Sex-dependent association study of complement C4 gene with treatment-resistant schizophrenia and hospitalization frequency.

The complement component 4 (C4) gene, codes for two isotypes, C4A and C4B, and can exist in long or short forms (C4L and C4S). The C4AL variant has been associated with elevated schizophrenia (SCZ) risk. Here, we investigated the relationship between C4 variation and clinical outcomes in SCZ.

Associating CYP2A6 structural variants with ovarian and lung cancer risk in the UK Biobank: replication and extension.

CYP2A6 is a polymorphic enzyme that inactivates nicotine; structural variants (SVs) include gene deletions and hybrids with the neighboring pseudogene CYP2A7. Two studies found that CYP2A7 deletions were associated with ovarian cancer risk. Using their methodology, we aimed to characterize CYP2A6 SVs (which may be misidentified by prediction software as CYP2A7 SVs), then assess CYP2A6 SV-associated risk for ovarian cancer, and extend analyses to lung cancer.

Heart rate variability: Evaluating a potential biomarker of anxiety disorders.

Establishing quantifiable biological markers associated with anxiety will increase the objectivity of phenotyping and enhance genetic research of anxiety disorders. Heart rate variability (HRV) is a physiological measure reflecting the dynamic relationship between the sympathetic and parasympathetic nervous systems, and is a promising target for further investigation. This review summarizes evidence evaluating HRV as a potential physiological biomarker of anxiety disorders by highlighting literature related to anxiety and HRV combined with investigations of endophenotypes, neuroimaging, treatment response, and genetics.

CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study.

CYP2A6, a genetically variable enzyme, inactivates nicotine, activates carcinogens, and metabolizes many pharmaceuticals. Variation in CYP2A6 influences smoking behaviors and tobacco-related disease risk. This phenome-wide association study examined associations between a reconstructed version of our weighted genetic risk score (wGRS) for CYP2A6 activity with diseases in the UK Biobank (N = 395 887).

Exploring the association of interleukin polymorphisms with aggression and internalizing behaviors in children and adolescents.

Background: There is growing evidence that inflammation influences mental health. Blood interleukin levels, which regulate inflammation, have been linked to aggression and internalizing behaviors. We performed a hypothesis-driven genetic study to (1) evaluate the association of IL1B, IL2, and IL6 gene variants with aggression and internalizing behaviors and (2) explore gene-environment interactions with childhood adversity in a deeply phenotyped childhood-onset aggression sample including 255 cases and 226 controls of European ancestry.

Pharmacogenetics of Antipsychotic Treatment in Schizophrenia.

Antipsychotics are the mainstay treatment for schizophrenia. There is large variability between individuals in their response to antipsychotics, both in efficacy and adverse effects of treatment. While the source of interindividual variability in antipsychotic response is not completely understood, genetics is a major contributing factor.

Transferability of Ancestry-Specific and Cross-Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations.

The Nicotine Metabolite Ratio (NMR; 3-hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in nonsmokers, former smokers, or intermittent smokers, for example, in evaluating tobacco-related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation.

Association Study of the Complement Component C4 Gene in Tardive Dyskinesia.

Tardive dyskinesia (TD) is a movement disorder that may develop in schizophrenia patients being treated long-term with antipsychotic medication. TD interferes with voluntary movements and leads to stigma, and can be associated with treatment non-adherence. The etiology of TD is unclear, but it appears to have a genetic component.

The complement system in schizophrenia: where are we now and what's next?

The complement system is a set of immune proteins involved in first-line defense against pathogens and removal of waste materials. Recent evidence has implicated the complement cascade in diseases involving the central nervous system, including schizophrenia. Here, we provide an up-to-date narrative review and critique of the literature on the relationship between schizophrenia and complement gene polymorphisms, gene expression, protein concentration, and pathway activity.

Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk.

Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases.

The Emerging Immunogenetic Architecture of Schizophrenia.

Schizophrenia is a severe psychiatric disorder of complex etiology. Immune processes have long been proposed to contribute to the development of schizophrenia, and accumulating evidence supports immune involvement in at least a subset of cases. In recent years, large-scale genetic studies have provided new insights into the role of the immune system in this disease.

