708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects:analysis for association with psychiatric disorder and cognitive traits

A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10-5, OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies. © 2014 Macmillan Publishers Limited

DISC1 genetics, biology and psychiatric illness

Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points towards DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans

Effects of a balanced translocation between chromosomes 1 and 11 disrupting the DISC1 locus on white matter integrity

Objective Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3). Method Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33). Results We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity. Conclusions We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis

Abstract 1122‐000154: Effect of Intravenous Thrombolysis on Early Clot Lysis in Large Vessel Occlusion Strokes Undergoing Thrombectomy

Introduction: Intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) are both standard of care treatments for acute ischemic stroke patients with large vessel occlusion (LVO) who are eligible for one or both treatments. IVT may result in early recanalization in some patients with LVO. The objective of this study is to analyze whether IVT influences pre‐thrombectomy clot lysis in LVO acute ischemic strokes. Methods: We reviewed prospectively collected data for all patients with LVO ischemic strokes who were transferred to the angiography suite with intention to perform EVT at a single comprehensive stroke center between January 2016 to December 2018. We identified subjects who showed partial or complete clot lysis vs no lysis based on the first angiographic picture of the occluded territory at the time of the initial vessel selection. Descriptive statistics were used to summarize demographic and clinical characteristics. We compared key predictor variables between lysis and no lysis groups including baseline variables, effect of IVT, time from IVT to groin puncture, LVO location, final modified treatment in cerebral ischemia (mTICI) score and discharge Modified Rankin Scale (mRS). t‐test or Kruskal‐Wallis test for continuous variables and chi square test or Fisher’s Exact test for categorical variables. Results: Two hundred and fifty‐nine patients were included. Among these patients, 10.8% (28/259) showed partial or complete lysis of the clot vs 89.2% (231/259) with no lysis. Among these patients who showed clot lysis, 16/28 (57.1%) received IVT. The use of IVT did not show differences between both groups (p = 0.18). There were no differences in the baseline characteristics except for gender, which was the only variable significantly associated with clot lysis. Men had 2‐fold higher odds of spontaneous lysis compared to females (OR [95%CI]: 2.39 [1.01, 5.65], p = 0.04). There was significant difference in the final mTICI between both groups (p <0.001). Conclusions: Our study showed that IVT in a modern practice was not associated with pre‐thrombectomy lysis. Some patients had pre‐thrombectomy lysis despite not receiving IVT

E-067 Importance of First Pass Reperfusion in Endovascular Stroke Care – Insights from STAR

BackgroundEndovascular therapy (EVT) has become the first line treatment strategy for patients with large vessel occlusion strokes (LVOS). However, often more than one thrombectomy maneuver - either using stent-retrievers, thrombus aspiration or combined approaches - is necessary to achieve reperfusion. A true first pass effect with improved functional outcomes after MT has been described previously in single center data. Aim of the present study is to investigate the effect of true first-pass complete recanalization vs. multi-pass complete recanalization on functional outcome in a large, multicenter stroke database.MethodsPatients who underwent MT for LVOS in the anterior cerebral circulation between January 2014 to January 2021 and achieved complete reperfusion were identified from the Stroke Thrombectomy and Aneurysm Registry (STAR). We compared functional outcomes of patients with first- (defined as mTICI 3 after a single thrombectomy maneuver) vs. multiple-pass complete reperfusion (defined as mTICI 3 after ≥1 thrombectomy maneuvers).ResultsA total of 1481 patients with anterior circulation LVOS and successful recanalization were included in the analysis. First-pass complete recanalization was achieved in 778 patients vs. 703 patients with multi-pass complete reperfusion. Patients with first pass complete recanalization had lower NIHSS at baseline (15 ± 7 vs 16 ± 7, p=0.056), had higher ASPECTS at baseline (8.3 vs 7.8, p<0.001), were less likely to be male (47% vs 51%, p=0.078) and to have intracranial ICA occlusions (14% vs. 27%) as well as more likely to have M1/M2 occlusions (86% vs. 73%, o<0.001), diabetes mellitus (28% vs. 24%, p=0.076), atrial fibrillation (37% vs. 32%, p=0.064). Patients with first pass complete reperfusion hat a trend towards a lower discharge NIHSS (8 vs. 10, p=0.075) and higher improvement of the NIHSS (7 vs. 5, p=0.168). Among the factors lower age (OR 0.966, p<0.010), lower pre-stroke mRS (OR 0.601, p<0.001), diabetes mellitus (OR 0.612, p=0.014), higher ASPECTS (OR 1.183, p<0.001) first pass complete recanalization persisted as a independent predictor of favorable functional outcome (defined as modified Rankin Scale ≤2; OR 1.49, p=0.026).ConclusionThis analysis of a large, multi-center stroke database confirms the importance of first pass reperfusion in endovascular stroke care.Disclosures I. Maier: None. M. Psychogios: None. J. Liman: None. S. Al Kasab: None. E. Almallouhi: None. A. Alawieh: None. S. Wolfe: None. K. Fargen: None. A. Arthur: None. N. Goyal: None. T. Dumont: None. P. Kan: None. J. Kin: None. R. De Leacy: None. J. Osbun: None. A. Rai: None. P. Jabbour: None. J. Grossberg: None. M. Park: None. R. Starke: None. R. Crosa: None. A. Spiotta: None. D. Behme: None

Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation

Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss