Cis-Acting Regulation of Brain-Specific ANK3 Gene Expression by a Genetic Variant Associated with Bipolar Disorder

Several genome-wide association studies (GWAS) for bipolar disorder (BD) have found a strong association of the Ankyrin3 (ANK3) gene. This association spans numerous linked single nucleotide polymorphisms (SNPs) in a ~250 kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as ankyrin-G (AnkG). Using RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE) to identify novel transcripts in conjunction with a highly sensitive, exon-specific multiplexed mRNA expression assay, we detected differential regulation of distinct ANK3 transcription start sites (TSSs) and coupling of specific 5’ ends with 3’ mRNA splicing events in post-mortem human brain and human stem cell-derived neural progenitors and neurons. Furthermore, allelic variation at the BD–associated SNP rs1938526 correlated with a significant difference in cerebellar expression of a brain-specific ANK3 transcript. These findings suggest a brain-specific cis-regulatory transcriptional effect of ANK3 may be relevant to BD pathophysiology

Joint contributions of rare copy number variants and common SNPs to risk for schizophrenia

Objective: Both rare copy number variants (CNVs) and common single-nucleotide polymorphisms (SNPs) contribute to liability to schizophrenia, but their etiological relationship has not been fully elucidated. The authors evaluated an additive model whereby risk of schizophrenia requires less contribution from common SNPs in the presence of a rare CNV, and tested for interactions. Method: Genetic data from 21,094 case subjects with schizophrenia and 20,227 control subjects from the Psychiatric Genomics Consortium were examined. Three classes of rare CNVs were assessed: CNVs previously associated with schizophrenia, CNVs with large deletions ≥500 kb, and total CNV burden. The mean polygenic risk scores (PRSs) between study subjects with and without rare CNVs were compared, and joint effects of PRS and CNVs on schizophrenia liability were modeled by using logistic regression. Results: Schizophrenia case subjects carrying risk CNVs had a lower polygenic risk than case subjects without risk CNVs but a higher risk than control subjects. For case subjects carrying known risk CNVs, the PRS was diminished in proportion to the effect size of the CNV. The strongly associated 22q11.2 deletion required little added PRS to produce schizophrenia. Large deletions and increased CNV burden were also associated with lower polygenic risk in schizophrenia case subjects but not in control subjects or after removal of known risk CNV carriers. Conclusions: The authors found evidence for interactive effects of PRS and previously associated CNVs for risk for schizophrenia, and the results for large deletions and total CNV burden support an additive model. These findings offer insights into the genetic architecture of schizophrenia by illuminating how different established genetic risk factors act and interact to influence liability to schizophrenia

Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe - A multi-professional survey study

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

Discovery and Statistical Genotyping of Copy-Number Variation from Whole-Exome Sequencing Depth

Sequencing of gene-coding regions (the exome) is increasingly used for studying human disease, for which copy-number variants (CNVs) are a critical genetic component. However, detecting copy number from exome sequencing is challenging because of the noncontiguous nature of the captured exons. This is compounded by the complex relationship between read depth and copy number; this results from biases in targeted genomic hybridization, sequence factors such as GC content, and batching of samples during collection and sequencing. We present a statistical tool (exome hidden Markov model [XHMM]) that uses principal-component analysis (PCA) to normalize exome read depth and a hidden Markov model (HMM) to discover exon-resolution CNV and genotype variation across samples. We evaluate performance on 90 schizophrenia trios and 1,017 case-control samples. XHMM detects a median of two rare

Overview of CAPICE-Childhood and Adolescence Psychopathology:unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe-an EU Marie Skłodowska-Curie International Training Network

Abstract The Roadmap for Mental Health and Wellbeing Research in Europe (ROAMER) identified child and adolescent mental illness as a priority area for research. CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) is a European Union (EU) funded training network aimed at investigating the causes of individual differences in common childhood and adolescent psychopathology, especially depression, anxiety, and attention deficit hyperactivity disorder. CAPICE brings together eight birth and childhood cohorts as well as other cohorts from the EArly Genetics and Life course Epidemiology (EAGLE) consortium, including twin cohorts, with unique longitudinal data on environmental exposures and mental health problems, and genetic data on participants. Here we describe the objectives, summarize the methodological approaches and initial results, and present the dissemination strategy of the CAPICE network. Besides identifying genetic and epigenetic variants associated with these phenotypes, analyses have been performed to shed light on the role of genetic factors and the interplay with the environment in influencing the persistence of symptoms across the lifespan. Data harmonization and building an advanced data catalogue are also part of the work plan. Findings will be disseminated to non-academic parties, in close collaboration with the Global Alliance of Mental Illness Advocacy Networks-Europe (GAMIAN-Europe)

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-alpha in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization. Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk

Combined Whole Methylome and Genomewide Association Study Implicates CNTN4 in Alcohol Use

BACKGROUND: Methylome-wide association (MWAS) studies present a new way to advance the search for biological correlates for alcohol use. A challenge with methylation studies of alcohol involves the causal direction of significant methylation-alcohol associations. One way to address this issue is to combine MWAS data with genomewide association study (GWAS) data. METHODS: Here, we combined MWAS and GWAS results for alcohol use from 619 individuals. Our MWAS data were generated by next-generation sequencing of the methylated genomic DNA fraction, producing over 60 million reads per subject to interrogate methylation levels at ~27 million autosomal CpG sites in the human genome. Our GWAS included 5,571,786 single nucleotide polymorphisms (SNPs) imputed with 1000 Genomes. RESULTS: When combining the MWAS and GWAS data, our top finding was a region in an intron of CNTN4 (p = 2.55 × 10(-8) ), located between chr3: 2,555,403 and 2,555,524, encompassing SNPs rs1382874 and rs1382875. This finding was then replicated in an independent sample of 730 individuals. We used bisulfite pyrosequencing to measure methylation and found significant association with regular alcohol use in the same direction as the MWAS (p = 0.021). Rs1382874 and rs1382875 were genotyped and found to be associated in the same direction as the GWAS (p = 0.008 and p = 0.009). After integrating the MWAS and GWAS findings from the replication sample, we replicated our combined analysis finding (p = 0.0017) in CNTN4. CONCLUSIONS: Through combining methylation and SNP data, we have identified CNTN4 as a risk factor for regular alcohol use

Do Dogs (Canis lupus familiaris) Make Counterproductive Choices Because They Are Sensitive to Human Ostensive Cues?

Dogs appear to be sensitive to human ostensive communicative cues in a variety of situations, however there is still a measure of controversy as to the way in which these cues influence human-dog interactions. There is evidence for instance that dogs can be led into making evaluation errors in a quantity discrimination task, for example losing their preference for a larger food quantity if a human shows a preference for a smaller one, yet there is, so far, no explanation for this phenomenon. Using a modified version of this task, in the current study we investigated whether non-social, social or communicative cues (alone or in combination) cause dogs to go against their preference for the larger food quantity. Results show that dogs' evaluation errors are indeed caused by a social bias, but, somewhat contrary to previous studies, they highlight the potent effect of stimulus enhancement (handling the target) in influencing the dogs' response. A mild influence on the dog's behaviour was found only when different ostensive cues (and no handling of the target) were used in combination, suggesting their cumulative effect. The discussion addresses possible motives for discrepancies with previous studies suggesting that both the intentionality and the directionality of the action may be important in causing dogs' social biases

Common genetic determinants of intraocular pressure and primary open-angle Glaucoma

10.1371/journal.pgen.1002611PLoS Genetics85