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With regard to suicidal behavior (SB) genetics, many novel genes have been implicated over the years, in particular by a variety of hypothesis-free genomic methods (e.g. GWAS and exome sequencing). In addition, many novel SB gene findings appear enigmatic in their biological relevance and have weak statistical support, e.g. lack direct replications. Adding to this is the comorbidity between psychiatric disorders and SB. Here we provide a synopsis of SB genes, by prioritization of 106 (out of ~2500) genes based on their highest level of evidence diversity across mainly five genetic evidence types (candidate/GWAS SNP, CNV, linkage and whole exome sequencing), supplemented by three functional categories. This is a representative set of both old and new SB gene candidates, implicated by all kinds of evidence. Furthermore, we define a subset of 40 SB "specific" genes, which are not found among ~3900 genes implicated in other neuropsychiatric disorders, e.g. Autism spectrum disorders (ASD) or Schizophrenia. Biological research of suicidality contains a major developmental focus, e.g. with regard to the gene-environment interactions and epigenetic effects during childhood. Less is known about early (fetal) development and SB genes. Inspired by huge efforts to understand the role early (fetal) neurodevelopment in e.g. ASD by using brain transcriptomic data, we here also characterize the 106 SB genes. We find interesting spatiotemporal expression differences and similarities between SB specific and non-specific genes during brain neurodevelopment. These aspects are of interest to investigate further, to better understand and counteract the genetic origins suicidality. [ABSTRACT FROM AUTHOR]

Emotional lability is strongly associated with Attention Deficit Hyperactivity Disorder (ADHD), represents a major source of impairment and predicts poor clinical outcome in ADHD. Given that no specific genes with a role in the co-occurrence of both conditions have been described, we conducted a GWAS of emotional lability in 563 adults with ADHD. Despite not reaching genome-wide significance, the results highlighted genes related with neurotransmission, cognitive function and a wide range of psychiatric disorders that have emotional lability as common clinical feature. By constructing polygenic risk scores on mood instability in the UK Biobank sample and assessing their association with emotional lability in our clinical dataset, we found suggestive evidence of common genetic variation contributing to emotional lability in general population and in clinically diagnosed ADHD. Although not conclusive, these tentative results are in agreement with previous studies that suggest emotion dysregulation as a transdiagnostic construct and highlight the need for further investigation to disentangle the genetic basis of mood instability in ADHD and co-occurring psychiatric disorders. [ABSTRACT FROM AUTHOR]

B Objective: b The aim of the study is the genotyping of polymorphisms rs614080 of gene glutathione S-transferase (GSTP1) and rs2069514 of gene cytochrome 1A2 (CYP1A2) in patients with schizophrenia with and without MetS and healthy individuals. We did not found significant differences when comparing the distributions of genotypes of polymorphisms rs614080 (GSTP1) and rs2069514 (CYP1A2) in patients with schizophrenia and healthy individuals ( 1=0.414, 1=1.776; 2=0.162, 2=3.639). Possibly, other polymorphisms of cytochrome system and glutathione S-transferase genes are more significant, as well as a great increase in the number of samples. [Extracted from the article]

In the interaction testing, based on the reviewed literature[2],[3], we analyzed the possible interactions between depression and the calculated childhood maltreatment score considering the polymorphisms of CDC45. At the same time, during the interaction analyses, the minor allele (A) of the two polymorphisms yielded significant (p=0.029 for rs13447271 and p=0.040 for rs13447279) protective effects in case of the interaction of childhood maltreatment depression score. [Extracted from the article]

Chromosome 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic condition, with a highly variable phenotypic expression is characterized by high rates of psychiatric disorders. Two studies who compared ASD symptoms exhibited by 22q11DS children with age- and sex-matched children with idiopathic ASD found that both groups were equally affected in reciprocal social interaction and stereotyped behavior domains, while those with 22q11DS were less affected in the communication domains [1], [4]. Unlike the broader ASD population, gender differences in ASD prevalence rates in 22q11.2DS have not been observed [4]. [Extracted from the article]

Dear Editor, We thank the author of the letter for the interest in our paper and for taking the time to express concern regarding lack of ethnic diversity in our work and within genetic research on schizophrenia overall. In the Russian Federation, an ethnically diverse country with more than 160 ethnic groups of European and Asian descent, the Genome Russia Project is underway "to close the largest remaining omission on the world Genome map" ([4]). We believe that candidate studies using homogeneous samples form the basis for interpopulation comparisons and complement large-scale multi-ethnic initiatives in uncovering genetics of schizophrenia. [Extracted from the article]

B Background: b Recent studies have demonstrated that genetic predisposing loci to SCZ are enriched in genes subjected to recent selection pressures (Srinivasan et al., 2014; Xu et al., 2015). Functional enrichment analysis reveal that genes associated to SCZ (MAGMA) that also harbor recent selection signals show stronger enrichments in neuronal specific (p = 6.06e-9), LoF intolerant (p = 1.8e-13) and SCZ-differently expressed genes (p = 0.00046). [Extracted from the article]

B Background: b Genome-wide association studies (GWAS) have successfully identified a large number of genetic variants associated with psychiatric disorders, but single GWAS significant variants can only explain a small proportion of trait heritability. These approaches combine expression quantitative trait locus (eQTL) studies with GWAS to investigate gene-trait relationships by determining whether GWAS-significant variants are also enriched for eQTLs. Among these approaches, Summary-data-based Mendelian Randomization (SMR) integrates summary statistics from GWAS and eQTL studies to identify genes whose expression levels are associated with a complex trait due to pleiotropy. [Extracted from the article]

We calculated our significance threshold after multiple test correction as 4.07E-10, based on the number of independent phenotypes from spectral decomposition, and the suggestive significance threshold for a single phenotype as 5.52E-08. B Results: b A significant association was identified between the second principal component of the P200 of Gating paradigm and rs56285512 (P = 1.72E-10), an intronic SNP of the brain-specific angiogenesis inhibitor 3 gene (BAI3). [Extracted from the article]

Interview transcripts were analyzed using grounded theory methodology to generate a theoretical framework on the process of parental awareness regarding the psychiatric risks associated with 22q and the strategies that they can use to protect and/or manage their child's mental health. The provision of PGC facilitates parents' awareness further into an active state of "being aware", where they have the "awareness to act" to protect and/or manage their child's mental health. [Extracted from the article]

B Background: b Major depressive disorder (MDD) is a leading cause of disability worldwide and it constitutes a severe economic burden for society. Up to 60% of MDD patients do not show a complete response to the first treatment with drugs for depression, and up to one-third do not respond to the second one (treatment-resistant depression, TRD). [Extracted from the article]

B Background: b A recent study performed in a large and heterogeneous sample of European ancestry implied that the 14 genes previously known to be related with susceptibility to schizophrenia may play little roles. We analyzed 2 single nucleotide polymorphisms (SNPs) of activity-dependent neuroprotective protein (ADNP) gene. B Results: b We found a significant SNP of activity-dependent neuroprotective protein-2 (ADNP2) gene in chromosome 18 (P-value<0.05) for the qualitative phenotype of schizophrenia. [Extracted from the article]

B Methods: b We performed whole-genome sequencing analysis of individuals diagnosed with schizophrenia. Whole genome sequencing of delineated a novel deleterious variant in PPEF2 as likely genetic risk factor for schizophrenia. [Extracted from the article]

B Background: b Recent studies revealed that the interplay between polygenic risk scores (PRSs) and large copy number variants (CNVs: >500kb) is essential for the etiology of schizophrenia (SCZ). B Discussion: b Although the present study failed to replicate the significant difference in PRS between SCZ with and without "clinically significant" CNVs, SCZ with well-established risk CNVs tended to have a lower PRSs. [Extracted from the article]

