The DISC1 Pathway in the Genetic Etiology of Schizophrenia

Schizophrenia is a severe psychotic disorder affecting 0.5-1 % of the population. The disorder is characterized by hallucinations; delusions; disorganized behavior and speech; avolition; anhedonia; flattened affect and cognitive deficits. The etiology of the disorder is complex with evidence for multiple genes contributing to the onset of the disorder along with environmental factors. DISC1 is one of the most promising candidate genes for schizophrenia. It codes for a protein which takes part in numerous molecular interactions along several pathways. This network, termed as the DISC1 pathway, is evidently important for the development and maturation of the central nervous system from the embryo until young adulthood. Disruption at these pathways is thought to predispose schizophrenia. In the present study, we have studied the DISC1 pathway in the etiology of schizophrenia in the Finnish population. We have utilized large Finnish samples; the schizophrenia family sample where DISC1 was originally shown to associate with schizophrenia and the Northern Finland birth cohort 1966 (NFBC66). Several DISC1 binding partners displayed evidence for association in the family sample along with DISC1. Through a genome-wide linkage study, we found a significant linkage signal to a locus where a DISC1 binding partner NDE1 is located at the carriers of a certain DISC1 risk variant. In a follow-up study, genetic markers in NDE1 displayed significant evidence for association with schizophrenia. Further exploration of association between 11 genes of the DISC1 pathway and schizophrenia led to recognition of novel variants in NDEL1, PDE4B and PDE4D that significantly either increased or decreased the risk for schizophrenia. Further, we found evidence that DISC1 itself has a significant role in the human mental functioning even in the healthy population. Variants in DISC1 had a significant effect on anhedonia which is a trait present at everybody but is in its severe form one of the main symptoms of schizophrenia and correlates with the risk of developing the disorder. Further, utilizing genome-wide marker data, we recognized three genes; MIR620; CCDC141 and LCT; that are closely related to the DISC1 pathway but which effects on anhedonia were observable only at the individuals who carried these specific DISC1 variants. Our findings significantly add up to the previous evidence for the involvement of DISC1 and the DISC1 pathway in the etiology of schizophrenia and psychosis. Our results support the concept of a number of DISC1 pathway related genes contributing in the etiology of schizophrenia along with DISC1 and provide new candidates for the studies of schizophrenia. Our findings also significantly increase the importance of DISC1 itself as having a role in psychological functioning in the general population.Skitsofrenia on vakava psykoottinen mielenterveyden häiriö, jota sairastaa 0.5-1 % väestöstä. Skitsofrenian tyypillisiin oireisiin kuuluvat aistiharhat, harhaluulot, hajanainen puhe ja käytös, kiinnostuksen puute, vähentynyt kyky tuntea mielihyvää (anhedonia), tunteiden ilmaisun köyhyys sekä kongtiviivisen kyvyn alentuminen. Skitsofrenian tausta on monitekijäinen, eli sairauden puhkeamiseen vaikuttavat useat geneettiset sekä ympäristötekijät yhdessä. DISC1 on yksi lupaavimmista skitsofrenian ehdokasgeeneistä. DISC1:n koodaama proteiini vuorovaikuttaa monien muiden proteiinien kanssa (DISC1-polku) osallistuen lukuisiin prosesseihin, jotka ovat nykykäsityksen mukaan tärkeitä keskushermoston kehityksessä sikiökaudelta varhaiseen aikuisuuteen ja joiden häiriintyminen voi altistaa skitsofrenialle. Tässä tutkimuksessa olemme kartoittaneet DISC1-polun merkitystä skitsofrenian taustatekijänä suomalaisessa väestössä. Käytössämme on ollut laaja skitsofreniaperheaineisto, jossa aiemmin on havaittu yhteys DISC1:n ja skitsofrenian välillä, sekä suuri pohjoissuomalainen syntymäkohortti vuodelta 1966. Perheaineistossa DISC1:n ohella myös useat muut DISC1-polun geenit osoittautuivat olevan yhteydessä skitsofreniaan. Genominlaajuisessa analyysissä havaitsimme kytkentäsignaalin lähellä DISC1:n kanssa vuorovaikuttavaa NDE1:tä henkilöillä, jotka kantoivat tiettyä DISC1-riskimuotoa. Tarkemmassa assosiaatioanalyysissä kartoitimme tämän ja 11 muun tunnetun DISC1-polun geenin yhteyttä skitsofreniaan ja tunnistimme geeneissä NDE1, NDEL1, PDE4B ja PDE4D uusia variantteja, jotka olivat yhteydessä joko kohonneesseen tai alentuneeseen skitsofreniariskiin. Tulostemme perusteella DISC1:llä näyttää olevan tärkeä rooli myös terveen väestön käyttäytymiselle. Tietyt DISC1:n muodot näyttävät olevan yhteydessä anhedoniaan, joka on kaikilta mitattavissa oleva ominaisuus, mutta joka vaikeassa muodossaan on yksi skitsofrenian pääoireista ja korreloi skitsofreniaan sairastumisen riskin kanssa. Lisäksi genominlaajuisessa aineistossa tunnistimme kolme geeniä, MIR620, CCDC141 ja LCT, jotka läheisesti liittyvät DISC1-polkuun ja joiden yhteys anhedoniaan oli havaittavissa vain näiden tiettyjen DISC1-muotojen kantajilla. Löydöksemme tuovat uutta tietoa DISC1:n ja DISC1-polun merkityksestä skitsofrenian ja psykoosialttiuden taustatekijänä suomalaisessa väestössä. Tuloksemme tukevat aiempaa käsitystä siitä, että useat DISC1-polun geenit vaikuttavat skitsofrenia-alttiuteen DISC1:n ohella ja tarjoavat uusia ehdokasgeenejä tarkempia jatkotutkimuksia varten. Se, että DISC1:llä näyttää olevan yhteys käyttäytymiseen myös väestötasolla, tekee DISC1:stä entistäkin merkityksellisemmän ihmisen psyykkisten toimintojen kannalta

