Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Validation of an instrument for characterizing and quantifying physiologic tremor (PT) in children

Mit dieser Arbeit wollte ich das „Tremormeter“ (eine Metallplatte mit neun vertikal angeordneten Öffnungen von abnehmendem Durchmesser, in die die Probanden für 30 Sekunden einen Metallstab halten müssen, ohne den Lochrand zu berühren) für die Charakterisierung und Quantifizierung des physiologischen Tremors (PT) bei Kindern evaluieren und validieren. Hierfür untersuchte ich 1.142 neurologisch gesunde Schüler im Alter zwischen sechs und 25 Jahren. In dieser Altersgruppe muss die motorische Entwicklung als Einflussfaktor auf die Testergebnisse berücksichtigt werden, weshalb ich die mittels „Tremormeter“ erhobenen Normwerte nach Alter und Geschlecht stratifizierte. Zusätzlich setzte ich Frostigs Entwicklungstest der visuellen Wahrnehmung (Subtest I) ein, um den Einfluss der Augen-Hand-Koordination auf die Ergebnisse des „Tremormeters“ zu quantifizieren. Auch überprüfte ich den Einfluss weiterer Faktoren (Händigkeit der Probanden, Nikotin-, Drogen- und Koffeinkonsum sowie die Schlafdauer in der Nacht vor Testdurchführung) auf die Ergebnisse des „Tremormeter“-Tests. Um zu beurteilen, inwieweit der objektiv messbare „reine“ Tremor in die Leistung des „Tremormeter“-Tests eingeht, untersuchte ich nach Abschluss meiner Testreihe mit den Schülern 102 Erwachsene sowohl mittels „Tremormeter“ als auch triaxialer Akzelerometrie. Meine Hypothesen zu Beginn der Untersuchung waren folgende: (1) eine in der Akzelerometrie gemessene hohe Tremorfrequenz bedingt im „Tremormeter“-Test viele Berührungen des Lochrandes und (2) eine akzelerometrisch gemessene große Tremoramplitude äußert sich im „Tremormeter“-Test in Berührungen in Öffnungen mit relativ großem Durchmesser. Diese Hypothesen ließen sich im Verlauf der Untersuchungen nicht verifizieren. Das Ausmaß des Einflusses, den die einzelnen Faktoren (Alter, Geschlecht und Händigkeit der Probanden, Nikotin-, Drogen- und Koffeinkonsum sowie die Schafdauer in der Nacht vor Testdurchführung) unabhängig voneinander auf die Testergebnisse des „Tremormeters“ haben, berechnete ich anhand der multiplen linearen Regressionsanalyse. Eine hochsignifikante Abhängigkeit der Testergebnisse (p<0,001) fand ich im Kindes- und Jugendalter für das Alter und Geschlecht der Probanden. Dieser alters- und geschlechtsspezifische Unterschied ließ sich im Erwachsenenalter nicht mehr nachweisen. Für Nikotin-, Drogen- und Koffeinkonsum konnte ich keinen Einfluss auf die Testergebnisse nachweisen, was jedoch auch auf die nicht quantitative, sondern nur qualitative Erhebung dieser Faktoren zurückzuführen sein mag. Die Händigkeit der Probanden und die Schlafdauer vor Testdurchführung zeigten auf einige gemessene Parameter des „Tremormeter“-Tests einen signifikanten Einfluss. Die mittels Frostig-Test beurteilte Visuomotorik stellte sich als signifikanter Einflussfaktor auf die Ergebnisse des „Tremormeters“ dar. Insgesamt ließen sich 28-42% der Leistung des „Tremormeter“-Tests durch die Ergebnisse des Frostig-Tests, verbunden mit den Parametern Alter, Geschlecht, Händigkeit, Schlafdauer, Nikotin-, Drogen- und Koffeinkonsum, erklären. Die Ergebnisse der Akzelerometrie, zusammen mit den Faktoren Alter, Geschlecht, Händigkeit, Nikotin-, Drogen- und Koffeinkonsum, erklärten 10-36% der Ergebnisse des „Tremormeters“. Der Einfluss vieler weiterer Faktoren auf die „Tremormeter“-Testergebnisse ist denkbar. Diese könnten zum Beispiel metabolischer, hormoneller oder toxikologischer Art sein. Da jedoch das Alter und Geschlecht im Alter bis 18 Jahren die bedeutsamsten Einflussfaktoren darstellen, ist vermutlich insbesondere der Stand der motorischen Entwicklung des Kindes für das Abschneiden im „Tremormeter“-Test von Bedeutung. Das „Tremormeter“/„Motormeter“ könnte daher als spielerische, nicht-invasive Methode in der pädiatrischen Sprechstunde gut eingesetzt werden. In diesem Setting würden die von mir erhobenen Normwerte vielleicht vielmehr der Beurteilung motorischer Störungen im Kindesalter als der Quantifizierung des Tremors dienen.The evaluation and validation of the „Tremormeter“ for characterizing and quantifying the physiologic tremor (PT) in children was the goal of this dissertation. The “Tremormeter” consists of a metal plate with nine holes of decreasing diameter. Subjects have to hold a metal stylus into each hole for 30 seconds without touching the edge. I examined 1.142 healthy students aged six to 25 years. In this age, motor development must be taken into account when evaluating the test performance. For this reason, I stratified the values age- and gender-specifically. The subjects also completed the Frostig Developmental Test of Visual Perception (Subtest I). This was to quantify the influence of the eye-hand-coordination on the results of the “Tremormeter”. I also evaluated the influence of other factors (handedness, consumption of nicotine, drugs and caffeine and the duration of sleep during the night before the test). After this test series, I also assessed the influence of the “real” tremor as objectified with accelerometry. I examined 102 adults with the “Tremormeter” as well as with triaxial accelerometry. My hypotheses were the following: (1) a high tremor frequency in accelerometry results in many contacts between the metal stylus and the edge of the hole and (2) a high tremor amplitude in accelerometry results in a contact between stylus and edge in a hole with a comparatively large diameter. These hypotheses could not be proven. I employed a multiple linear regression analysis to quantify the influence of the different factors (age, gender, handedness, consumption of nicotine, drugs and caffeine and the duration of sleep during the night before the test) on the “Tremormeter” results. For the subjects aged six to 18 years, I found a highly significant (p<0,001) influence of age and gender on the test results. This influence could not be shown in the adult subjects. I could not find any influence by the consumption of nicotine, drugs or caffeine. This might also be due to the only qualitative (not quantitative) analysis of these factors. Handedness and sleep duration showed a significant influence on some parameters of the “Tremormeter” test. The eye-hand-coordination as assessed by the Frostig Developmental Test of Visual Perception (Subtest I) showed to be a significant influence on the performance in the “Tremormeter” test. The eye- hand-coordination (together with the factors age, gender, handedness, consumption of nicotine, drugs and caffeine and sleep duration) accounts for 28-42% of the “Tremormeter” results. The results of accelerometry (together with age, gender, handedness, consumption of nicotine, drugs and caffeine) account for 10-36% of the results. Further factors are probably influencing the test results. These could be metabolic, hormonal or toxicologic factors. But since age and gender have proven to be the most important influences, especially motor development is probably very strongly influencing the test results. The “Tremormeter”/”Motormeter” is a playful, non-invasive method that can be administered easily in pediatric consultations. The standard values I collected might – even more than for the assessment of tremor – provide a basis for evaluating motor dysfunctions in children

