Locus-level antagonistic selection shaped the polygenic architecture of human complex diseases.

BACKGROUND: We aimed to evaluate the potential role of antagonistic selection in polygenic diseases: if one variant increases the risk of one disease and decreases the risk of another disease, the signals of genetic risk elimination by natural selection will be distorted, which leads to a higher frequency of risk alleles. METHODS: We applied local genetic correlations and transcriptome-wide association studies to identify genomic loci and genes adversely associated with at least two diseases. Then, we used different population genetic metrics to measure the signals of natural selection for these loci and genes. RESULTS: First, we identified 2120 cases of antagonistic pleiotropy (negative local genetic correlation) among 87 diseases in 716 genomic loci (antagonistic loci). Next, by comparing with non-antagonistic loci, we observed that antagonistic loci explained an excess proportion of disease heritability (median 6%), showed enhanced signals of balancing selection, and reduced signals of directional polygenic adaptation. Then, at the gene expression level, we identified 31,991 cases of antagonistic pleiotropy among 98 diseases at 4368 genes. However, evidence of altered signals of selection pressure and heritability distribution at the gene expression level is limited. CONCLUSION: We conclude that antagonistic pleiotropy is widespread among human polygenic diseases, and it has distorted the evolutionary signal and genetic architecture of diseases at the locus level.

Association between Tumor Necrosis factor-Alpha(TNF-a) polymorphisms and Schizophrenia: an updated meta-analysis.

BACKGROUND: Previous studies have explored associations between Tumour Necrosis factor-Alpha (TNF-a) polymorphisms and Schizophrenia. Their results were controversial. We conducted a meta-analysis to clarify the association between TNF-a - 308 G/A(rs1800629), -1031T/C(rs1799964), -863C/A(rs1800630) and -857 C/T (rs1799724) polymorphisms and Schizophrenia. METHODS: All the studies that investigated the association between TNF-a polymorphisms and Schizophrenia published before 15 October 2020 were included in. The literature were comprehensively searched and identified in 2 English databases and 2 Chinese databases. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: For -1031 T/C polymorphism, at the overall analysis, significantly decreased Schizophrenia risk was found in T allele in the allele model (p = 0.006, OR = 0.88) and increased Schizophrenia risk was found in TC + CC genotype in the dominant model (p = 0.005, OR = 1.17). Similarly, the same results were obtained when pooled analyses were included in high-quality studies (allele model: p = 0.005, OR = 0.86; dominant model: p = 0.007, OR = 1.20). In addition, when stratified by ethnicity, the results showed that in allele model, the T allele decreased Schizophrenia risk in East Asian (p = 0.031, OR = 0.90). CONCLUSION: The association may most likely result from less-credible, rather than from true associations or biological factors on the TNF-a - 1031 T/C polymorphism with Schizophrenia risk.KeypointsFor -1031T/C polymorphism, at the overall analysis, significantly decreased schizophrenia risk was found in T allele in the allele model, and increased schizophrenia risk was found in TC + CC genotype in the dominant model.In allele model, the T allele decreased schizophrenia risk in East Asian when stratified by ethnicity, and in the dominant model, TC + CC genotype increased schizophrenia risk in East Asian.

Mendelian randomization studies of brain MRI yield insights into the pathogenesis of neuropsychiatric disorders.

BACKGROUND: Observational studies have identified various associations between neuroimaging alterations and neuropsychiatric disorders. However, whether such associations could truly reflect causal relations remains still unknown. RESULTS: Here, we leveraged genome-wide association studies (GWAS) summary statistics for (1) 11 psychiatric disorders (sample sizes varied from n = 9,725 to 1,331,010); (2) 110 diffusion tensor imaging (DTI) measurement (sample size n = 17,706); (3) 101 region-of-interest (ROI) volumes, and investigate the causal relationship between brain structures and neuropsychiatric disorders by two-sample Mendelian randomization. Among all DTI-Disorder combinations, we observed a significant causal association between the superior longitudinal fasciculus (SLF) and the risk of Anorexia nervosa (AN) (Odds Ratio [OR] = 0.62, 95 % confidence interval: 0.50 ~ 0.76, P = 6.4 × 10- 6). Similar significant associations were also observed between the body of the corpus callosum (fractional anisotropy) and Alzheimer's disease (OR = 1.07, 95 % CI: 1.03 ~ 1.11, P = 4.1 × 10- 5). By combining all observations, we found that the overall p-value for DTI - Disorder associations was significantly elevated compared to the null distribution (Kolmogorov-Smirnov P = 0.009, inflation factor λ = 1.37), especially for DTI - Bipolar disorder (BP) (λ = 2.64) and DTI - AN (λ = 1.82). In contrast, for ROI-Disorder combinations, we only found a significant association between the brain region of pars triangularis and Schizophrenia (OR = 0.48, 95 % CI: 0.34 ~ 0.69, P = 5.9 × 10- 5) and no overall p-value elevation for ROI-Disorder analysis compared to the null expectation. CONCLUSIONS: As a whole, we show that SLF degeneration may be a risk factor for AN, while DTI variations could be causally related to some neuropsychiatric disorders, such as BP and AN. Also, the white matter structure might have a larger impact on neuropsychiatric disorders than subregion volumes.

Retinol-binding protein 4 in combination with lipids to predict the regression phenomenon of autism spectrum disorders.

BACKGROUND: About 20-40 % of autistic people experience a phenomenon of regression. Retinol binding protein 4 (RBP4) plays an important role as an inflammatory neurotrophic adipokine and is a promising mediator of the fat-brain axis. Abnormal fatty acid metabolism and lipid mediators have been reported to be related to the etiological mechanism in autism, and amelioration of impaired lipid metabolism can be recognized as a treatment strategy for autism. The purpose of this study is to explore the relationship between RBP4, lipids, and the autistic regression phenomenon, and to discuss their potentials as biomarkers for the autistic regression phenomenon. METHODS: A total of 60 autistic individuals (18 with regression phenomenon, 42 without regression phenomenon) (ASD group) and 36 healthy controls were enrolled in this case-control study. The levels of RBP4, total cholesterol (TC), high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglyceride (TG) were measured. Childhood Autism Rating Scale (CARS) is used to assess the severity of autism. Ethical measures were performed in compliance with the current Declaration of Helsinki and written informed consent was obtained from the parents before enrollment of the children and adolescents. RESULTS: Compared with control subjects, autistic individuals had lower levels of TC (P = 0.007), RBP4 (P = 0.001), and HDLC (P = 0.027). The levels of RBP4 in ASD group were positively correlated with TG (r = 0.355, P = 0.005), HDLC (r = 0.257, P = 0.047), TG/TC (r = 0.376, P = 0.003) and TG/LDLC (r = 0.363, P = 0.004), and were negatively correlated with CARS (r=-0.296, P = 0.003). Further logistic regression demonstrated that decreased RBP4 concentration was associated with the presentation of the autistic regression phenomenon even after the adjustment of the potential confounding factors. CONCLUSIONS: Serum RBP4 is associated with the autistic regression phenomenon and the severity of ASD. Further studies are needed to expound whether decreased RBP4 participates in the development of the autistic regression phenomenon.

Mutation screening of the UBE3A gene in Chinese Han population with autism.

BACKGROUND: 15q11-13 region is one of the most complex chromosomal regions in the human genome. UBE3A is an important candidate gene of autism spectrum disorder (ASD), which located at the 15q11-13 region and encodes ubiquitin-protein ligase E3A. Previous studies about UBE3A gene and ASD have shown inconsistent results and few studies were performed in Chinese population. This study aimed to detect the genetic mutations of UBE3A gene in Chinese Han population with ASD and analyze genetic association between these variants and ASD. METHODS: The samples consisted of 192 patients with autism according to the DSM-IV diagnostic criteria and 192 healthy controls. We searched for mutations at coding sequence (CDS) regions and their adjacent non-coding regions of UBE3A gene using the high resolution melting (HRM) and Sanger sequencing methods. We further increased sample size to validate the detected variants using HRM and conducted association analysis between case and control groups. RESULTS: A known single nucleotide polymorphism (T > C, rs150331504) located at the CDS4 and a known 5 bp insertion/deletion variation (AACTC+/-, rs71127053) located at the intron region of the upstream 288 bp of the CDS2 of UBE3A gene were detected using Sanger sequencing method. The ASD samples of case group were 391 for rs71127053, 384 for rs150331504 and 384 healthy controls, which were used to make an association analysis. The results of association analysis suggested that there were no significant difference about the allele and genotype frequencies of rs71127053 and rs150331504 between case and control groups after extending the sample size. Besides, rs150331504 is a synonymous mutation and we compared the secondary structure and minimum free energy (MFE) of mRNA harboring the allele T or C of rs150331504 using RNAfold software. We found that the centroid secondary structure apparently differs along with the polymorphisms of rs150331504 T > C, the results suggested that this variant might change the secondary structure of mRNA of UBE3A gene. We did not detect mutations in other coding regions of UBE3A gene. CONCLUSIONS: These findings showed that UBE3A gene might not be a major disease gene in Chinese ASD cases.

The Chinese version of obsessive compulsive drug use scale: validation in outpatient methadone maintenance treatment program.

BACKGROUND: The Obsessive Compulsive Drug Use Scale (OCDUS) measures the overall craving level within a period from a multidimensional perspective. However, no studies have addressed the validity of the new OCDUS factor structure, presented in 2016, in China. Additionally, there is lack of evidence on the interaction among risk factors for relapse. We aimed to assess the psychometric properties of the scores of the Chinese version of the OCDUS in patients with heroin dependence receiving methadone maintenance treatment (MMT). Further, we aimed to assess the correlations of the OCDUS scores with withdrawal symptoms, depression, anxiety, and nicotine dependence. METHODS: We enrolled 113 adults (age 32-64 years) and administered them with the OCDUS, Subjective Opioid Withdrawal Scale (SOWS), Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory (STAI), and Fagerstrom Test for Nicotine Dependence (FTND). RESULTS: Exploratory factor analysis identified a 3-dimensional component that included "Frequency of craving," "Inference of heroin," and "Control of heroin." These factors showed acceptable internal consistency, adequate item-total correlations, and significant item-subscale correlations. There was no correlation between the OCUDS scores and age, education, duration of receiving MMT, and MMT dosages. However, there was a significant correlation between the OCDUS total scores and the SOWS, STAI, BDI-II, and FTND scores. The scores of all the subscales were associated with the SOWS scores; further, the scores of the first two subscales were associated with BDI-II scores while only the scores of the first subscale were associated with the FTND scores. CONCLUSIONS: Our findings support the reliability and structure validity of the OCDUS scores. Heroin craving, withdrawal symptoms, negative emotions, and nicotine dependence, which are considered as risk factors for heroin relapse, might interact with each other. There is a need for further studies on the underlying mechanism of these clinical phenomena.

Expression alteration of microRNAs in Nucleus Accumbens is associated with chronic stress and antidepressant treatment in rats.

BACKGROUND: Nucleus Accumbens (NAc) is a vital brain region for the process of reward and stress, whereas microRNA plays a crucial role in depression pathology. However, the abnormality of NAc miRNA expression during the stress-induced depression and antidepressant treatment, as well as its biological significance, are still unknown. METHODS: We performed the small RNA-sequencing in NAc of rats from three groups: control, chronic unpredictable mild stress (CUMS), and CUMS with an antidepressant, Escitalopram. We applied an integrative pipeline for analyzing the miRNA expression alternation in different model groups, including differential expression analysis, co-expression analysis, as well as a subsequent pathway/network analysis to discover both miRNA alteration pattern and its biological significance. RESULT: A total of 423 miRNAs were included in analysis.18/8 differential expressing (DE) miRNA (adjusted p < 0.05, |log2FC| > 1) were observed in controls Vs. depression/depression Vs. treatment, 2 of which are overlapping. 78% (14/18) of these miRNAs showed opposite trends of alteration in stress and treatment. Two micro RNA, miR-10b-5p and miR-214-3p, appeared to be hubs in the regulation networks and also among the top findings in both differential analyses. Using co-expression analysis, we found a functional module that strongly correlated with stress (R = 0.96, P = 0.003), and another functional module with a moderate correlation with anhedonia (R = 0.89, P = 0.02). We also found that predicted targets of these miRNAs were significantly enriched in the Ras signaling pathway, which is associated with both depression, anhedonia, and antidepressant treatment. CONCLUSION: Escitalopram treatment can significantly reverse NAc miRNA abnormality induced by chronic stress. However, the novel miRNA alteration that is absent in stress pathology also emerges, which means that antidepressant treatment is unlikely to bring miRNA expression back to the same level as the controls. Also, the Ras-signaling pathway may be involved in explaining the depression disease etiology, the clinical symptom, and treatment response of stress-induced depression.

