Genetic Contribution to the Heterogeneity of Major Depressive Disorder: Evidence From a Sibling-Based Design Using Swedish National Registers.

OBJECTIVE: Major depressive disorder (MDD) is highly heterogeneous. Standard typology partly captures the disorder's symptomatic heterogeneity, although whether it adequately captures etiological heterogeneity remains elusive. The aim of this study was to investigate the genetic characterization of MDD heterogeneity. METHODS: Using Swedish patient register data on 1.5 million individuals, the authors identified 46,255 individuals with specialist-diagnosed MDD. Eighteen subgroups were identified based on nine comparison groups defined by clinical and psychosocial features, including severity, recurrence, comorbidities, suicidality, impairment, disability, care unit, and age at diagnosis. A sibling-based design and classic quantitative genetic models were applied to estimate heritability of MDD subgroups and genetic correlations between subgroups. RESULTS: Estimates of heritability ranged from 30.5% to 58.3% across subgroups. The disabled and youth-onset subgroups showed significantly higher heritability (55.1%-58.3%) than the overall MDD sample (45.3%, 95% CI=43.0-47.5), and the subgroups with single-episode MDD and without psychiatric comorbidity showed significantly lower estimates (30.5%-34.4%). Estimates of genetic correlations between the subgroups within comparison groups ranged from 0.33 to 0.90. Seven of nine genetic correlations were significantly smaller than 1, suggesting differences in underlying genetic architecture. These results were largely consistent with previous work using genomic data. CONCLUSIONS: The findings of differential heritability and partially distinct genetic components in subgroups provide important insights into the genetic heterogeneity of MDD and a deeper etiological understanding of MDD clinical subgroups.

Epidemiological overview of major depressive disorder in Scandinavia using nationwide registers.

Background: Major depressive disorder (MDD) is a common psychiatric disorder associated with a high disease burden. This study gives a comprehensive overview of the prevalence, outcomes, treatment, and genetic epidemiology of MDD within and across the Scandinavian countries. Methods: This study has aimed to assess and compare across Norway, Denmark, and Sweden 1) the prevalence and trajectories of MDD and comorbidity, 2) outcomes and treatment, and 3) heritability (Denmark and Sweden only). The analyses leveraged data on 272,944 MDD cases (and 6.2 million non-cases) from Norway, Sweden, and Denmark in specialist care in national longitudinal health registers covering 1975-2013. Relying on harmonized public data global comparisons of socioeconomic and health metrics were performed to assess to what extent findings are generalizable. Findings: MDD ranked among the most prevalent psychiatric disorders. For many cases, the disorder trajectory was severe, with varying proportions experiencing recurrence, developing comorbid disorders, requiring inpatient treatment, or dying of suicide. Important country differences in specialist care prevalence and treatment were observed. Heritability estimates were moderate (35-48%). In terms of socioeconomic and health indices, the Scandinavian nations were comparable to one another and grouped with other Western nations. Interpretation: The Scandinavian countries were similar with regards to MDD epidemiological measures, but we show that differences in health care organization need to be taken into consideration when comparing countries. This study demonstrates the utility of using comprehensive population-wide registry data, outlining possibilities for other applications. The findings will be of use to policy makers for developing better prevention and intervention strategies. Funding: Swedish Research Council (Vetenskapsrådet, award D0886501 to PFS), US National Institutes of Mental HealthR01 MH123724 (to PFS), European Union's Horizon 2020 Research and Innovation Program (847776 and 964874, to OA) and European Research Council grant (grant agreement ID 101042183, to YL).

Repurposing antidiabetic drugs for rheumatoid arthritis: results from a two-sample Mendelian randomization study.

Despite increasing therapeutic options to treat rheumatoid arthritis (RA), many patients fail to reach treatment targets. The use of antidiabetic drugs like thiazolidinediones has been associated with lower RA risk. We aimed to explore the repurposing potential of antidiabetic drugs in RA prevention by assessing associations between genetic variation in antidiabetic drug target genes and RA using Mendelian randomization (MR). A two-sample MR design was used to estimate the association between the antidiabetic drug and RA risk using summary statistics from genome-wide association studies (GWAS). We selected independent genetic variants from the gene(s) that encode the target protein(s) of the investigated antidiabetic drug as instruments. We extracted the associations of instruments with blood glucose concentration and RA from the UK Biobank and a GWAS meta-analysis of clinically diagnosed RA, respectively. The effect of genetic variation in the drug target(s) on RA risk was estimated by the Wald ratio test or inverse-variance weighted method. Insulin and its analogues, thiazolidinediones, and sulfonylureas had valid genetic instruments (n = 1, 1, and 2, respectively). Genetic variation in thiazolidinedione target (gene: PPARG) was inversely associated with RA risk (odds ratio [OR] 0.38 per 0.1mmol/L glucose lowering, 95% confidence interval [CI] 0.20-0.73). Corresponding ORs (95%CIs) were 0.83 (0.44-1.55) for genetic variation in the targets of insulin and its analogues (gene: INSR), and 1.12 (0.83, 1.49) 1.25 (0.78-2.00) for genetic variation in the sulfonylurea targets (gene: ABCC8 and KCNJ11). In conclusion, genetic variation in the thiazolidinedione target is associated with a lower RA risk. The underlying mechanisms warrant further exploration.