Motor function in survivors of pediatric acute lymphoblastic leukemia treated with chemotherapy-only

BACKGROUND: Up to 43% of survivors of pediatric acute lymphoblastic leukemia (ALL) may exhibit fine-motor problems. Information on manual dexterity in this cohort is still limited. OBJECTIVES: We tested survivors of childhood ALL treated with chemotherapy-only for fine-motor function in terms of drawing and handwriting abilities using a Digitizing Tablet (DT) with three tasks for drawing and handwriting of varying complexity, for ataxia using the International Cooperative Ataxia Rating Scale (ICARS), and for tremor and hand-eye coordination using the Nine Hole Steadiness Tester (NHST). RESULTS: We examined a cohort of non-irradiated survivors (n = 31) after a median time of 3.5 years after end of therapy. In all tasks of the DT the cohort demonstrated significant (p < 0.05) impairment of speed, automation, and variability in at least two tasks and significantly more pressure. Impaired speed (SPV) inversely correlated with lag time since end of therapy. Dexterity performance of six survivors (19%) lay below the 5th percentile. No survivor exhibited ataxia, tremor, or impaired hand-steadiness. CONCLUSION: Despite the absence of gross ataxia, tremor, and impaired hand-eye coordination, we nevertheless detected significant fine-motor impairment in a relevant number of survivors of childhood ALL. Prospective studies are needed to reveal the pathophysiological underpinnings and genetic risk factors for development of such deficits due to ALL and its treatment

Serious suicidal behaviors: socio-demographic and clinical features in a multinational, multicenter sample.

BACKGROUND: Declared suicidal intent and physical danger are both considered important components in defining suicidal behaviors (SB). AIMS: 1) To investigate characteristics of serious suicidal behaviors (SSB), defined by either suicidal intent or lethality; 2) To determine any difference in terms of socio-demographic, clinical and/or service usage variables between SSB and non-serious suicidal behaviors (NSSB). METHODS: A total of 2631 contacts for SB were registered in the context of the MONSUE (Monitoring Suicidal Behavior in Europe) study project. Demographic and clinical information were registered. ICD-10 was used for classifying data about psychiatric diagnoses, methods used for SB and injuries reported. Clear intentionality, high-case fatality methods and serious injuries all defined SSB (n = 1169; 44.4%) RESULTS: SSB were more often preceded by a contact with an inpatient (either psychiatric or somatic) rather than an outpatient service. Among those having a previous history of SB, SSB subjects had fewer contacts with health services before the previous attempt. The strongest predictors for SSB appeared to be older age and not professing a religion. CONCLUSION: Many of the known factors contributing to the risk of completed suicide were also present for SSB. Our findings on service usage by suicide attempters show which aspects of mental health services should be strengthened in order to improve suicide prevention

Serious suicidal behaviors: socio-demographic and clinical features in a multinational, multicenter sample

BACKGROUND: Declared suicidal intent and physical danger are both considered important components in defining suicidal behaviors (SB). AIMS: 1) To investigate characteristics of serious suicidal behaviors (SSB), defined by either suicidal intent or lethality; 2) To determine any difference in terms of socio-demographic, clinical and/or service usage variables between SSB and non-serious suicidal behaviors (NSSB). METHODS: A total of 2631 contacts for SB were registered in the context of the MONSUE (Monitoring Suicidal Behavior in Europe) study project. Demographic and clinical information were registered. ICD-10 was used for classifying data about psychiatric diagnoses, methods used for SB and injuries reported. Clear intentionality, high-case fatality methods and serious injuries all defined SSB (n = 1169; 44.4%) RESULTS: SSB were more often preceded by a contact with an inpatient (either psychiatric or somatic) rather than an outpatient service. Among those having a previous history of SB, SSB subjects had fewer contacts with health services before the previous attempt. The strongest predictors for SSB appeared to be older age and not professing a religion. CONCLUSION: Many of the known factors contributing to the risk of completed suicide were also present for SSB. Our findings on service usage by suicide attempters show which aspects of mental health services should be strengthened in order to improve suicide prevention

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%(1), much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factorSP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies