Kyung Sue Hong

Objectives: In this study, we aimed to compare the genetic architecture of schizophrenia (SCZ) and bipolar disorder (BD) in a Korean population by analyzing polygenic risk scores (PRS) derived from large-scale psychiatric disorder genome-wide association study data, based on genetic information collected from SCZ, BD, and healthy control groups.Methods: The study included 713 Korean patients with SCZ, 1,317 with BD, 526 healthy controls. Genotyping was performed using the Korean Biobank Array. PRS-continuous shrinkage method was used to calculate the PRS. Analysis of covariance (ANCOVA) was conducted to determine the association between SCZ or BD disorder and PRS after adjusting for sex.Results: ANCOVA revealed significant differences in PRS values by diagnosis for PRS for SCZ (F=215.281, p<0.001), PRS for BD (F=13.811, p<0.001), and PRS for major depressive disorder (F=6.042, p=0.002). Post-hoc analysis showed that PRS for SCZ was highest in SCZ, followed by BD, and healthy controls. PRS for BD was elevated in both BD and SCZ compared to healthy controls.Conclusion: Our study revealed quantitative differences in genetic architecture between SCZ and BD compared to healthy controls, while also suggesting a shared genetic background between the two disorders.

BackgroundBipolar disorder (BD) shows heterogeneous illness presentation both cross-sectionally and longitudinally. This phenotypic heterogeneity might reflect underlying genetic heterogeneity. At the same time, overlapping characteristics between BD and other psychiatric illnesses are observed at clinical and biomarker levels, which implies a shared biological mechanism between them. Incorporating these two issues in a single study design, this study investigated whether phenotypically heterogeneous subtypes of BD have a distinct polygenic basis shared with other psychiatric illnesses.MethodsSix lifetime phenotype dimensions of BD identified in our previous study were used as target phenotypes. Associations between these phenotype dimensions and polygenic risk scores (PRSs) of major psychiatric illnesses from East Asian (EA) and other available populations were analyzed.ResultsEach phenotype dimension showed a different association pattern with PRSs of mental illnesses. PRS for EA schizophrenia showed a significant negative association with the cyclicity dimension (p = 0.044) but a significant positive association with the psychotic/irritable mania dimension (p = 0.001). PRS of EA major depressive disorder demonstrated a significant negative association with the elation dimension (p = 0.003) but a significant positive association with the comorbidity dimension (p = 0.028).ConclusionThis study demonstrates that well-defined phenotype dimensions of lifetime-basis in BD have distinct genetic risks shared with other major mental illnesses. This finding supports genetic heterogeneity in BD and suggests a pleiotropy among BD subtypes and other psychiatric disorders beyond BD. Further genomic analyses adopting deep phenotyping across mental illnesses in ancestrally diverse populations are warranted to clarify intra-diagnosis heterogeneity and inter-diagnoses commonality issues in psychiatry.

Background: Bipolar disorder (BD) has the greatest suicide risk among mental and physical disorders. A recent genome-wide association study (GWAS) of European ancestry (EUR) samples revealed that the genetic etiology of suicide attempt (SA) was not only polygenic but also, in part, diagnosis-specific. The authors aimed to examine whether the polygenic risk score (PRS) for SA derived from that study is associated with SA or repeated attempts in Korean patients with BD. This study also investigated the shared heritability of SA and mental disorders which showed an increased risk of SA and a high genetic correlation with BD. Methods: The study participants were 383 patients with BD. The history of SA was assessed on a lifetime basis. PRSs for reference disorders were calculated using the aforementioned GWAS data for SA and the Psychiatric Genomics Consortium data of BD, schizophrenia, major depressive disorder (MDD), and obsessive–compulsive disorder (OCD). Results: The PRS for SA was significantly associated with lifetime SA in the current subjects (Nagelkerke’s R² = 2.73%, odds ratio [OR] = 1.36, p = 0.007). Among other PRSs, only the PRS for OCD was significantly associated with lifetime SA (Nagelkerke’s R² = 2.72%, OR = 1.36, p = 0.007). The PRS for OCD was higher in multiple attempters than in single attempters (Nagelkerke’s R² = 4.91%, OR = 1.53, p = 0.043). Conclusion: The PRS for SA derived from EUR data was generalized to SA in Korean patients with BD. The PRS for OCD seemed to affect repeated attempts. Genetic studies on suicide could benefit from focusing on specific psychiatric diagnoses and refined sub-phenotypes, as well as from utilizing multiple PRSs for related disorders.

Objective Bipolar disorder (BD) is complex genetic disorder. Therefore, approaches using clinical phenotypes such as biological rhythm disruption could be an alternative. In this study, we explored the relationship between melatonin pathway genes with circadian and seasonal rhythms of BD.Methods We recruited clinically stable patients with BD (n=324). We measured the seasonal variation of mood and behavior (seasonality), and circadian preference, on a lifetime basis. We analyzed 34 variants in four genes (MTNR1a, MTNR1b, AANAT, ASMT) involved in the melatonin pathway.Results Four variants were nominally associated with seasonality and circadian preference. After multiple test corrections, the rs116879618 in AANAT remained significantly associated with seasonality (corrected p=0.0151). When analyzing additional variants of AANAT through imputation, the rs117849139, rs77121614 and rs28936679 (corrected p=0.0086, 0.0154, and 0.0092) also showed a significant association with seasonality.Conclusion This is the first study reporting the relationship between variants of AANAT and seasonality in patients with BD. Since AANAT controls the level of melatonin production in accordance with light and darkness, this study suggests that melatonin may be involved in the pathogenesis of BD, which frequently shows a seasonality of behaviors and symptom manifestations.

Objective Adult attention deficit hyperactivity disorder (ADHD) has a heterogeneous clinical presentation with patients showing very frequent emotional problems. In the present study, patients with adult ADHD were subtyped based on their psychopathology using a person-centered approach. Methods In the present chart review study, detailed findings of psychological evaluation conducted as part of routine care were utilized. A total of 77 subjects with adult ADHD were included in the analysis. Detailed ADHD symptoms, psychiatric comorbid Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses, and severity of mood and anxiety symptoms were evaluated in the person-centered analysis. Results Three clusters were generated using clustering analysis. DSM comorbid conditions did not significantly impact the clustering. Cluster 1 consisted of ADHD combined presentation (ADHD-C) with less mood symptoms, cluster 2 of ADHD predominantly inattentive presentation and cluster 3 of ADHD-C with significant mood symptoms. Patients in cluster 3 had adulthood functional impairment more frequently compared with patients in cluster 1. Patients in cluster 3 showed recurrent thoughts of death and suicidal ideation more frequently compared with patients in cluster 1. Conclusion Further studies are needed to confirm the relationships observed in the present study.

Objective To investigate the association between genetic polymorphisms of brain-derived neurotrophic factor (BDNF) or serotonin transporter gene-linked polymorphic region (5-HTTLPR) and tinnitus, and the mediating effects of psychological distress on this association.Methods Eighty-six patients experiencing tinnitus and 252 controls were recruited. The Tinnitus Handicap Inventory was used to assess the severity of tinnitus and the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory-II (BAI-II), and the Korean version of the Brief Encounter Psychosocial Instrument (BEPSI-K) were used to assess psychological distress. We compared the association of BDNF rs6265 (Val66Met) and 5-HTTLPR variants in the two groups. The mediating effects of BDI-II, BAI-II, and BEPSI-K were examined using multiple regression analysis and validated by the Sobel test and bootstrapping.Results No significant differences were found between the groups regarding BDNF Val66Met and 5-HTTLPR, but the 5-HTTLPR variants trended toward association. Depressive symptoms appeared to act as a mediator on the relationship within the 5-HTTLPR s/s genotype and the severity of tinnitus.Conclusion Our findings provide a speculative idea on the association between the serotonergic system and tinnitus and suggest that depressive symptoms act as a mediator in tinnitus. Therefore, screening for depressive symptoms in patients with tinnitus is essential and intervention for depressive symptoms may help alleviate the severity of tinnitus.

최민준, et al. J Korean Neuropsychiatr Assoc. 2021 Aug;60(3):167-173. https://doi.org/10.4306/jknpa.2021.60.3.167