A Comprehensive Analysis of Nuclear-Encoded Mitochondrial Genes in Schizophrenia.

Background: The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest that mitochondrial dysfunction may play a role in SCZ, but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ.

Joint evaluation of serum C-Reactive Protein levels and polygenic risk scores as risk factors for schizophrenia.

Several studies have indicated infectious and immune-related abnormalities in schizophrenia (Scz), including elevated serum C-reactive protein (CRP) - a well-known proxy for infections/immune abnormalities. A portion of the genetic risk for Scz can be estimated using the polygenic risk score (PGRS). It is not known whether there is an interaction in the risks traceable to CRP and PGRS.

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases.

Objectives: We assessed the current genetic evidence for the involvement of various cell types and tissue types in the etiology of neurodegenerative diseases, especially in relation to the neuroinflammatory hypothesis of neurodegenerative diseases.

Methods: We obtained large-scale genome-wide association study (GWAS) summary statistics from Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We used multiple sclerosis (MS), an autoimmune disease of the central nervous system, as a positive control.

Impact of histamine receptors H1 and H3 polymorphisms on antipsychotic-induced weight gain.

Objectives: A positive correlation between antipsychotic-induced weight gain (AIWG) and the antagonist effect of antipsychotic drugs at the histamine H1 receptor (HRH1) as well as the agonist effect at the histamine H3 receptor (HRH3) in the brain has been consistently demonstrated. We investigated the potential impact of single-nucleotide polymorphisms (SNPs) in HRH1 and HRH3 genes on AIWG.

Methods: We analysed 40 tagSNPs in HRH1 (n = 34) and HRH3 (n = 6) in schizophrenia/schizoaffective disorder patients (n = 193) primarily treated with clozapine or olanzapine for up to 14 weeks.

Rapporteur summaries of plenary, symposia, and oral sessions from the XXIIIrd World Congress of Psychiatric Genetics Meeting in Toronto, Canada, 16-20 October 2015.

The XXIIIrd World Congress of Psychiatric Genetics meeting, sponsored by the International Society of Psychiatric Genetics, was held in Toronto, ON, Canada, on 16-20 October 2015. Approximately 700 participants attended to discuss the latest state-of-the-art findings in this rapidly advancing and evolving field. The following report was written by trainee travel awardees.

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study.

Background: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.

Methods And Findings: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs).

Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases.

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se.

A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases.

There is growing evidence of shared risk alleles for complex traits (pleiotropy), including autoimmune and neuropsychiatric diseases. This might be due to sharing among all individuals (whole-group pleiotropy) or a subset of individuals in a genetically heterogeneous cohort (subgroup heterogeneity). Here we describe the use of a well-powered statistic, BUHMBOX, to distinguish between those two situations using genotype data.

Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles.

Cerebrovascular and microglial states are not altered by functional neuroinflammatory gene variant.

The translocator protein, a microglial-expressed marker of neuroinflammation, has been implicated in Alzheimer's disease, which is characterized by alterations in vascular and inflammatory states. ATSPOvariant, rs6971, determines binding affinity of exogenous radioligandsin vivo; however, the effect of these altered binding characteristics on inflammatory and cerebrovascular biomarkers has not been assessed. In 2345 living subjects (Alzheimer's Disease Neuroimaging Initiative, n = 1330) and postmortem brain samples (Religious Orders Study and Memory and Aging Project, n = 1015), we analyzed effects of rs6971 on white matter hyperintensisites, cerebral infarcts, circulating inflammatory biomarkers, amyloid angiopathy, and microglial activation.

Increased Nigral SLC6A3 Activity in Schizophrenia Patients: Findings From the Toronto-McLean Cohorts.

SLC6A3, which encodes the primary regulator of extracellular dopamine (DA) concentration, the DA transporter, has been implicated in schizophrenia (SCZ). However, the details of its genetic effect on risk remain largely unknown. The purpose of this candidate gene study was to identify a specificSLC6A3activity associated with SCZ by using functional genetic approaches.