, there are no biomarkers available to support objective laboratory testing for this disorder. Here, a nuclear magnetic resonance spectroscopy-based metabonomic method was used to characterize the urinary metabolic profiling of BD subjects and healthy controls in order to identify and validate urinary metabolite biomarkers for BD. Four metabolites, α-hydroxybutyrate, choline, isobutyrate, and N-methylnicotinamide, were defined as biomarkers. A combined panel of these four urinary metabolites could effectively discriminate between BD subjects and healthy controls, achieving an area under the receiver operating characteristic curve (AUC) of 0.89 in a training set (n = 60 BD patients and n = 62 controls). Moreover, this urinary biomarker panel was capable of discriminating blinded test samples (n = 26 BD patients and n = 34 controls) with an AUC of 0.86. These findings suggest that a urine-based laboratory test using these biomarkers may be useful in the diagnosis of BD.     

Heritability of Morningness‐Eveningness and Self‐Report Sleep Measures in a Family‐Based Sample of 521 Hutterites

Individual variation in the phase and amplitude of human circadian rhythms is well known, but the impact of heritable factors on such variation is less clear. We estimated the narrow‐sense heritability for selected circadian and sleep timing, quality, and duration measures among related members of the Hutterites, an endogamous, religious community (n=521 participants). “Morningness‐eveningness” (M/E), a stable trait reflecting circadian phase, was evaluated using the Composite Scale (CS). Subjective sleep measures were assessed using the Sleep Timing Questionnaire. Initial analyses reconfirmed the impact of age on M/E. Previously reported correlations between M/E scores and the sleep measures were also noted, demonstrating the construct validity of the questionnaires among the participants. Following corrections for age, gender, and colony of residence, significant narrow‐sense heritability was noted for M/E (23%). The heritability for subjective sleep measures (related to timing, duration, and quality) were statistically significant for all but one variable, and varied between 12.4% and 29.4%. Thus, significant heritable influences on human circadian phase and subjective sleep indices can be detected through family‐based studies. In view of the impact of circadian malfunction on human health, it may be worthwhile to map genetic factors impacting circadian and sleep variation.     

Lithium and bipolar disorder: Impacts from molecular to behavioural circadian rhythms

Bipolar disorder (BD) is a severe and common psychiatric disorder. BD pathogenesis, clinical manifestations and relapses are associated with numerous circadian rhythm abnormalities. Lithium (Li) is the first-line treatment in BD, and its therapeutic action has been related to its ability to alter circadian rhythms. We systematically searched the PubMed database until January 2016, aiming to critically examine published studies investigating direct and indirect effects of Li on circadian rhythms. The results, from the 95 retained studies, indicated that Li: acts directly on the molecular clocks; delays the phase of sleep–wakefulness rhythms and the peak elevation of diurnal cycle body temperature; reduces the amplitude and shortens the duration of activity rhythms and lengthens free-running rhythms. Chronic Li treatment stabilizes free-running activity rhythms, by improving day-to-day rhythmicity of the activity, with effects that appear to be dose related. Pharmacogenetics demonstrate several associations of Li’s response with circadian genes (NR1D1, GSK3β, CRY1, ARNTL, TIM, PER2). Finally, Li acts on the retinal-hypothalamic pineal pathway, influencing light sensitivity and melatonin secretion. Li is a highly investigated chronobiologic agent, and although its chronobiological effects are not completely understood, it seems highly likely that they constitute an inherent component of its therapeutic action in the treatment of mood disorders.     

Serum prolidase enzyme activity and oxidative status in patients with Behçet's disease

Abstract

Objectives

To assess serum prolidase enzyme activity and oxidative stress in patients with Behçet's disease (BD).

Methods

The study population consisted of BD patients (n = 42) and healthy participants (n = 29). BD patients were classified as active (n = 18) or inactive (n = 24) according to disease activity. Serum prolidase enzyme activity, total antioxidant status (TAS), total oxidative status (TOS), oxidative stress index (OSI), and malondialdehyde (MDA) levels were measured.

Results

In BD patients with active disease, serum prolidase activity was significantly higher compared with the inactive and control participants. Serum prolidase activity was also significantly higher in all BD patients in comparison with controls. Serum prolidase activity was also positively correlated with OSI, C-reactive protein, and active BD. MDA, TOS, and OSI levels were all significantly higher in the BD group when compared with the healthy control participants. Serum TAS levels were significantly lower in BD patients in comparison with healthy controls.

Conclusion

High prolidase activity may indicate critical biological activities relevant to pathological events in BD, and this activity may be a biological indicator of disease. Further studies are needed to verify these findings.     

Does childhood experience of attention-deficit hyperactivity disorder symptoms increase sleep/wake cycle disturbances as measured with actigraphy in adult patients with bipolar disorder?

