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A genetic variant in 12q13, a possible risk factor for bipolar disorder, is associated with depressive state, accounting for stressful life events.

ABSTRACT: Genome-wide association studies (GWASs) have identified a number of susceptibility genes for schizophrenia (SCZ) and bipolar disorder (BD). However, the identification of risk genes for major depressive disorder (MDD) has been unsuccessful because the etiology of MDD is more influenced by environmental factors; thus, gene-environment (G × E) interactions are important, such as interplay with stressful life events (SLEs). We assessed the G×E interactions and main effects of genes targeting depressive symptoms. Using a case-control design, 922 hospital staff members were evaluated for depressive symptoms according to Beck Depressive Inventory (BDI; "depression" and "control" groups were classified by scores of 10 in the BDI test), SLEs, and personality. A total of sixty-three genetic variants were selected on the basis of previous GWASs of MDD, SCZ, and BD as well as candidate-gene (SLC6A4, BDNF, DBH, and FKBP5) studies. Logistic regression analysis revealed a marginally significant interaction (genetic variant × SLE) at rs4523957 (P uncorrected = 0.0034) with depression and a significant association of single nucleotide polymorphism identified from evidence of BD GWAS (rs7296288, downstream of DHH at 12q13.1) with depression as the main effect (P uncorrected = 9.4 × 10(-4), P corrected = 0.0424). We also found that SLEs had a larger impact on depression (odds ratio ? 3), as reported previously. These results suggest that DHH plays a possible role in depression etiology; however, variants from MDD or SCZ GWAS evidence or candidate genes showed no significant associations or minimal effects of interactions with SLEs on depression.

SUBMITTER: Shimasaki A

PROVIDER: S-EPMC4269417 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A genetic variant in 12q13, a possible risk factor for bipolar disorder, is associated with depressive state, accounting for stressful life events.

Shimasaki Ayu A Kondo Kenji K Saito Takeo T Esaki Kosei K Otsuka Yasuyo Y Mano Keiko K Ikeda Masashi M Iwata Nakao N

PloS one 20141217 12

Genome-wide association studies (GWASs) have identified a number of susceptibility genes for schizophrenia (SCZ) and bipolar disorder (BD). However, the identification of risk genes for major depressive disorder (MDD) has been unsuccessful because the etiology of MDD is more influenced by environmental factors; thus, gene-environment (G × E) interactions are important, such as interplay with stressful life events (SLEs). We assessed the G×E interactions and main effects of genes targeting depres ...[more]

PMID: 25517604

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Project description:Introduction:Schizophrenia(SCZ) and Bipolar disorder (BD) are frequently occurring and impairing disorders that affect around 1% of the population. Important endophenotypes in the genetic research of SCZ and BD are cognitive functions. Core symptoms for SCZ and BD are impairments in working memory, declarative memory and attention, all of which fulfill the criteria for an endophenotype. The FK506 Binding Protein 5 (FKBP5) gene codes for a co-chaperone of the glucocorticoid receptor and has been reported to be associated with cognition. Aim:The aims of our research were to determine the degree of cognitive impairment in patients suffering from SCZ and BD and to explore the association of the FKBP5 variant rs3800373 genotype with the cognitive endophenotypes. Material and Methods:Patients and healthy controls were recruited over a period of two years from the Psychiatric Clinic, Clinical Center University of Sarajevo. Genotyping and neuropsychological assessments were performed for 263 subjects (129 SCZ, 53 BD, and 81 healthy controls [HC]). Neuropsychological assessments were performed for all patients with the Trail Making Test-A&B (TMT-A&B) and Digit-span forward&backwards tasks. The single nucleotide polymorphism (SNP) rs3800373 in the FKBP5 gene was genotyped using Infinium PsychArray Bead Chips. Results and Conclusion:SCZ and BD patients performed lower than HC in the TMT-A&B and in the Digit-span backwards task, while no differences were observed between SCZ and BD patients. While SCZ patients performed lower than HC in the Digit-span forwards task, there were no differences between BD and HC or between BD and SCZ. Rs 3800373 was not associated with performance in the TMT-A&B or Digit-span forwards&backwards tasks. SCZ and BD share largely overlapping neurocognitive characteristics. Rs3800373 was not associated with performance in the neuropsychological tests. However, given the limited sample size, the results do not exclude an association with the rs3800373 variant in a larger sample. Furthermore, as the analysis was limited to one SNP, the results cannot be generalized to other genetic variants in FKBP5.

