Showing papers by "Per Hoffmann published in 2021"
Niamh Mullins1, Andreas J. Forstner2, Andreas J. Forstner3, Andreas J. Forstner4 +396 more•Institutions (119)
TL;DR: The authors performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci, including genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics.
Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
378 citations
Itziar de Rojas1, Itziar de Rojas2, Sonia Moreno-Grau2, Sonia Moreno-Grau1 +356 more•Institutions (96)
TL;DR: In this article, a large genetic association study was performed by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190).
Abstract: Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.
97 citations
Max Planck Society1, Technische Universität München2, Ludwig Maximilian University of Munich3, University of Bonn4, University of Bristol5, Hungarian Academy of Sciences6, Paris Diderot University7, Boston Children's Hospital8, University of Toulouse9, University of Lausanne10, University of Liverpool11, University of Oxford12, University of Manchester13, University of Colorado Boulder14, University of Nebraska Medical Center15, University of Denver16, Maastricht University17, The Chinese University of Hong Kong18, University of Jyväskylä19, Karolinska Institutet20, Aston University21, Fraunhofer Society22, Leipzig University23, Tufts University24, École Normale Supérieure25, University of Graz26, University of Helsinki27, Walter and Eliza Hall Institute of Medical Research28, University of St Andrews29
TL;DR: An important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility are suggested.
Abstract: Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
55 citations
University of Adelaide1, Mental Health Services2, United States Department of Health and Human Services3, Ludwig Maximilian University of Munich4, University of Göttingen5, University of Bonn6, National Institutes of Health7, Harvard University8, University of California, San Diego9, Charité10, Dokkyo Medical University11, University of Barcelona12, Geneva College13, Karolinska University Hospital14, Karolinska Institutet15, Paris Diderot University16, Medical University of Graz17, Mayo Clinic18, McGill University Health Centre19, National Taiwan University20, University Hospital of Basel21, Douglas Mental Health University Institute22, Poznan University of Medical Sciences23, University of Cagliari24, Johns Hopkins University25, French Institute of Health and Medical Research26, University of Basel27, Neuroscience Research Australia28, University of New South Wales29, Dalhousie University30, Osaka University31, University of Lorraine32, Goethe University Frankfurt33, Hokkaido University34, University of Gothenburg35, University of Paris36, Veterans Health Administration37, University of Perugia38, University of Cincinnati39, Carlos III Health Institute40, Max Planck Society41, University of Salerno42, Seconda Università degli Studi di Napoli43, Nagoya University44, Dresden University of Technology45, Montreal Neurological Institute and Hospital46, Heidelberg University47, University of Münster48, University of Melbourne49, Florey Institute of Neuroscience and Mental Health50
TL;DR: The findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
Abstract: Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
39 citations
Charité1, University of Würzburg2, University of Tartu3, Imperial College London4, Max Planck Society5, University of Gothenburg6, Karolinska University Hospital7, Karolinska Institutet8, University Hospital Bonn9, Harvard University10, University of Bonn11, University of Duisburg-Essen12, University of Marburg13, University of Basel14, Goethe University Frankfurt15, University of Mannheim16, University of Münster17, Humboldt University of Berlin18, University of Cologne19, University of Greifswald20, Dresden University of Technology21, Heidelberg University22, University of Freiburg23, University of Helsinki24, Stockholm County Council25, Public Health Research Institute26, VU University Amsterdam27, deCODE genetics28, University of Liverpool29, University of Copenhagen30, Mental Health Services31, Aarhus University32, Lundbeck33, Statens Serum Institut34, University of North Carolina at Chapel Hill35, Aarhus University Hospital36, Emory University37, Broad Institute38
TL;DR: The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
38 citations
TL;DR: In this paper, a modified, highly scalable reverse transcription loop-mediated isothermal amplification (RT-LAMP) method is presented, which can be readily deployed for frequent testing as part of an integrated public health surveillance program.
Abstract: Frequent testing of large population groups combined with contact tracing and isolation measures will be crucial for containing Coronavirus Disease 2019 outbreaks. Here we present LAMP-Seq, a modified, highly scalable reverse transcription loop-mediated isothermal amplification (RT-LAMP) method. Unpurified biosamples are barcoded and amplified in a single heat step, and pooled products are analyzed en masse by sequencing. Using commercial reagents, LAMP-Seq has a limit of detection of ~2.2 molecules per µl at 95% confidence and near-perfect specificity for severe acute respiratory syndrome coronavirus 2 given its sequence readout. Clinical validation of an open-source protocol with 676 swab samples, 98 of which were deemed positive by standard RT-qPCR, demonstrated 100% sensitivity in individuals with cycle threshold values of up to 33 and a specificity of 99.7%, at a very low material cost. With a time-to-result of fewer than 24 h, low cost and little new infrastructure requirement, LAMP-Seq can be readily deployed for frequent testing as part of an integrated public health surveillance program.
35 citations
TL;DR: This is a first comprehensive, systematic, integrated genome-wide analysis including relapse cases aimed towards identifying molecular markers of prognostic relevance for T-LBL, and mutated KMT2D was identified as a prognostic marker.
26 citations
TL;DR: In this paper, the two major subtypes of bipolar disorder (BD), BD-I and BD-II, are distinguished based on the presence of manic or hypomanic episodes.
Abstract: The two major subtypes of bipolar disorder (BD), BD-I and BD-II, are distinguished based on the presence of manic or hypomanic episodes. Historically, BD-II was perceived as a less severe form of BD-I. Recent research has challenged this concept of a severity continuum. Studies in large samples of unrelated patients have described clinical and genetic differences between the subtypes. Besides an increased schizophrenia polygenic risk load in BD-I, these studies also observed an increased depression risk load in BD-II patients. The present study assessed whether such clinical and genetic differences are also found in BD patients from multiplex families, which exhibit reduced genetic and environmental heterogeneity. Comparing 252 BD-I and 75 BD-II patients from the Andalusian Bipolar Family (ABiF) study, the clinical course, symptoms during depressive and manic episodes, and psychiatric comorbidities were analyzed. Furthermore, polygenic risk scores (PRS) for BD, schizophrenia, and depression were assessed. BD-I patients not only suffered from more severe symptoms during manic episodes but also more frequently showed incapacity during depressive episodes. A higher BD PRS was significantly associated with suicidal ideation. Moreover, BD-I cases exhibited lower depression PRS. In line with a severity continuum from BD-II to BD-I, our results link BD-I to a more pronounced clinical presentation in both mania and depression and indicate that the polygenic risk load of BD predisposes to more severe disorder characteristics. Nevertheless, our results suggest that the genetic risk burden for depression also shapes disorder presentation and increases the likelihood of BD-II subtype development.
19 citations
TL;DR: In this article, the authors investigated differential DNA methylation in gingival tissues in periodontal health, gingivitis, and periodontitis and its association with differential mRNA expression.
Abstract: AIM We investigated differential DNA methylation in gingival tissues in periodontal health, gingivitis, and periodontitis, and its association with differential mRNA expression. MATERIALS AND METHODS Gingival tissues were harvested from individuals and sites with clinically healthy and intact periodontium, gingivitis, and periodontitis. Samples were processed for differential DNA methylation and mRNA expression using the IlluminaEPIC (850 K) and the IlluminaHiSeq2000 platforms, respectively. Across the three phenotypes, we identified differentially methylated CpG sites and regions, differentially expressed genes (DEGs), and genes with concomitant differential methylation at their promoters and expression were identified. The findings were validated using our earlier databases using HG-U133Plus2.0Affymetrix microarrays and Illumina (450 K) methylation arrays. RESULTS We observed 43,631 differentially methylated positions (DMPs) between periodontitis and health, and 536 DMPs between gingivitis and health (FDR < 0.05). On the mRNA level, statistically significant DEGs were observed only between periodontitis and health (n = 126). Twelve DEGs between periodontitis and health (DCC, KCNA3, KCNA2, RIMS2, HOXB7, PNOC, IRX1, JSRP1, TBX1, OPCML, CECR1, SCN4B) were also differentially methylated between the two phenotypes. Spearman correlations between methylation and expression in the EPIC/mRNAseq dataset were largely replicated in the 450 K/Affymetrix datasets. CONCLUSIONS Concomitant study of DNA methylation and gene expression patterns may identify genes whose expression is epigenetically regulated in periodontitis.
19 citations
Ida E Sønderby1, Ida E Sønderby2, Dennis van der Meer1, Dennis van der Meer3 +194 more•Institutions (73)
TL;DR: In this article, the authors systematically called copy number variants (CNV) in 38 cohorts from the ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites.