ABSTRACT

Childhood attention-deficit hyperactivity disorder (ADHD) is a common precursor of adult bipolar disorders (BD). Furthermore, actigraphy studies demonstrate that each disorder may be associated with abnormalities in sleep and activity patterns. This study investigates whether the presence or absence of self-reported childhood experiences of ADHD symptoms is associated with different sleep and activity patterns in adults with BD. A sample of 115 euthymic adult patients with BD was assessed for childhood ADHD symptoms using the Wender Utah Rating Scale (WURS) and then completed 21 days of actigraphy monitoring. Actigraphic measures of sleep quantity and variability and daytime activity were compared between BD groups classified as ADHD+ (n = 24) or ADHD? (n = 91), defined according to established cutoff scores for the WURS; then we examined any associations between sleep–wake cycle parameters and ADHD dimensions (using the continuous score on the WURS). Neither approach revealed any statistically significant associations between actigraphy parameters and childhood ADHD categories or dimensions. We conclude that the sleep and activity patterns of adult patients with BD do not differ according to their self-reported history of ADHD symptoms. We discuss the implications of these findings and suggest how future studies might confirm or refute our findings.     

Neuropsychological effects of the CSMD1 genome‐wide associated schizophrenia risk variant rs10503253

The single‐nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains‐1 (CSMD1) gene on 8p23.2, was recently identified as genome‐wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non‐carriers of the risk ‘A’ allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk ‘A’ allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified ‘A’ risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.     

The impact of CACNA1C gene,and its epistasis with ZNF804A,on white matter microstructure in health,schizophrenia and bipolar disorder1

Genome‐wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium‐channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract‐based spatial statistics and threshold‐free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ‐specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.     

Investigation of Associations between NR1D1, RORA and RORB Genes and Bipolar Disorder

Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and gene-based association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test gene-gene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6×10−6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0.027), respectively. Gene-based association was significant for RORA gene (P = 0.0007). Our results support for the involvement of RORs genes in the risk of developing BD. Investigation of the functional properties of genes in the circadian pathway may further enhance our understanding about the pathogenesis of bipolar illness.     

Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: A randomized,double-blind,placebo-controlled study

Blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We hypothesized that wearing blue-blocking (BB) glasses in the evening may influence circadian rhythm disturbances in patients with major depressive disorder (MDD), resulting in improved sleep and mood. We used a randomized placebo-controlled double-blinded design. Patients with MDD with sleep onset insomnia were randomly assigned to wearing either BB glasses or clear glasses (placebo). Patients were instructed to wear the glasses from 20:00 hours until bedtime for 2 weeks. We assessed sleep state (sleep quality on a visual analog scale, the Morningness–Eveningness Questionnaire [MEQ], and a sleep diary) and depressive symptoms at baseline and after 2 weeks. Data were analyzed with a full analysis set. In total, 20 patients were randomly assigned to the BB and placebo groups (BB group, n = 10; placebo group, n = 10). There were three dropouts (BB group, n = 1; placebo group, n = 2). At baseline, sleep quality, sleep latency (assessed via a sleep diary), and antipsychotics use differed between the groups. To take account of these differences, the baseline sleep state or depressive symptoms and antipsychotics use were used as covariates in the later analysis. The change scores for sleep quality did not show a significant improvement in the BB group compared with the placebo group (mean [standard deviation, SD] scores for BB versus placebo: 36.1 [31.7] versus 16.2 [15.1], p = 0.43), although half of the BB group showed a clear improvement in sleep quality. The change in MEQ scores did not significantly differ between the groups (p = 0.14), although there was a trend of a shift to morning type in the BB group (3.10 [4.95] points) and to evening type in the placebo group (0.50 [3.89] points). There were no statistically significant changes in depressive symptoms in either group. Across both groups, 40% of the participants reported pain or discomfort from wearing the glasses, which were available in only one size. Thus, the failure to find significant differences may have resulted from the glasses used in this study. Glasses fitted to individual patients may improve efficacy and safety. Replication of the study with a larger sample size and size-adjustable glasses is needed.     

Association of the GABRD gene and childhood‐onset mood disorders

The chromosome 1p36 region was previously indicated as a locus for susceptibility to recurrent major depressive disorder based on a linkage study in a sample of 497 sib pairs. We investigated the gamma‐aminobutyric acid A (GABA_A) δ receptor subunit gene, GABRD, as a susceptibility gene to childhood‐onset mood disorders (COMD) because of substantial evidence implicating GABAergic dysfunction in mood disorders and the position of this gene near the 1p36 linkage region. Using a sample consisting of 645 Hungarian families with a child/adolescent proband diagnosed with a mood disorder with the onset of the first episode before age 15, we found some evidence for the association of two polymorphisms located within the gene, rs2376805 and rs2376803, as well as significant evidence for biased transmission of the haplotypes of these two markers (global χ² test for haplotypes = 12.746, 3 df, P = 0.0052). Furthermore, significant evidence of association was only observed in male subjects (n = 438) when the results were analyzed by sex (χ² = 9.000 1 df, P = 0.003 for rs2376805). This was in contrast with the previous linkage findings, as LOD scores exceeding 3 were only in female–female pairs in that study. These findings point to the GABRD gene as a susceptibility gene for COMD; however, this gene may not explain the previous linkage finding.