Die Feinabstimmung der QC- und Imputations Pipeline Ricopili zeigt eine genetische Überlappung der Panikstörung mit Neurotizismus und Depression

A genome-wide association study (GWAS) is a standard study design for examining the association between genotype and disease status without knowledge of the underlying biological mechanisms. GWASs have led to the identification and classification of numerous variants associated with human traits. However, while this design has been widely used in contemporary genetic research, it is prone to technical biases and errors, which necessitate the development of a standardized workflow and analysis methodology. To address this problem, we developed a simulation-based framework for calibrating GWAS pipelines. Using Ricopili, our comprehensive GWAS pipeline, we developed a standard common-variant analysis workflow and then demonstrated the pipeline’s various functionalities and features. Furthermore, we demonstrated that this pipeline’s current framework could be successfully used to perform full-scale analyses of genotype data, ranging from quality control to the downstream analysis of variants. Furthermore, this thesis investigated the genetic architecture of panic disorder (PD) in six independent collections taken from four European countries. Given the comparably small total sample size of 2,147 cases and 7,760 controls, no genome-wide significant single nucleotide polymorphism (SNPs) were identified; however, we demonstrated a highly significant polygenic risk score (PRS) that explained up to 2.6% of the phenotypic variance. The SNP-based heritability for PD was estimated at 28.0–34.2%, and 135 out of the 255 most significant SNPs exhibited the same direction of effect in an independent replication sample (p = 0.048). In a combined meta-analysis, rs144783209 in the gene SMAD1 exhibited the strongest association (Pcomb = 3.10 × 10−7) with PD. A significant genomic correlation was detected with published GWAS results for major depressive disorder (p = 0.025), depressive symptoms (p = 0.010), and neuroticism (p = 0.002). Moreover, in a distinct psychiatric phenotype, we found a highly significant genetic correlation (30–60%) between borderline personality disorder (998 cases and 1,545 controls) and three published adult psychiatric disorders, namely schizophrenia (p = 4.37 × 10−5), bipolar disorder (p 6 = 2.99 × 10−3), and major depression (p = 1.04 × 10−3). In a third analysis, we demonstrated that PRSs in the IMAGEN cohort (n = 1,475) derived from published GWASs of intelligence significantly explained 0.33–3.2% of the variance in general IQ. In summary, our meta-analysis of PD represents a significant advancement in elucidating its genetic architecture, including the first SNP-based heritability estimate. We observed a notable genetic connection between PD and neuroticism. Additionally, the significant genetic correlation of borderline personality disorder (BPD) with other psychiatric disorders suggests that BPD shares underlying factors with these disorders, consistent with clinical observations. Finally, our research affirms the polygenic nature of general intelligence within the IMAGEN cohort.Die genomweite Assoziationsstudie (GWAS) ist eine Standardmethode, die Assoziationen von Allel- oder Genotyphäufigkeiten sogenannter SNPs (Single Nucleotide Polymorphisms) zu Fall/Kontroll-Verteilungen oder zu quantitativen Merkmalen untersucht. Während GWAS das Verständnis der genetischen Grundlage komplexer Merkmale stark vorantreibt, ist sie auch anfällig für technisch/statistische Verzerrungen und Fehler, die die Einhaltung eines hoch standardisierten Arbeitsablaufs und Analysemethodik erfordert. Um diese zu erarbeiten, haben wir ein simulationsbasiertes Framework zur Kalibrierung von GWAS Pipelines entwickelt. Mit Hilfe unserer umfassenden GWAS-Pipeline Ricopili entwickelten wir einen standardisierte Analyseplan und demonstrieren die verschiedenen Funktionalitäten und Eigenschaften unserer Pipeline. Wir zeigen, wie mit dieser Pipeline erfolgreiche Analyse von Genotyp-Rohdaten durchgeführt werden können, angefangen von der Qualitätskontrolle bis hin zur endgültigen Assoziationsanalyse. Wir untersuchen den Einfluss von häufigen genetischen Varianten auf die Panikstörung (PD) in einer Meta-Analyse von sechs unterschiedlichen Kohorten aus vier europäischen Ländern. Wie erwartet identifizierten wir bei einer vergleichsweise kleinen Gesamtstichprobengröße von 2,147 Patienten und 7,760 Kontrollen keine genomweit signifikanten Varianten, jedoch konnten wir einen signifikanten polygenen Risikoscore (PRS) nachweisen, der bis zu 2.6% der phänotypischen Varianz erklärt. Die SNP-basierte Heritabilität für PD schätzen wir auf 28.0-34.0 %. In einer unabhängigen Replikationskohorte zeigen 135 der 255 signifikantesten SNPs mit Schwellenwert die gleiche Effektrichtung wie in unserem Hauptdatensatz (signifikant mit p = 0.048). In der kombinierten Meta-Analyse zeigte sich rs144783209 im Gen SMAD1 als stärkste Gesamt - Assoziation (p = 3.10 × 10-7). Schliesslich konnten wir eine signifikante Korrelationen mit der Unipolaren Depression (Major Depressive Disorder - MDD) (p = 1.04 × 10−3), depressiven Symptomen (p = 0.025) und Neurotizismus (p = 0.002) finden. Bei einer weiteren psychiatrischen Erkrankung fanden wir eine hochsignifikante genetische Korrelation (zwischen 30 und 60 %) zwischen der Borderline-Persönlichkeitsstörung (998 Fälle 8 und 1,545 Kontrollen) und den drei zentralen psychiatrischen Erkrankungen: Schizophrenie (p = 4.37 × 10−5), Bipolare Störung (p = 2.99 × 10−3) und Major Depression (p = 1.04 × 10−3). In einer dritten hier vorgestellten Analyse konnten wir polygene Riskoscores in der IMAGEN-Kohorte (n=1,475), aus GWASs der Intelligenz abgeleiten, die signifikant 0.33% bis. 3.2% der Varianz des allgemeinen IQ erklären. Zusammenfassend stellt unsere Meta-Analyse von PD einen bedeutenden Fortschritt bei der Aufklärung seiner genetischen Architektur dar, einschließlich der ersten Schätzung der erblichen Veranlagung basierend auf SNPs. Wir haben eine bemerkenswerte genetische Verbindung zwischen PD und Neurotizismus beobachtet. Darüber hinaus legt die signifikante genetische Korrelation der Borderline-Persönlichkeitsstörung (BPS) mit anderen psychiatrischen Störungen nahe, dass BPS gemeinsame zugrunde liegende Faktoren mit diesen Störungen teilt, was mit klinischen Beobachtungen übereinstimmt. Schließlich bestätigt unsere Forschung die polygene Natur der allgemeinen Intelligenz innerhalb der IMAGEN-Kohorte

Genome-wide association study of borderline personality disorder reveals genetic overlap with the bipolar disorder, schizophrenia and major depression

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of Bipolar Disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was: (i) to detect genes and gene-sets involved in BOR; and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, Major Depression (MDD) and Schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests,and gene-set-analyses were performed in 998 BOR patients and 1,545 controls. LD score regression was used to detect genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Genebased analysis yielded two significant genes: DPYD (p=4.42x10-7) and PKP4 (p=8.67x10-7); and gene-set-analysis yielded a significant finding for exocytosis (GO:0006887, pFDR=0.019). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [p=2.99x10-3]), SCZ (rg=0.34 [p=4.37x10-5]), and MDD (rg=0.57 [p=1.04x10-3]). Our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies

How alcohol makes the epigenetic clock tick faster and the clock reversing effect of abstinence

This study investigated the recently reported association between alcohol dependence and accelerated ageing and the potential effects of abstinence and relapse on DNA methylation status using Levine's epigenetic clock to estimate DNA methylation age in two independent cohorts. The first sample comprised 88 (15 female) detoxified patients with alcohol use disorder (AUD) and 32 (5 female) healthy control (CON) subjects (NCT02615977), and the second included 69 (10 female) AUD patients that were followed up for 12 months with respect to relapse (n = 38, 4 female) and abstinence (n = 31, 6 female) (NCT01679145). To account for the different aspects of ageing captured by various clocks, we performed additional analyses of the first-generation Horvath clock and next-generation Zhang clock. To account for the genetic liability of AUD and its potential influence on DNA methylation, we calculated a polygenic risk score for alcohol dependence. We found that ageing was accelerated by 3.64 years in AUD patients compared with the CON group according to Levine's DNAm PhenoAge. Furthermore, in a second longitudinal sample, we found that abstaining AUD patients displayed a decrease in DNAm PhenoAge by 3.1 years, but we found an over proportional increase by 2.7 years in those who relapsed. Polygenic risk did not affect epigenetic ageing within our sample. These results confirm the age acceleration associated with AUD and provide the first evidence for a recovery of this effect upon abstinence from alcohol

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

Polygenetic risk scores and phenotypic constellations of obsessive–compulsive disorder in clozapine-treated schizophrenia

Obsessive–compulsive symptoms (OCS) are frequently observed in individuals with schizophrenia (SCZ) treated with clo- zapine (CLZ). This study aimed to analyze prevalence of OCS and obsessive–compulsive disorder (OCD) in this subgroup and find possible correlations with different phenotypes. Additionally, this is the first study to examine polygenetic risk scores (PRS) in individuals with SCZ and OCS. A multicenter cohort of 91 individuals with SCZ who were treated with CLZ was recruited and clinically and genetically assessed. Symptom severity was examined using the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI), the Calgary Depression Scale for Schizophrenia (CDSS), Global Assessment of Functioning Scale (GAF) and Yale–Brown Obsessive–Compulsive Scale (Y-BOCS). Participants were divided into subgroups based on phenotypic OCS or OCD using Y-BOCS scores. Genomic-wide data were generated, and PRS analyses were performed to evaluate the association between either phenotypic OCD or OCS severity and genotype-predicted predisposition for OCD, SCZ, cross-disorder, and CLZ/norclozapine (NorCLZ) ratio, CLZ metabolism and NorCLZ metabo- lism. OCS and OCD were frequent comorbidities in our sample of CLZ-treated SCZ individuals, with a prevalence of 39.6% and 27.5%, respectively. Furthermore, the Y-BOCS total score correlated positively with the duration of CLZ treatment in years (r = 0.28; p = 0.008) and the PANSS general psychopathology subscale score (r = 0.23; p = 0.028). A significant cor- relation was found between OCD occurrence and PRS for CLZ metabolism. We found no correlation between OCS severity and PRS for CLZ metabolism. We found no correlation for either OCD or OCS and PRS for OCD, cross-disorder, SCZ, CLZ/NorCLZ ratio or NorCLZ metabolism. Our study was able to replicate previous findings on clinical characteristics of CLZ-treated SCZ individuals. OCS is a frequent comorbidity in this cohort and is correlated with CLZ treatment dura- tion in years and PANSS general psychopathology subscale score. We found a correlation between OCD and PRS for CLZ metabolism, which should be interpreted as incidental for now. Future research is necessary to replicate significant findings and to assess possible genetic predisposition of CLZ-treated individuals with SCZ to OCS/OCD. Limitations attributed to the small sample size or the inclusion of subjects on co-medication must be considered. If the association between OCD and PRS for CLZ metabolism can be replicated, it should be further evaluated if CYP1A2 alteration, respectively lower CLZ plasma level, is relevant for OCD development

Polymorphisms of TNF-enhancer and gene for FcγRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population

<p>Abstract</p> <p>Background</p> <p>Susceptibility/resistance to <it>Plasmodium falciparum </it>malaria has been correlated with polymorphisms in more than 30 human genes with most association analyses having been carried out on patients from Africa and south-east Asia. The aim of this study was to examine the possible contribution of genetic variants in the <it>TNF </it>and <it>FCGR2A </it>genes in determining severity/resistance to <it>P. falciparum </it>malaria in Indian subjects.</p> <p>Methods</p> <p>Allelic frequency distribution in populations across India was first determined by typing genetic variants of the <it>TNF </it>enhancer and the <it>FCGR2A </it>G/A SNP in 1871 individuals from 55 populations. Genotyping was carried out by DNA sequencing, single base extension (SNaPshot), and DNA mass array (Sequenom). Plasma TNF was determined by ELISA. Comparison of datasets was carried out by Kruskal-Wallis and Mann-Whitney tests. Haplotypes and LD plots were generated by PHASE and Haploview, respectively. Odds ratio (OR) for risk assessment was calculated using EpiInfo™ version 3.4.</p> <p>Results</p> <p>A novel single nucleotide polymorphism (SNP) at position -76 was identified in the <it>TNF </it>enhancer along with other reported variants. Five <it>TNF </it>enhancer SNPs and the <it>FCGR2A </it>R131H (G/A) SNP were analyzed for association with severity of <it>P. falciparum </it>malaria in a malaria-endemic and a non-endemic region of India in a case-control study with ethnically-matched controls enrolled from both regions. <it>TNF </it>-1031C and -863A alleles as well as homozygotes for the TNF enhancer haplotype CACGG (-1031T>C, -863C>A, -857C>T, -308G>A, -238G>A) correlated with enhanced plasma TNF levels in both patients and controls. Significantly higher TNF levels were observed in patients with severe malaria. Minor alleles of -1031 and -863 SNPs were associated with increased susceptibility to severe malaria. The high-affinity IgG2 binding FcγRIIa AA (131H) genotype was significantly associated with protection from disease manifestation, with stronger association observed in the malaria non-endemic region. These results represent the first genetic analysis of the two immune regulatory molecules in the context of <it>P. falciparum </it>severity/resistance in the Indian population.</p> <p>Conclusion</p> <p>Association of specific <it>TNF </it>and <it>FCGR2A </it>SNPs with cytokine levels and disease severity/resistance was indicated in patients from areas with differential disease endemicity. The data emphasizes the need for addressing the contribution of human genetic factors in malaria in the context of disease epidemiology and population genetic substructure within India.</p

Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction

Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. We performed a genome-wide association study of 5708 MG cases and 432,028 controls of European ancestry and a replication study in 3989 cases and 226,643 controls provided by 23andMe Inc. We identified 12 independent genome-wide significant hits (P < 5e−8) across 11 loci. Subgroup analyses revealed two of these were associated with early-onset (at age <50) and four with late-onset MG (at age ≥ 50). Imputation of human leukocyte antigen alleles revealed inverse effect sizes for late- and early-onset, suggesting a potential modulatory influence on the time of disease manifestation. We assessed the performance of polygenic risk scores for MG, which significantly predicted disease status in an independent target cohort, explaining 4.21% of the phenotypic variation (P = 5.12e−9). With this work, we aim to enhance our understanding of the genetic architecture of MG

Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies

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