Gene fusions are important cancer drivers in pediatric cancer and their accurate detection is essential for diagnosis and treatment. Clinical decision-making requires high confidence and precision of ...detection. Recent developments show RNA sequencing (RNA-seq) is promising for genome-wide detection of fusion products but hindered by many false positives that require extensive manual curation and impede discovery of pathogenic fusions.
We developed Fusion-sq to overcome existing disadvantages of detecting gene fusions. Fusion-sq integrates and "fuses" evidence from RNA-seq and whole genome sequencing (WGS) using intron-exon gene structure to identify tumor-specific protein coding gene fusions. Fusion-sq was then applied to the data generated from a pediatric pan-cancer cohort of 128 patients by WGS and RNA sequencing.
In a pediatric pan-cancer cohort of 128 patients, we identified 155 high confidence tumor-specific gene fusions and their underlying structural variants (SVs). This includes all clinically relevant fusions known to be present in this cohort (30 patients). Fusion-sq distinguishes healthy-occurring from tumor-specific fusions and resolves fusions in amplified regions and copy number unstable genomes. A high gene fusion burden is associated with copy number instability. We identified 27 potentially pathogenic fusions involving oncogenes or tumor-suppressor genes characterized by underlying SVs, in some cases leading to expression changes indicative of activating or disruptive effects.
Our results indicate how clinically relevant and potentially pathogenic gene fusions can be identified and their functional effects investigated by combining WGS and RNA-seq. Integrating RNA fusion predictions with underlying SVs advances fusion detection beyond extensive manual filtering. Taken together, we developed a method for identifying candidate gene fusions that is suitable for precision oncology applications. Our method provides multi-omics evidence for assessing the pathogenicity of tumor-specific gene fusions for future clinical decision making.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Since 2008, multiple studies have reported on copy number variations (CNVs) in schizophrenia. However, many regions are unique events with minimal overlap between studies. This makes it ...difficult to gain a comprehensive overview of all CNVs involved in the etiology of schizophrenia. We performed a systematic CNV study on the basis of a homogeneous genome-wide dataset aiming at all CNVs ≥50 kilobase pair. We complemented this analysis with a review of cytogenetic and chromosomal abnormalities for schizophrenia reported in the literature with the purpose of combining classical genetic findings and our current understanding of genomic variation. Methods We investigated 834 Dutch schizophrenia patients and 672 Dutch control subjects. The CNVs were included if they were detected by QuantiSNP ( http://www.well.ox.ac.uk/QuantiSNP/ ) as well as PennCNV ( http://www.neurogenome.org/cnv/penncnv/ ) and contain known protein coding genes. The integrated identification of CNV regions and cytogenetic loci indicates regions of interest (cytogenetic regions of interest CROIs). Results In total, 2437 CNVs were identified with an average number of 2.1 CNVs/subject for both cases and control subjects. We observed significantly more deletions but not duplications in schizophrenia cases versus control subjects. The CNVs identified coincide with loci previously reported in the literature, confirming well-established schizophrenia CROIs 1q42 and 22q11.2 as well as indicating a potentially novel CROI on chromosome 5q35.1. Conclusions Chromosomal deletions are more prevalent in schizophrenia patients than in healthy subjects and therefore confer a risk factor for pathogenicity. The combination of our CNV data with previously reported cytogenetic abnormalities in schizophrenia provides an overview of potentially interesting regions for positional candidate genes.
Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the ...brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide ...association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147C, upstream of vaccinia-related kinase 2 (VRK2) odds ratio (OR) = 1.09, P = 1.9 × 10−9 and rs4309482A, between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10−9).
Background Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct ...heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. Methods Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. Results In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume ( R2 =.048, p =1.6×10−4 ) and white matter volume ( R2 =.051, p =8.6×10−5 ) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter ( n =2020) was much smaller than the entire set of SNPs that modulated disease status ( n =14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. Conclusions These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.
Emerging evidence suggests that schizophrenia (SZ) susceptibility involves variation at genetic, epigenetic and transcriptome levels. We describe an integrated approach that leverages DNA methylation ...and gene expression data to prioritize genetic variation involved in disease. DNA methylation levels were obtained from whole blood of 260 SZ patients and 250 unaffected controls of which a subset with gene expression data was available. By assessing DNA methylation and gene expression in cases and controls, we identified 432 CpG sites with differential methylation levels that are associated with differential gene expression. We hypothesized that genetic factors involved in these methylation levels may be associated with the genetic risk of SZ susceptibility. To test this hypothesis, we used results from the Psychiatric Genomics Consortium SZ genome-wide association study (GWAS). We observe an enrichment of SZ-associated SNPs in the mQTLs of which the associated CpG site is also correlated with differential gene expression in SZ. While this enrichment was already apparent when using nominal significant thresholds, enrichment was even more pronounced when applying more stringent significance levels. One locus, previously identified as susceptibility locus in a SZ GWAS, involves SNP rs11191514:C>T, which regulates DNA methylation of calcium homeostasis modulator 1 that is also associated with differential gene expression in patients. Overall, our results suggest that epigenetic variation plays an important role in SZ susceptibility and that the integration of analyses of genetic, epigenetic and gene expression profiles may be a biologically meaningful approach for identifying disease susceptibility loci, even when using whole blood data in studies of brain-related disorders.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have ...identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19 000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10−3), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10−5), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10−3; NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10−5). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
Animal studies have revealed seasonal patterns in cerebrospinal fluid (CSF) monoamine (MA) turnover. In humans, no study had systematically assessed seasonal patterns in CSF MA turnover in a large ...set of healthy adults.
Standardized amounts of CSF were prospectively collected from 223 healthy individuals undergoing spinal anesthesia for minor surgical procedures. The metabolites of serotonin (5-hydroxyindoleacetic acid, 5-HIAA), dopamine (homovanillic acid, HVA) and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MPHG) were measured using high performance liquid chromatography (HPLC). Concentration measurements by sampling and birth dates were modeled using a non-linear quantile cosine function and locally weighted scatterplot smoothing (LOESS, span = 0.75). The cosine model showed a unimodal season of sampling 5-HIAA zenith in April and a nadir in October (p-value of the amplitude of the cosine = 0.00050), with predicted maximum (PC(max)) and minimum (PC(min)) concentrations of 173 and 108 nmol/L, respectively, implying a 60% increase from trough to peak. Season of birth showed a unimodal 5-HIAA zenith in May and a nadir in November (p = 0.00339; PC(max) = 172 and PC(min) = 126). The non-parametric LOESS showed a similar pattern to the cosine in both season of sampling and season of birth models, validating the cosine model. A final model including both sampling and birth months demonstrated that both sampling and birth seasons were independent predictors of 5-HIAA concentrations.
In subjects without mental illness, 5-HT turnover shows circannual variation by season of sampling as well as season of birth, with peaks in spring and troughs in fall.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic ...risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10
; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.
Abstract Season of birth – in particular winter birth – has been persistently related to increased schizophrenia risk. Variation in folate intake is among the explanations for this seasonal effect. ...Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate mediated methylation transfer reactions. Interestingly, the MTHFR gene has been related to schizophrenia risk in various studies. We investigated a possible interaction between MTHFR 677 C>T polymorphism and winter birth in the development of schizophrenia in a group of 742 schizophrenia patients and 884 control subjects. All subjects were of Dutch ancestry. Winter birth (December up to and including February) was associated with a 20% increase in schizophrenia risk (odds ratio (OR) of 1.20 and 95% confidence interval (CI), 0.96–1.5; P = 0.113). The MTHFR 677TT genotype was associated with an overall schizophrenia risk of 1.13 (95% CI, 0.82–1.57; P = 0.454) compared with the MTHFR 677CC genotype. In the winter period the MTHFR 677TT genotype associated schizophrenia risk was 0.90 (95% CI, 0.47–1.70; P = 0.744). In conclusion, neither winter birth nor MTHFR genotype were significantly associated with increased schizophrenia risk. There was no evidence for interaction between MTHFR 677TT genotype and winter birth in the development of schizophrenia.
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