Genetics of age-at-onset in major depression.

Major depression (MD) is a complex, heterogeneous neuropsychiatric disorder. An early age at onset of major depression (AAO-MD) has been associated with more severe illness, psychosis, and suicidality. However, not much is known about what contributes to individual variation in this important clinical characteristic. This study sought to investigate the genetic components underlying AAO-MD. To investigate the genetics of AAO-MD, we conducted a genome-wide association meta-analysis of AAO-MD based on self-reported age of symptoms onset and self-reported age at first diagnosis from the UK Biobank cohort (total N = 94,154). We examined the genetic relationship between AAO-MD and five other psychiatric disorders. Polygenic risk scores were derived to examine their association with five psychiatric outcomes and AAO-MD in independent sub-samples. We found a small but significant SNP-heritability (~6%) for the AAO-MD phenotype. No SNP or gene reached SNP or gene-level significance. We found evidence that AAO-MD has genetic overlap with MD risk ([Formula: see text] = -0.49). Similarly, we found shared genetic risks between AAO-MD and autism-spectrum disorder, schizophrenia, bipolar disorder, and anorexia nervosa ([Formula: see text] range: -0.3 to -0.5). Polygenic risk scores for AAO-MD were associated with MD, schizophrenia, and bipolar disorder, and AAO-MD was in turn associated with polygenic risk scores derived from these disorders. Overall, our results indicate that AAO-MD is heritable, and there is an inverse genetic relationship between AAO-MD and both major depression and other psychiatric disorders, meaning that SNPs associated with earlier age at onset tend to increase the risk for psychiatric disorders. These findings suggest that the genetics of AAO-MD contribute to the shared genetic architecture observed between psychiatric disorders.

A Flexible, Wearable, and Wireless Biosensor Patch with Internet of Medical Things Applications.

Monitoring the vital signs and physiological responses of the human body in daily activities is particularly useful for the early diagnosis and prevention of cardiovascular diseases. Here, we proposed a wireless and flexible biosensor patch for continuous and longitudinal monitoring of different physiological signals, including body temperature, blood pressure (BP), and electrocardiography. Moreover, these modalities for tracking body movement and GPS locations for emergency rescue have been included in biosensor devices. We optimized the flexible patch design with high mechanical stretchability and compatibility that can provide reliable and long-term attachment to the curved skin surface. Regarding smart healthcare applications, this research presents an Internet of Things-connected healthcare platform consisting of a smartphone application, website service, database server, and mobile gateway. The IoT platform has the potential to reduce the demand for medical resources and enhance the quality of healthcare services. To further address the advances in non-invasive continuous BP monitoring, an optimized deep learning architecture with one-channel electrocardiogram signals is introduced. The performance of the BP estimation model was verified using an independent dataset; this experimental result satisfied the Association for the Advancement of Medical Instrumentation, and the British Hypertension Society standards for BP monitoring devices. The experimental results demonstrated the practical application of the wireless and flexible biosensor patch for continuous physiological signal monitoring with Internet of Medical Things-connected healthcare applications.

Genetic heterogeneity and subtypes of major depression.

Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment, and postpartum depression; N ~ 3000-47000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders/traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (-0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.

Bifunctional Chloroplastic DJ-1B from Arabidopsis thaliana is an Oxidation-Robust Holdase and a Glyoxalase Sensitive to H2O2.

Members of the DJ-1 protein family are multifunctional enzymes whose loss increases the susceptibility of the cell to oxidative stress. However, little is known about the function of the plant DJ-1 homologs. Therefore, we analyzed the effect of oxidation on the structure and function of chloroplastic AtDJ-1B and studied the phenotype of T-DNA lines lacking the protein. In vitro oxidation of AtDJ-1B with H2O2 lowers its glyoxalase activity, but has no effect on its holdase chaperone function. Remarkably, upon oxidation, the thermostability of AtDJ-1B increases with no significant alteration of the overall secondary structure. Moreover, we found that AtDJ-1B transcript levels are invariable, and loss of AtDJ-1B does not affect plant viability, growth and stress response. All in all, two discrete functions of AtDJ-1B respond differently to H2O2, and AtDJ-1B is not essential for plant development under stress.