B Background: b In neuropsychiatric disorders including schizophrenia and autism spectrum disorder (ASD), the population allele frequencies are restricted by natural selection such that causal variants with larger effects are likely to be very rare. B Methods: b For case-control datasets, we will select variants that are not present in control (non-psychiatric) datasets, while for family-based datasets we will select variants in affected children that are not present in either parent or siblings. Subsequently, we will use single cell RNA sequencing (scRNA-seq) data to investigate which specific brain cell types are implicated by rare variants, and evaluate the biological functions driving cell type-trait associations using gene sets. [Extracted from the article]

Previous work has implicated common loci, de novo variation and rare, high odds ratio copy number variation (CNVs) as contributory genetic factors for psychiatric illnesses like schizophrenia. One explanation for the discordance between MZ twins is that both individuals share a common genetic risk which is insufficient alone to be causal for the phenotype, but rare, post-zygotic variation present in the affected twin only increases the disease burden for that individual. B Methods: b To test the hypothesis that post-zygotic variation is implicated in phenotypic discordance, we investigated a cohort of 18 pairs of MZ twins discordant for major psychiatric illness using whole genome sequencing (WGS). [Extracted from the article]

B Background: b Disabled 1 (DAB1) is an intracellular adaptor protein of the Reelin signaling pathway and plays an essential role for correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal and postmortem studies. B Methods: b In this study, we performed coding exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency < 1%. [Extracted from the article]

B Background: b The endocannabinoid (eCB) system is a neuroregulatory lipid-signalling pathway involved in neurodevelopment and response to endogenous and exogenous danger signals. Finally, we ran sensitivity analysis adding as a covariate in the logistic model the full SZ-BD Polygenic Risk Score, based on all the genes but excluding the eCB gene-set (no-eCB-RS). One-thousand common variants within the eCB gene-set were retained for eCB-RS calculation after clumping. [Extracted from the article]

B Background: b Schizophrenia (SCZ) and major depressive disorder (MDD) have a partly shared genetic etiology, with the genetic correlation estimated at approximately 0.32 from the latest large-scale genome-wide association studies (GWAS). B Results: b 39 Pardinas risk loci for SCZ contained a total of 131 TCF4 binding sites, while 38 Howard risk loci contained a total of 134 TCF4 binding sites. SCZ risk loci with TCF4 binding sites were significantly enriched (FDR<0.1) in the "nicotine pharmacodynamics pathway", primarily driven by CHRNA3 and CHRNA5, whereas the MDD risk loci with TCF4 binding sites were significantly enriched in "N-cadherin signaling events". [Extracted from the article]

B Background: b Executive functions, i.e. cognition involving control and coordination of mental processes, are impaired in severe mental disorders. To fully take advantage of the PsyCourse sample, we included all genotyped patients and healthy control individuals which had at least one measurement point and performed linear mixed model (LMM) analyses to study the interactions of SNP and time on a genome-wide level. B Results: b In our preliminary analysis, nine SNPs reached genome-wide significance (5 × 10^-8) for the phenotype TMT-B, located within the same LD block (r^2>0.85) on chromosome 5. [Extracted from the article]

B Background: b Rare deleterious coding variants can have large effects on gene dosage potentially increasing risk for disease. B Methods: b Genome-sequencing quality control (QC) followed GATK best practices using Variant Quality Score Recalibration (VQSR) tool along with additional filtering steps. We analyzed the data from 394 samples of European descent in the Common Mind Consortium, where all samples had both genome-sequencing and RNA-sequencing of the dorsal lateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC) or both. [Extracted from the article]

B Background: b Nocturnal enuresis (NE) also known as bedwetting is a common disorder affecting more than 10-15% of all 6-year-old children and 1-2% of young adults. Positional, cis-eQTL and chromatin interaction gene mapping based in the NE associated variants and their LD friends (r2>=0.6) identified 12 protein coding candidate NE risk genes (PRDM13, PNISR, FAXC, COQ3, CCNC, SIM1, SLAIN1, EDNRB, POU4F1, RNF219, and RBM26). B Discussion: b Although sample sizes are modest in the present study, we have identified the first ever genome-wide significant loci in NE, estimated the SNP heritability and provided evidence for shared genetic risk with ADHD. [Extracted from the article]

B Background: b GWAS results indicate that the vast majority of genetic risk reside in gene regulatory regions, particularly enhancers and super-enhancers (SE). The SE located in the RERE gene was selected for functional studies based on the position of the associated markers for schizophrenia and major depressive disorder located entirely within the RERE-SE and our HiC data identifying compelling target genes, including RERE, PARK7 and PER3. [Extracted from the article]

B Background: b Autism spectrum disorder (ASD) is characterized as a group of neurodevelopmental disorders that begin early in childhood and can affect all ethnic groups. B Methods: b Here, we aimed to identify overlap in common genetic variants between ASD, loneliness and intelligence/cognition (COG) using genome-wide association study data on ASD (n= 46350), loneliness (n=452302) and COG (n=269867) applying the conditional false discovery rate (condFDR) method. Using conjunctional FDR (conjFDR) analysis, we leveraged this enrichment to increase statistical power and identified 7 distinct genomic loci associated with both ASD and loneliness, and 22 loci associated with both ASD and COG at conj FDR < 0.05. [Extracted from the article]

Next, Dr. Tian Ge will deliver a presentation on machine learning (ML) in a health care system with a focus on accessibility to ensure knowledge is transmitted effectively. Additionally, Dr. Ge will discuss the construction of polygenic risk scores using ML approaches and their application to the EHR. [Extracted from the article]

Here, we perform a large-scale genome-wide meta-analysis of insomnia in over 2million individuals by combining genome-wide association (GWAS) results in the UK Biobank (N=386,988) and 23andMe, Inc. (N=1,978,022) leading to a total current sample of 2,365,010 individuals. Gene-based association tests and gene mapping in FUMA, including positional, eQTL and chromatin interaction mapping, identified 3,073 genes. [Extracted from the article]

B Overall Abstract: b The quest to understand the genetic architecture of the human brain has been greatly accelerated by large-scale consortia pooling neuroimaging and genetic data worldwide on an unprecedented scale. In this symposium, leaders of the ENIGMA Consortium report on the largest studies to date of common and rare genetic variation and their effects on the human brain. [Extracted from the article]

B Overall Abstract: b Our current classification system divides severe mental illness (SMI) into dichotomous diagnostic categories; psychotic disorders and mood disorders. Dr. Carlos Lopez will present the Paisa project, including the sample diagnosis-naïve recruitment strategy and deep and uniform phenotyping, which involves diagnostic interview, symptom assessment and a neurocognitive battery. Dr. Carrie Bearden will present results from the Spanish-language Penn Computerized Neurocognitive Battery, evaluating contributions of both diagnosis and symptom domains to cognitive performance. [Extracted from the article]

B Overall Abstract: b The field of psychiatric genetics has witnessed rapid advances in our ability to probe the genetic factors that increase risk for psychiatric disorders such as depression, PTSD, and schizophrenia. This symposium will feature emerging research at the interface of genomics and resilience, highlighting methodological and conceptual distinctions from the study of psychiatric risk. Dr. Stein will then present GWAS data on resilience to combat-related PTSD from the Million Veteran Program, currently the largest single genomic database with linked electronic health record data for psychiatric phenotypes. [Extracted from the article]

B Abstract: b Schizophrenia and bipolar disorder are common, heritable, and chronic neuropsychiatric syndromes affecting tens of millions of individuals worldwide, and for which a significant fraction of the underlying genetic liability is shared. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P < 10-52), Latino (Nagelkerke's R2 = 0.089; liability R2 = 0.021; P < 10-58), and European individuals (Nagelkerke's R2 = 0.089; liability R2 = 0.037; P < 10-113). We further extend this research via a joint analysis with 3,942 schizophrenia and 5,414 bipolar I disorder cases from Veterans Affairs (VA) Cooperative Studies Program (CSP) #572: The Genetics of Functional Disability in Schizophrenia and Bipolar Illness (~40% of African American ancestry), and more than 100,000 screened control participants from the Million Veteran Program (MVP). [Extracted from the article]

B Abstract: b Advances in genomic technologies have significantly increased our ability to detect rare genetic etiologies of neuropsychiatric disorders (NPD), including schizophrenia (SCZ), bipolar disorder (BPD), and autism spectrum disorder (ASD). The phenotypic expression of a 1q21.1 deletion, for example, may take the form of a specific language impairment in one person, subthreshold ASD symptoms in another, and SCZ in another, even within the same family. Other individuals with the same rare variant, but having a different combination of background genomic and other risk factors, may never develop SCZ yet may manifest a different NPD presentation, such as BPD. [Extracted from the article]

B Abstract: b Background: Severe mental illnesses (SMI), such as bipolar disorder (BP), schizophrenia (SCZ) or schizoaffective disorder (SZA), are clinically heterogeneous and have symptoms and genetic risk in common. In order to create comparable dimensional phenotypes across diagnoses, we created statistical models based on the alignment method (Asparouhov & Muthén, 2014), which optimizes item-response theory (IRT) parameters to harmonize symptom-level data collected at different sites using different instruments. Symptom item-level data from different instruments are used to create factor scores for mania (n=37,088), depression (n=37,122), hallucinations (n=36,339), delusions (n=36,350), negative (n=4,927) and disorganized symptoms (n=36,194). [Extracted from the article]

Highlights from the article: Su139genome-wide association analysis of lifetime cannabis use (n=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use B Background: b Cannabis use is a heritable trait that has been associated with adverse mental health outcomes, including schizophrenia. B Discussion: b In summary, our GWAS of lifetime cannabis use revealed significant SNP and genes associations in 16 regions, 15 of which have not been previously implicated in cannabis use.

Highlights from the article: B Background: b Despite epidemiological and genetic reports on the association between schizophrenia and substance use, there has been limited research on the nature of causality with respect to these psychiatric disorders, particularly in cohorts of diverse ancestry. We also tested whether polygenic risk scores constructed from the results of the Tobacco and Genetics Consortium (TAG) meta-analyses of smoking behaviors and the International Cannabis Consortium (ICC) were associated with schizophrenia risk or substance use behaviors among schizophrenia cases. Comparing substance use behaviors among schizophrenia cases to the general population (TAG, ICC), we observe positive genetic correlations for smoking initiation and cannabis use.

Highlights from the article: Su106is genetic liability to schizophrenia mapping to the psychosis continuum model? Our hypothesis is that genetic liability to schizophrenia is associated with a gradient of psychosis expression, from "mild" psychosis phenotypes to fully diagnosed schizophrenia. B Discussion: b Our results show that genetic liability for schizophrenia, as measured by the PRS, is associated with a gradient of psychosis phenotypes, supporting the psychosis continuum model.

Highlights from the article: B Background: b The atypical antipsychotic drug clozapine is the only effective drug for treatment-resistant schizophrenia, but also bears the risk of inducing severe adverse drug responses including neutropenia and agranulocytosis. The Clozapine-Induced Agranulocytosis Consortium (CIAC) identified two independent loci in the major histocompatibility complex genome-wide associated with clozapine-induced agranulocytosis: A single amino acid in HLA-DQB1 (126Q) (OR=0.19, P=4.7E-14) and an amino acid change in HLA-B (158T) (OR=3.3, P=6.4E-10). B Results: b The genome-wide association analysis revealed 9 genome-wide hits in 2 independent regions, confirming the most associated marker from CIAC and the meta-analysis of CIAC and CLOZUK.