Thrombectomy in acute ischemic stroke in the extended time window : Real-life experience in a high-volume center

Objectives: Selected patients with acute ischemic stroke (AIS) caused by proximal middle cerebral artery (MCA) or internal carotid artery occlusion benefit from endovascular thrombectomy (EVT) in extended time window (6-24 h from last seen well) based on two landmark randomized controlled trials (RCTs) DAWN and DEFUSE-3. We evaluated patients' outcome in the real-life with the focus on adherence to protocol of the two RCTs. Materials and methods: We included consecutive patients with AIS (excluding basilar artery occlusions) referred to EVT in our stroke center in the extended time window between January 2018 and December 2019 and compared the outcome of patients who fulfilled criteria of the RCTs with those who did not. Results: Of the total of 100 patients, 23 complied with RCT's criteria and 18 presented with minor non-adherence (lower NIHSS score or longer treatment delay), whereas 22 patients had large baseline ischemia (>1/3 MCA), 28 presented with M2 and more distal occlusions, and 9 patients did not undergo perfusion imaging prior to EVT. Good 3-month outcome (modified Rankin Scale 0-2) was observed in 54% of those who either met the RCT criteria or presented with lower NIHSS score or longer treatment delay, but only in 30% of M2 occlusions, and in none of the patients with large baseline ischemia. Conclusions: Our findings highlight the impact of mostly large baseline ischemia but also vessel status when selecting patients for EVT in the extended time window and emphasize the need for further data in these patient subgroups. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Peer reviewe

An interaction between NDE1 and high birth weight increases schizophrenia susceptibility