Abstract: Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
18 citations
University of Adelaide1, Mental Health Services2, University of New South Wales3, Heidelberg University4, Charité5, United States Department of Health and Human Services6, Dokkyo Medical University7, University of Barcelona8, Geneva College9, Karolinska University Hospital10, University of California, San Diego11, Paris Diderot University12, Medical University of Graz13, Mayo Clinic14, McGill University Health Centre15, National Taiwan University16, University of Bonn17, University Hospital of Basel18, Douglas Mental Health University Institute19, Poznan University of Medical Sciences20, University of Cagliari21, Johns Hopkins University22, Ludwig Maximilian University of Munich23, University of Basel24, Neuroscience Research Australia25, Dalhousie University26, Osaka University27, Harvard University28, Paris 12 Val de Marne University29, University of Lorraine30, Juntendo University31, Goethe University Frankfurt32, Hokkaido University33, Karolinska Institutet34, University of Gothenburg35, University of Paris36, Veterans Health Administration37, Seconda Università degli Studi di Napoli38, University of Cincinnati39, Carlos III Health Institute40, University of Salerno41, National Institutes of Health42, Nagoya University43, Dresden University of Technology44, Montreal Neurological Institute and Hospital45, University of Perugia46, University of Münster47, University of Melbourne48, Florey Institute of Neuroscience and Mental Health49
TL;DR: In this paper, the authors used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD).
Abstract: Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
TL;DR: In this paper, a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years).
Abstract: Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E-04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).
Oslo University Hospital1, University of Kiel2, National Institutes of Health3, University of Tübingen4, Innsbruck Medical University5, French Institute of Health and Medical Research6, Centre national de la recherche scientifique7, Ludwig Maximilian University of Munich8, Greifswald University Hospital9, University of Greifswald10, University of Bonn11, University College London12, German Center for Neurodegenerative Diseases13, Johns Hopkins University14
TL;DR: This work aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci and to investigate shared Genetic loci of MSA patients with known autoimmune diseases.
Abstract: Background Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci. Methods Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls. Results We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts. Conclusion Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
TL;DR: In this article, the authors reported genome-wide single and multimarker as well as gene-level associations with venous thromboembolism in 964 cases and 899 healthy controls of European ancestry.
Abstract: Previous genome-wide association studies (GWASs) have established several susceptibility genes for venous thromboembolism (VTE) and suggested many others. However, a large proportion of the genetic variance in VTE remains unexplained. Here, we report genome-wide single- and multimarker as well as gene-level associations with VTE in 964 cases and 899 healthy controls of European ancestry. We report 19 loci at the genome-wide level of association (p ≤ 5 × 10−8). Our results add to the strong support for the association of genetic variants in F5, NME7, ABO, and FGA with VTE, and identify several loci that have not been previously associated with VTE. Altogether, our novel findings suggest that 20 susceptibility genes for VTE were newly discovered by our study. These genes may impact the production and prothrombotic functions of platelets, endothelial cells, and white and red blood cells. Moreover, the majority of these genes have been previously associated with cardiovascular diseases and/or risk factors for VTE. Future studies are warranted to validate our findings and to investigate the shared genetic architecture with susceptibility factors for other cardiovascular diseases impacting VTE risk.
University of Zurich1, Ludwig Maximilian University of Munich2, University of Basel3, University Hospital Bonn4, University of Göttingen5, Max Planck Society6, University of Münster7, University of Melbourne8, Florey Institute of Neuroscience and Mental Health9, University of Tübingen10, University of Ulm11, Ruhr University Bochum12, University of Hamburg13, Medical University of Graz14, Augsburg College15, University of Aveiro16, German Center for Neurodegenerative Diseases17, Heidelberg University18, University of Marburg19, Forschungszentrum Jülich20, Technische Universität München21, Charité22, University of São Paulo23, Johns Hopkins University School of Medicine24, State University of New York Upstate Medical University25
TL;DR: In this article, polygenic risk scores for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies.
Abstract: As early detection of symptoms in the subclinical to clinical psychosis spectrum may improve health outcomes, knowing the probabilistic susceptibility of developing a disorder could guide mitigation measures and clinical intervention. In this context, polygenic risk scores (PRSs) quantifying the additive effects of multiple common genetic variants hold the potential to predict complex diseases and index severity gradients. PRSs for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies (Psychiatric Genomics Consortium, third release). Eight well-phenotyped groups (n = 1580; 56% males) were assessed: control (n = 305), lower (n = 117) and higher (n = 113) schizotypy (both groups of healthy individuals), at-risk for psychosis (n = 120), BD type-I (n = 359), BD type-II (n = 96), schizoaffective disorder (n = 86), and SZ groups (n = 384). PRS differences were investigated for binary traits and the quantitative Positive and Negative Syndrome Scale. Both BD-PRS and SZ-PRS significantly differentiated controls from at-risk and clinical groups (Nagelkerke's pseudo-R2: 1.3-7.7%), except for BD type-II for SZ-PRS. Out of 28 pairwise comparisons for SZ-PRS and BD-PRS, 9 and 12, respectively, reached the Bonferroni-corrected significance. BD-PRS differed between control and at-risk groups, but not between at-risk and BD type-I groups. There was no difference between controls and schizotypy. SZ-PRSs, but not BD-PRSs, were positively associated with transdiagnostic symptomology. Overall, PRSs support the continuum model across the psychosis spectrum at the genomic level with possible irregularities for schizotypy. The at-risk state demands heightened clinical attention and research addressing symptom course specifiers. Continued efforts are needed to refine the diagnostic and prognostic accuracy of PRSs in mental healthcare.
TL;DR: In this paper, the causal effects of copper on the risk of cardiometabolic endpoints (stroke, coronary artery disease and type 2 diabetes) and cardiometric risk factors in two-sample Mendelian randomization studies were investigated.
Abstract: Observational evidence links higher blood levels of copper with higher risk of cardiovascular diseases. However, whether those associations reflect causal links or can be attributed to confounding is still not fully clear. We investigated causal effects of copper on the risk of cardiometabolic endpoints (stroke, coronary artery disease and type 2 diabetes) and cardiometabolic risk factors in two-sample Mendelian randomization studies. Selection of genetic instruments for blood copper levels relied on meta-analysis of genome-wide association studies in three independent studies (European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, Queensland Institute of Medical Research (QIMR) studies). For the selected instruments, outcome associations were drawn from large public genetic consortia on the respective disease endpoints (MEGASTROKE, Cardiogram, DIAGRAM) and cardiometabolic risk factors. Mendelian randomization results indicate an inverse association for genetically higher copper levels with risk of coronary artery disease (Odds ratio [95% CI] = 0.92 [0.86-0.99], p = 0.022) and systolic blood pressure (beta [SE] = -0.238 [0.121]; p = 0.049). Multivariable Mendelian randomization incorporating copper and systolic blood pressure into one model suggested systolic blood pressure as mediating factor between copper and coronary artery disease risk. In contrast to previous observational evidence establishing higher blood copper levels as risk-increasing factor for cardiometabolic diseases, this study suggests that higher levels of genetically predicted copper might play a protective role for the development of coronary artery disease and systolic blood pressure.
Conservatoire national des arts et métiers1, University of Paris2, University of Münster3, University of Melbourne4, Florey Institute of Neuroscience and Mental Health5, University of Adelaide6, Mental Health Services7, United States Department of Health and Human Services8, Ludwig Maximilian University of Munich9, University Hospital Bonn10, National Institutes of Health11, Harvard University12, University of California, San Diego13, Charité14, Dokkyo Medical University15, University of Barcelona16, Geneva College17, Karolinska Institutet18, Karolinska University Hospital19, Paris Diderot University20, Medical University of Graz21, Mayo Clinic22, McGill University Health Centre23, National Taiwan University24, University Hospital of Basel25, Forschungszentrum Jülich26, Douglas Mental Health University Institute27, Poznan University of Medical Sciences28, University of Cagliari29, Johns Hopkins University30, Paris 12 Val de Marne University31, University of Marburg32, Neuroscience Research Australia33, University of New South Wales34, Dalhousie University35, Osaka University36, University of Lorraine37, Juntendo University38, Goethe University Frankfurt39, Hokkaido University40, University of Gothenburg41, Veterans Health Administration42, University of Perugia43, University of Cincinnati44, Carlos III Health Institute45, Seconda Università degli Studi di Napoli46, University of Salerno47, Nagoya University48, Dresden University of Technology49, Montreal Neurological Institute and Hospital50, Sigmund Freud University Vienna51, Heidelberg University52
TL;DR: In this article, a GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region.
Abstract: Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10-3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
TL;DR: In this article, human induced pluripotent stem cell (iPSC) lines have been derived from four male patients with childhood attention-deficit hyperactivity disorder (ADHD).
Technische Universität München1, Max Planck Society2, University of Basel3, University of Düsseldorf4, Forschungszentrum Jülich5, Greifswald University Hospital6, German Center for Neurodegenerative Diseases7, University of Münster8, University of Oslo9, University of Bonn10, University of Marburg11, University of Giessen12, Stanford University13, Veterans Health Administration14, University of Liverpool15, University Hospital of Basel16
TL;DR: In this paper, the authors investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease, and conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts.
Abstract: A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex-areas that constitute hub nodes of the salience network-represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.
TL;DR: In this article, 10 human induced pluripotent stem cells (iPSC) lines were derived from five healthy controls matched to a study including Attention-Deficit Hyperactivity Disorder patients (ADHD).
TL;DR: In this paper, the authors investigated the association between genetic variants in cholinergic candidate genes according to the Kyoto encyclopedia of genes and genomes with the development of postoperative delirium (POD) and postoperative cognitive dysfunction (POCD).
Abstract: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are frequent and serious complications after surgery. We aim to investigate the association between genetic variants in cholinergic candidate genes according to the Kyoto encyclopedia of genes and genomes - pathway: cholinergic neurotransmission with the development of POD or POCD in elderly patients. This analysis is part of the European BioCog project (
www.biocog.eu
), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini-Mental-State-Examination score ≤ 23 points were excluded. POD was assessed up to seven days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method and a patient chart review. POCD was assessed three months after surgery with a neuropsychological test battery. Genotyping was performed on the Illumina Infinium Global Screening Array. Associations with POD and POCD were analyzed using logistic regression analysis, adjusted for age, comorbidities and duration of anesthesia (for POCD analysis additionally for education). Odds ratios (OR) refer to minor allele counts (0, 1, 2). 745 patients could be included in the POD analysis, and 452 in the POCD analysis. The rate of POD within this group was 20.8% (155 patients), and the rate of POCD was 10.2% (46 patients). In a candidate gene approach three genetic variants of the cholinergic genes CHRM2 and CHRM4 were associated with POD (OR [95% confidence interval], rs8191992: 0.61[0.46; 0.80]; rs8191992: 1.60[1.22; 2.09]; rs2067482: 1.64[1.10; 2.44]). No associations were found for POCD. We found an association between genetic variants of CHRM2 and CHRM4 and POD. Further studies are needed to investigate whether disturbances in acetylcholine release and synaptic plasticity are involved in the development of POD. Trial registration: ClinicalTrials.gov: NCT02265263.
TL;DR: In this paper, Mendelian randomization (MR) methodology was used to search for factors influencing AL amyloidosis risk using summary data from genome-wide association studies (GWASs) of multiple phenotypes.
TL;DR: In this article, the authors identify genetic overlaps at the gene level between 7 mental disorders (schizophrenia, autism spectrum disorder, major depressive disorder, anorexia nervosa, ADHD, bipolar disorder and anxiety), 8 brain morphometric traits, 2 cognitive traits (educational attainment and general cognitive function) and 9 personality traits (subjective well-being, depressive symptoms, neuroticism, extraversion, openness to experience, agreeableness and conscientiousness, children's aggressive behaviour, loneliness) based on publicly available GWASs.
Abstract: Major mental disorders are highly prevalent and make a substantial contribution to the global disease burden. It is known that mental disorders share clinical characteristics, and genome-wide association studies (GWASs) have recently provided evidence for shared genetic factors as well. Genetic overlaps are usually identified at the single-marker level. Here, we aimed to identify genetic overlaps at the gene level between 7 mental disorders (schizophrenia, autism spectrum disorder, major depressive disorder, anorexia nervosa, ADHD, bipolar disorder and anxiety), 8 brain morphometric traits, 2 cognitive traits (educational attainment and general cognitive function) and 9 personality traits (subjective well-being, depressive symptoms, neuroticism, extraversion, openness to experience, agreeableness and conscientiousness, children's aggressive behaviour, loneliness) based on publicly available GWASs. We performed systematic conditional regression analyses to identify independent signals and select loci associated with more than one trait. We identified 48 genes containing independent markers associated with several traits (pleiotropy at the gene level). We also report 9 genes with different markers that show independent associations with single traits (allelic heterogeneity). This study demonstrates that mental disorders and related traits do show pleiotropy at the gene level as well as the single-marker level. The identification of these genes might be important for prioritizing further deep genotyping, functional studies, or drug targeting.
