Abstract
Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. ...The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a
MYC
translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in
MCL1
and
IRF4
. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.
Abstract Serotonergic neurotransmission dysfunctions have been well documented in patients with suicidal behaviour. We investigated monoamine oxidase A (MAOA: rs2064070, rs6323, rs909525) and B(MAOB: ...rs1799836, rs2311013, rs2205655) genetic modulation of personality traits (Temperament and Character Inventory, TCI) as endophenotype for suicidal behaviour. 108 suicide attempters and 286 healthy controls of German origin were screened. Among females, allelic analyses revealed associations between MAOA rs6323 A allele and higher Harm Avoidance in suicide attempters and MAOB rs2205655 A allele and higher Cooperativeness scores in healthy controls. Among males, MAOA rs909525 A allele was associated with higher Reward Dependence in suicide attempters. Multivariate analyses controlling for age and educational level mainly confirmed results. Case-control analyses in this subsample do not differ from our previously reported one. Despite of the small sample size, a possible involvement of these genes in the modulation of personality traits closely related to suicidal behaviour cannot be excluded.
The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular ...features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ∼20% of newly diagnosed FL in which the detection rate of t(14;18) is only ∼50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an “advanced-stage signature” in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio HR, 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a “localized-stage signature” had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.
•Development of a robust GE signature discriminating localized-stage and advanced-stage FL.•The genetic signature may be responsible for the superior outcome of localized-stage FL.
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Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different ...instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.
GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic ...spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA)≥250 and (GAA)200-249 expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine.
Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial.
Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA)≥250 expansion. FGF14 (GAA)200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2191; OR, 15.20; 95% CI, 7.52–30.80; p < 0.0001). The phenotype of patients carrying a (GAA)200-249 allele closely mirrored that of patients carrying a (GAA)≥250 allele. Patients carrying a (GAA)≥250 or a (GAA)200-249 allele had a significantly greater clinician-reported (80%, 33/41 vs 31%, 5/16; RR, 2.58; 95% CI, 1.23–5.41; Fisher's exact test, p = 0.0011) and self-reported (59%, 32/54 vs 11%, 2/19; RR, 5.63; 95% CI, 1.49–21.27; Fisher's exact test, p = 0.00033) response to 4-aminopyridine treatment compared to patients carrying a (GAA)<200 allele. Placebo-controlled video-oculography data, available for four patients carrying an FGF14 (GAA)≥250 expansion, showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo.
This study confirms that FGF14 GAA expansions are a frequent cause of DBN syndromes. It provides preliminary evidence that (GAA)200-249 alleles might be pathogenic. Finally, it provides large real-world and preliminary piloting placebo-controlled evidence for the efficacy of 4-aminopyridine in GAA-FGF14 disease.
This work was supported by the Clinician Scientist program “PRECISE.net” funded by the Else Kröner-Fresenius-Stiftung (to CW, AT, and MSy), the grant 779257 “Solve-RD” from the European’s Union Horizon 2020 research and innovation program (to MSy), and the grant 01EO 1401 by the German Federal Ministry of Education and Research (BMBF) (to MSt). This work was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) N° 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575 (to MSy, BB and—as associated partner—SZ), the NIH National Institute of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to SZ), the Fondation Groupe Monaco (to BB), and the Montreal General Hospital Foundation (grant PT79418 to BB). The Care4Rare Canada Consortium is funded in part by Genome Canada and the Ontario Genomics Institute (OGI-147 to KMB), the Canadian Institutes of Health Research (CIHR GP1-155867 to KMB), Ontario Research Foundation, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation. The funders had no role in the conduct of this study.
This study investigates the association of four single nucleotide polymorphisms (SNPs) in the serotonin 2A (5-HT-2A) receptor gene with anger-, aggression- and suicide-related behavior in a total of ...566 subjects (203 German suicide attempters and 363 German community-based healthy volunteers).
Anger- and aggression-related traits were assessed by using the State Trait Anger Expression Inventory (STAXI) and the Questionnaire for Measuring Factors of Aggression (FAF).
Three (rs643627–rs594242–rs6311: A–C–T), two (rs594242–rs6311: C–T) and a single functional (rs6311: T) marker were protective against suicidal behavior. The complementary makers (rs594242–rs6311: G–C and rs6311: C) were associated with increased risk for non-violent (
p
=
0.01;
p
=
0.009 respectively) and impulsive suicidal behavior (
p
=
0.03;
p
=
0.01 respectively). Furthermore, CC-homozygotes for the functional SNP rs6311 reported more anger- (
p
=
0.004) and aggression-related behavior (
p
=
0.011).
We conclude that variations in the 5-HT-2A gene may modify the phenotype of suicide-, anger-, and aggression-related behavior. Further studies should especially focus on intermediate personality traits in this context.
Abstract Toxoplasma gondii (T. gondii ) chronic infection and elevated kynurenine (KYN) levels have been individually associated with non-fatal suicidal self-directed violence (NF-SSDV). We aimed to ...test the hypothesis that the association between T. gondii seropositivity and history of NF-SSDV would be stronger in schizophrenia patients with high plasma KYN levels than in those with lower KYN levels. We measured anti- T. gondii IgG antibodies and plasma KYN in 950 patients with schizophrenia, and used logistic regression to evaluate the relationship between NF-SSDV and KYN in patients who were either seropositive or seronegative for T. gondii . For those with KYN levels in the upper 25th percentile, the unadjusted odds ratio for the association between NF-SSDV history and KYN in T. gondii seropositive patients was 1.63 (95% CI 1.01 to 2.66), p = 0.048; the adjusted odds ratio was 1.95 (95% CI 1.15 to 3.30), p = 0.014. Plasma KYN was not associated with a history of NF-SSDV in T. gondii seronegative patients. The results suggest that T. gondii and KYN may have a nonlinear cumulative effect on the risk of NF-SSDV among those with schizophrenia. If confirmed by future longitudinal studies, this result is expected to have both theoretical and clinical implications for the prevention and treatment of suicidal behavior.
The aim of the study was to detect the genetic predictors of reseponse to haloperidol.
Haloperidol is a benchmark drug for the pharmacological treatment of schizophrenia, but the genetics of its ...efficacy is yet to be elucidated.
A genome-wide association analysis was carried out in a small sample of patients treated with haloperidol (n=96) and the results were replicated in a larger sample of patients treated with second-generation antipsychotics or perphenazine (final n=169, available from the Clinical Antipsychotic Trials for Intervention Effectiveness study). The Positive and Negative Symptom Scale % score decrease was the outcome in both samples. The period of observation was restricted to 1 month in the replication sample and the most severe cases were included to best balance the replication. The quality control (QC) for the investigation and replication sample included a minor allele frequency at least 0.01, call rate at least 0.95, and Hardy-Weinberg equilibrium P at least 0.0001. The source for imputation was the 1000 Genomes Pilot+HapMap 3 dataset. In total 1 080 870 single nucleotide polymorphisms (SNPs) were available after imputation and QC in the investigation sample. After QC of real genotypes, locus-targeted imputations were restricted to windows of 10 kb on either side of the sentinel SNP in the replication sample. Sentinel SNPs were the most significant findings in the investigation sample. Analysis of variance was the test of choice, PLINK, SNPTEST, and GTOOL were used in the analysis.
Two SNPs (rs7912580 and rs2412459) were associated with response in both samples, respectively, located in an intergenic region between the AT-rich interactive domain 5B (ARID5B, MRF1-like) gene and rhotekin 2 (RTKN2) gene, an intronic region located in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene (P=1.358e-06 and 0.015 for the Positive and Negative Symptom Scale % total score decrease in the investigation and replication samples, respectively). The direction of association was opposite in the two samples, a finding that is sometimes reported as a flip-flop association.
Heterozygosis for the ancestral allele was associated with the best improvement in the investigation sample and with poorer outcome in the replication sample. This discrepancy can be because of differences in the replication and investigation sample including the drugs used and the severity at baseline. Nevertheless, this finding is in line with two relevant hypothesis of schizophrenia, related to alterations in the immunological system (RTKN2) and in the neurodevelopment of the central nervous system (EIF2AK4). More studies are warranted to further investigate these associations.
Previous research revealed experiences of childhood adversity (CA) to be related to less favorable parenting behavior. It can further be expected that maternal oxytocin receptor (OXTR) genes may ...influence parenting behavior and moderate relationships between CA and parenting behavior. Moreover, associations between the OXTR gene and plasma oxytocin (OT) have been discussed. The present study investigated main effects of the OXTR gene on parenting behavior and plasma OT of mothers, and moderating effects of the OXTR gene on the relationship between mothers’ experiences of CA and parenting behavior. We relied on a sample of 193 mothers and their on average 8-year-old children. Maternal experiences of CA were assessed using a standardized interview. A questionnaire for the assessment of child abuse potential and observations of mother–child interaction were used as indicators of parenting behavior. For mothers, we analyzed three polymorphisms (rs53576, rs1042778, rs2254298) of the OXTR gene and plasma OT. Only the rs53576 was associated with mothers’ parenting behavior, specifically with maternal sensitivity. The rs2254298 significantly moderated relations between mothers’ experiences of CA and parenting behavior. Significant relations could be found only for mothers who were homozygous for the G allele. The G allele of the rs2254298 was further related to increased plasma OT levels. Our findings underline the importance of considering genetic variation when investigating consequences of CA and developing intervention programs that are adapted to an individual’s needs.
Disturbances in the gamma-frequency band of electroencephalography (EEG) measures are among the most consistently observed intermediate phenotypes in schizophrenia. We assessed whether genetic ...variations are associated with gamma-band activity.
We performed a genome-wide association analysis of the early auditory evoked gamma-band response in schizophrenia affected subjects and healthy control individuals (in total N = 315).
No marker surpassed the threshold for genome-wide significant association. Several of the markers that were closest to significance mapped to genes involved in neuronal development and the Neuregulin-ErbB signalling network, such as NRG2 and KALRN. Using a gene-set enrichment analysis, we found suggestive evidence for association with genes involved in EEG abnormality (P = .048).
We identified no marker genome-wide significantly associating with gamma response; independent replication of the gene-set analysis result and larger sample sizes will be required to provide leads to cellular pathways involved in gamma-band activity.
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