Brain-derived neurotrophic factor levels and bipolar disorder in patients in their first depressive episode: 3-year prospective longitudinal study.

BACKGROUND: Early identification of patients with bipolar disorder during their first depressive episode is beneficial to the outcome of the disorder and treatment, but traditionally this has been a great challenge to clinicians. Recently, brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the pathophysiology of bipolar disorder and major depressive disorder (MDD), but it is not clear whether BDNF levels can be used to predict bipolar disorder among patients in their first major depressive episode. AIMS: To explore whether BDNF levels can differentiate between MDD and bipolar disorder in the first depressive episode. METHOD: A total of 203 patients with a first major depressive episode as well as 167 healthy controls were recruited. After 3 years of bi-annual follow-up, 164 patients with a major depressive episode completed the study, and of these, 21 were identified as having bipolar disorder and 143 patients were diagnosed as having MDD. BDNF gene expression and plasma levels at baseline were compared among the bipolar disorder, MDD and healthy control groups. Logistic regression and decision tree methods were applied to determine the best model for predicting bipolar disorder at the first depressive episode. RESULTS: At baseline, patients in the bipolar disorder and MDD groups showed lower BDNF mRNA levels (P<0.001 and P = 0.02 respectively) and plasma levels (P = 0.002 and P = 0.01 respectively) compared with healthy controls. Similarly, BDNF levels in the bipolar disorder group were lower than those in the MDD group. These results showed that the best model for predicting bipolar disorder during a first depressive episode was a combination of BDNF mRNA levels with plasma BDNF levels (receiver operating characteristics (ROC) = 0.80, logistic regression; ROC = 0.84, decision tree). CONCLUSIONS: Our findings suggest that BDNF levels may serve as a potential differential diagnostic biomarker for bipolar disorder in a patient's first depressive episode.

Identification of ANKK1 rs1800497 variant in schizophrenia: new data and meta-analysis.

One functional polymorphism (rs1800497) within the ankyrin repeat and kinase domain containing-1 gene (ANKK1) was reported to be associated with schizophrenia, but results among different studies vary and conclusions remain controversial. The present study sought to clarify this potential association among a population of Han Chinese with early onset schizophrenia using a case-control (396 patients and 399 controls) and family based study (103 trios). We then performed a meta-analysis (comprising 11 case-control and 2 family-based studies) based on the present literature. Results of the association study revealed no significant difference in allele and genotype frequencies between the cases and controls, and no significant transmission distortion was detected. Kaplan-Meier survival analysis showed that age at onset in schizophrenia was significantly associated with the rs1800497 polymorphism in female patients, but not in males. Female T allele carriers had a lower age at onset than those without T allele (log rank statistic χ(2) = 5.16, P = 0.023; corrected P = 0.046). Meta-analysis results indicated that rs1800497 is not associated with schizophrenia in the overall population (P = 0.77 for the case-control studies; P = 0.06 for the family-based studies). Our results support the hypothesis that rs1800497 polymorphism is likely to have a modifying rather than causative effect on schizophrenia. These findings may represent a significant genetic clue for the etiology of schizophrenia in females, but further investigation is required to clarify the exact role of ANKK1 in the development of schizophrenia.