TL;DR: In this paper, the association of DNA repair gene polymorphisms with chromosomal aberrations (CAs) was studied using linear and logistic regression models, and the results suggest pathways with mechanistic rationale for the formation of CAs and emphasize the need to further develop techniques for measuring individual sensitivity to genotoxic exposure.
Abstract: DNA damage and unrepaired or insufficiently repaired DNA double-strand breaks as well as telomere shortening contribute to the formation of structural chromosomal aberrations (CAs). Non-specific CAs have been used in the monitoring of individuals exposed to potential carcinogenic chemicals and radiation. The frequency of CAs in peripheral blood lymphocytes (PBLs) has been associated with cancer risk and the association has also been found in incident cancer patients. CAs include chromosome-type aberrations (CSAs) and chromatid-type aberrations (CTAs) and their sum CAtot. In the present study, we used data from our published genome-wide association studies (GWASs) and extracted the results for 153 DNA repair genes for 607 persons who had occupational exposure to diverse harmful substances/radiation and/or personal exposure to tobacco smoking. The analyses were conducted using linear and logistic regression models to study the association of DNA repair gene polymorphisms with CAs. Considering an arbitrary cutoff level of 5 × 10-3, 14 loci passed the threshold, and included 7 repair pathways for CTA, 4 for CSA, and 3 for CAtot; 10 SNPs were eQTLs influencing the expression of the target repair gene. For the base excision repair pathway, the implicated genes PARP1 and PARP2 encode poly(ADP-ribosyl) transferases with multiple regulatory functions. PARP1 and PARP2 have an important role in maintaining genome stability through diverse mechanisms. Other candidate genes with known roles for CSAs included GTF2H (general transcription factor IIH subunits 4 and 5), Fanconi anemia pathway genes, and PMS2, a mismatch repair gene. The present results suggest pathways with mechanistic rationale for the formation of CAs and emphasize the need to further develop techniques for measuring individual sensitivity to genotoxic exposure.
TL;DR: In this paper, the authors identified differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and integrated the results with findings from genome and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD.
Abstract: Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. In the dorsal striatum, we discovered differential expression (FDR
TL;DR: In this article, the authors investigated whether HMGRI intake interacts with the diabetes-associated genetic risk score (GRS) to affect coronary artery disease (CAD) progression using data from the population-based Heinz Nixdorf Recall (HNR) study.
Abstract: HMG-CoA-Reductase inhibitors (HMGRIs) are currently the most widely used group of drugs in patients with coronary artery disease (CAD) and are given preemptively to patients with high levels of cholesterol, including those with diabetes mellitus (DM). However, intake of HMGRIs also increases the progression of coronary artery calcification (CAC) and the risk of developing DM. This study aimed to investigate whether HMGRI intake interacts with the diabetes-associated genetic risk score (GRS) to affect CAC progression using data from the population-based Heinz Nixdorf Recall (HNR) study. CAC was measured in 3157 participants using electron-beam computed tomography twice, at baseline (CACb) and 5 years later (CAC5y). CAC progression was classified as slow, expected, or rapid based on predicted values. Weighted DM GRS was constructed using 100 diabetes mellitus–associated single nucleotide polymorphisms (SNPs). We used log-linear regression to evaluate the interaction of HMGRI intake with diabetes-associated GRS and individual SNPs on CAC progression (rapid vs. expected/slow), adjusting for age, sex, and log(CACb + 1). The prevalence of rapid CAC progression in the HNR study was 19.6%. We did not observe any association of the weighted diabetes mellitus GRS with the rapid progression of CAC (relative risk (RR) [95% confidence interval (95% CI)]: 1.01 [0.94; 1.10]). Furthermore, no indication of an interaction between GRS and HMGRI intake was observed (1.08 [0.83; 1.41]). Our analyses showed no indication that the impact of HMGRIs on CAC progression is significantly more severe in patients with a high genetic risk of developing DM than in those with a low GRS.