Project description:BackgroundPatients with major depressive disorder (MDD) usually have high risk of suicidality. Few studies have investigated the effects of stressful life events (SLEs) on the risk of suicide in Chinese patients who have developed MDD. This study aimed to investigate the impact of SLEs on suicidal risk in Chinese patients with MDD.MethodsIn total, 1029 patients with MDD were included from nine psychiatric hospitals to evaluate the impact of SLEs on suicidal risk. Patients fulfilling the Mini-International Neuropsychiatric Interview (MINI) criteria for MDD were included in the study. Patients were excluded if they had lifetime or current diagnoses of psychotic disorder, bipolar disorder, and alcohol or substance dependence. Depressive symptoms were assessed by the 17-item Hamilton Depression Scale (HAMD-17). The suicidal risk of MDD patients was determined by the suicide risk module of MINI. SLEs were assessed by the Life Events Scale.ResultsNo gender difference was found for suicidal risk in MDD patients. Patients with suicidal risk had younger ages, lower education levels, more drinking behavior, and lower marriage rate, and fewer people had child and more severe depressive symptoms than nonsuicidal risk group. High-level perceived stressfulness (HPS) and number of SLEs that patients were exposed to were significantly greater in patients with suicidal risk than patients without. In multivariate logistic analysis, HPS of SLEs (odds ratio [OR] = 1.54, 95% confidence interval [CI]: 1.16-2.05, P = 0.003) and depressive symptoms (OR = 1.08, 95% CI: 1.05-1.11, P < 0.001) were associated with suicidal risk even after adjustment of gender, age, marriage, drinking behavior, and childless.ConclusionsHPS of SLEs is associated with suicide risk in Chinese patients with MDD. Further suicide prevention programs targeting this risk factor are needed.Trial registrationClinicalTrials.gov: NCT02023567; https://clinicaltrials.gov/ct2/show/NCT02023567?term=NCT02023567&rank=1.

Project description:Family and genetic studies indicate overlapping liability for major depressive disorder and bipolar disorder. The purpose of the present study was to determine whether this shared genetic liability influences clinical presentation.A polygenic risk score for bipolar disorder, derived from a large genome-wide association meta-analysis, was generated for each subject of European-American ancestry (n = 1,274) in the Sequential Treatment Alternatives to Relieve Depression study (STAR*D) outpatient major depressive disorder cohort. A hypothesis-driven approach was used to test for association between bipolar disorder risk score and features of depression associated with bipolar disorder in the literature. Follow-up analyses were performed in two additional cohorts.A generalized linear mixed model including seven features hypothesized to be associated with bipolar spectrum illness was significantly associated with bipolar polygenic risk score [F = 2.07, degrees of freedom (df) = 7, p = 0.04]. Features included early onset, suicide attempt, recurrent depression, atypical depression, subclinical mania, subclinical psychosis, and severity. Post-hoc univariate analyses demonstrated that the major contributors to this omnibus association were onset of illness at age ? 18 years [odds ratio (OR) = 1.2, p = 0.003], history of suicide attempt (OR = 1.21, p = 0.03), and presence of at least one manic symptom (OR = 1.16, p = 0.02). The maximal variance in these traits explained by polygenic score ranged from 0.8% to 1.1%. However, analyses in two replication cohorts testing a five-feature model did not support this association.Bipolar genetic loading appeared to be associated with bipolar-like presentation in major depressive disorder in the primary analysis. However, the results were at most inconclusive because of lack of replication. Replication efforts were challenged by different ascertainment and assessment strategies in the different cohorts. The methodological approach described here may prove useful in applying genetic data to clarify psychiatric nosology in future studies.

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A genetic variant in 12q13, a possible risk factor for bipolar disorder, is associated with depressive state, accounting for stressful life events.

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A genetic variant in 12q13, a possible risk factor for bipolar disorder, is associated with depressive state, accounting for stressful life events.

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