Pre- and perinatal environmental factors have been shown to increase schizophrenia risk particularly when combined with genetic liability. The investigation of specific gene environment interactions in the etiology of psychiatric disorders has gained momentum. We used multivariate GEE regression modeling to investigate the interaction between genes of the DISCI pathway and birth weight, in relation to schizophrenia susceptibility in a Finnish schizophrenia family cohort. The study sample consisted of 457 subjects with both genotype and birth weight information. Gender and place of birth were adjusted for in the models. We found a significant interaction between birth weight and two NDE1 markers in relation to increased schizophrenia risk: a four SNP haplotype spanning NDE1 (b = 1.26, SE= 0.5, p = 0.012) and one of its constituent SNPs rs4781678 (b = 1.33, SE = 0.51, p = 0.010). Specifically, high birth weight (> 4000 g) was associated with increased schizophrenia risk among subjects homozygous for the previously identified risk alleles. The study was based on a family study sample with high genetic loading for schizophrenia and thus our findings cannot directly be generalized as representing the general population. Our results suggest that the functions mediated by NDE1 during the early stages of neurodevelopment are susceptible to the additional disruptive effects of pre- and perinatal environmental factors associated with high birth weight, augmenting schizophrenia susceptibility. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.Peer reviewe

Sfenopalatiiniganglion stimulaatio - kroonisen sarjoittaisen päänsäryn uusi hoitomuoto

English summaryPeer reviewe

DISC1 Conditioned GWAS for Psychosis Proneness in a Large Finnish Birth Cohort

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Genomic risk scores and oral contraceptive-associated ischemic stroke risk: a call for collaboration

BackgroundOral contraceptives (OCs) are generally safe but vascular risk factors increase OC-associated ischemic stroke risk. We performed a case-control study to evaluate whether a genomic risk score for ischemic stroke modifies OC-associated ischemic stroke risk.MethodsThe Genetics of Early-Onset Stroke study includes 332 premenopausal women (136 arterial ischemic stroke cases and 196 controls) with data on estrogen-containing OC use within 30 days before the index event (for cases) or interview (for controls). Using a previously validated genetic risk score (metaGRS) for ischemic stroke based on 19 polygenic risk scores for stroke and stroke-associated risk factors, we stratified our combined case-control sample into tertiles of genomic risk. We evaluated the association between OC use and ischemic stroke within each tertile. We tested if the association between OC use and ischemic stroke depended on the genomic risk of stroke using logistic regression with an OC use × metaGRS interaction term. These analyses were performed with and without adjustment for smoking, hypertension, diabetes, coronary heart disease, and body mass index.ResultsAfter adjustment for vascular risk factors, the odds ratio of OC use was 3.2 (1.7–6.3) overall and increased from the lower, middle, and upper tertile of genomic risk from 1.6 (0.5–5.4) to 2.5 (0.08–8.2) to 13.7 (3.8–67.3) respectively, and a p-value for interaction of 0.001.ConclusionsOur results suggest that genomic profile may modify the OC-associated ischemic stroke risk. Larger studies are warranted to determine whether a genomic risk score could be clinically useful in reducing OC-associated ischemic stroke

Prediction of early recurrent thromboembolic event and major bleeding in patients with acute stroke and atrial fibrillation by a risk stratification schema: the ALESSA score study

Background and Purposes—This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation. Methods—The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00–1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08–2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P=0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30–1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632–0.763; P=0.0001) for ischemic outcome events and 0.585 (0.493–0.678; P=0.10) for major bleedings. Results—The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529–0.763; P=0.009) for ischemic outcome events and 0.407 (0.275–0.540; P=0.14) for hemorrhagic outcome events. Conclusions—In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings

Stroke genetics informs drug discovery and risk prediction across ancestries

Daniel Strbian työryhmän jäsenenä Correction; Early Access DOI: 10.1038/s41586-022-05492-5 Early Access: NOV 2022Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.Peer reviewe

Timing of initiation of oral anticoagulants in patients with acute ischemic stroke and atrial fibrillation comparing posterior and anterior circulation strokes

Background: The aim of this study in patients with acute posterior ischemic stroke (PS) and atrial fibrillation (AF) were to evaluate the risks of recurrent ischemic event and severe bleeding and these risks in relation with oral anticoagulant therapy (OAT) and its timing. Methods: Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of: stroke recurrence, TIA, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. Results: A total of 2,470 patients were available for the analysis: 473 (19.1%) with PS and 1,997 (80.9%) AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39-2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16-1.80). Conclusions: Patients with posterior or anterior stroke and AF appear to have similar risks of ischemic or hemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT