Publications by authors named "Lukas Tittmann"

12 Publications

  • Page 1 of 1

Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease.

Mov Disord 2020 07 8;35(7):1245-1248. Epub 2020 Apr 8.

Department of Neurology, Universitätsklinikum Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.

Objective: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD.

Methods: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes.

Results: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C.

Conclusion: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28037DOI Listing
July 2020

No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors.

Transl Neurodegener 2019 3;8:11. Epub 2019 Apr 3.

1Department of Neurology, University Hospital Schleswig Holstein, Arnold-Heller Str. 3, 24105 Kiel, Germany.

Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment ( = 296) and controls ( = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.

Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.

Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.

Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
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http://dx.doi.org/10.1186/s40035-019-0153-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446289PMC
April 2019

Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery - a sub-analysis of the RIPHeart-Study.

BMC Cardiovasc Disord 2019 01 24;19(1):26. Epub 2019 Jan 24.

Department of Anaesthesiology, University Hospital Wuerzburg, Wuerzburg, Germany.

Background: The aim of our study was the identification of genetic variants associated with postoperative complications after cardiac surgery.

Methods: We conducted a prospective, double-blind, multicenter, randomized trial (RIPHeart). We performed a genome-wide association study (GWAS) in 1170 patients of both genders (871 males, 299 females) from the RIPHeart-Study cohort. Patients undergoing non-emergent cardiac surgery were included. Primary endpoint comprises a binary composite complication rate covering atrial fibrillation, delirium, non-fatal myocardial infarction, acute renal failure and/or any new stroke until hospital discharge with a maximum of fourteen days after surgery.

Results: A total of 547,644 genotyped markers were available for analysis. Following quality control and adjustment for clinical covariate, one SNP reached genome-wide significance (PHLPP2, rs78064607, p = 3.77 × 10) and 139 (adjusted for all other outcomes) SNPs showed promising association with p < 1 × 10 from the GWAS.

Conclusions: We identified several potential loci, in particular PHLPP2, BBS9, RyR2, DUSP4 and HSPA8, associated with new-onset of atrial fibrillation, delirium, myocardial infarction, acute kidney injury and stroke after cardiac surgery.

Trial Registration: The study was registered with ClinicalTrials.gov NCT01067703, prospectively registered on 11 Feb 2010.
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http://dx.doi.org/10.1186/s12872-019-1002-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345037PMC
January 2019

Predicting Matching Quality of Record Linkage Algorithms on Growing Data Sets.

Stud Health Technol Inform 2018 ;253:70-74

Institute of Medical Informatics and Statistics, University of Kiel, Germany.

A record linkage algorithm tries to identify records which belong to the same individual. We analyze the matching behavior of an approach used in the E-PIX matching tool on the very limited attribute set of first name, last name, date of birth and sex. Our benchmark set contains almost 37,000 records from the Popgen biobank. We develop a model which allows us to predict the workload on clerical review for data sets growing up to a factor of 10 or even more, without the need for a data set of this size. Based on this model we show two parameter sets with comparable detection rate of true duplicates, but where only one of them scales well on growing data sets. Our model provides realistic example records for each predicted matching of an upscaled data set. Thus, it enables to identify the parameters which need to be adjusted in order to improve the quality of the matching candidates. We also show that unreviewed merging of records is prone to homonym errors on data sets with 200,000 records and the limited attribute set above, while the merged record pairs are obviously different in clerical review.
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November 2018

Reduced microbiome alpha diversity in young patients with ADHD.

PLoS One 2018 12;13(7):e0200728. Epub 2018 Jul 12.

Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, Germany.

ADHD is a psychiatric disorder which is characterized by hyperactivity, impulsivity and attention problems. Due to recent findings of microbial involvement in other psychiatric disorders like autism and depression, a role of the gut microbiota in ADHD pathogenesis is assumed but has not yet been investigated. In this study, the gut microbiota of 14 male ADHD patients (mean age: 11.9 yrs.) and 17 male controls (mean age: 13.1 yrs.) was examined via next generation sequencing of 16S rDNA and analyzed for diversity and biomarkers. We found that the microbial diversity (alpha diversity) was significantly decreased in ADHD patients compared to controls (pShannon = 0.036) and that the composition (beta diversity) differed significantly between patients and controls (pANOSIM = 0.033, pADONIS = 0.006, pbetadisper = 0.002). In detail, the bacterial family Prevotellacae was associated with controls, while patients with ADHD showed elevated levels of Bacteroidaceae, and both Neisseriaceae and Neisseria spec. were found as possible biomarkers for juvenile ADHD. Our results point to a possible link of certain microbiota with ADHD, with Neisseria spec. being a very promising ADHD-associated candidate. This finding provides the basis for a systematic, longitudinal assessment of the role of the gut microbiome in ADHD, yielding promising potential for both prevention and therapeutic intervention.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200728PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042771PMC
January 2019

Phenotypes of organ involvement in sarcoidosis.

Eur Respir J 2018 01 25;51(1). Epub 2018 Jan 25.

University College Dublin, Dublin, Ireland.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.
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http://dx.doi.org/10.1183/13993003.00991-2017DOI Listing
January 2018

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.

Lancet Neurol 2017 11;16(11):898-907

Center for Restless Legs Study, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

Background: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets.

Methods: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest.

Findings: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1).

Interpretation: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.

Funding: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.
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http://dx.doi.org/10.1016/S1474-4422(17)30327-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755468PMC
November 2017

Genome-wide association study in essential tremor identifies three new loci.

Brain 2016 12 20;139(Pt 12):3163-3169. Epub 2016 Oct 20.

15 Neurogenetics, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, CIBERNED, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
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http://dx.doi.org/10.1093/brain/aww242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382938PMC
December 2016

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Nat Genet 2016 09 25;48(9):1043-8. Epub 2016 Jul 25.

Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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http://dx.doi.org/10.1038/ng.3622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556360PMC
September 2016

The impact of rare variants in FUS in essential tremor.

Mov Disord 2015 Apr 28;30(5):721-4. Epub 2015 Jan 28.

Department of Neurology, University Hospital Schleswig Holstein, Kiel, Germany.

Objective: We analyzed the coding region of the Fused in Sarcoma (FUS) gene in familial essential tremor (ET) and reviewed previous studies assessing FUS variants in ET.

Background: ET is often a familial disorder with an autosomal dominant inheritance pattern. A potentially causative variant in FUS has been identified in one ET family. Subsequent studies described further putatively causal variants.

Methods: We performed DNA sequencing of FUS in 85 unrelated, familial German and French definite ET patients.

Results: We did not find novel variants affecting the protein sequence. Seven previously published studies and data from the exome variant server (EVS) showed that rare exonic variants in FUS are not more frequent in ET than in the general population.

Conclusions: Our findings provide no evidence for a role of rare genetic variants in the pathogenesis of ET, apart from the initially published FUS mutation segregating in a large ET family.
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http://dx.doi.org/10.1002/mds.26145DOI Listing
April 2015

Rare variants in ANO3 are not a susceptibility factor in essential tremor.

Parkinsonism Relat Disord 2014 Jan 27;20(1):134-5. Epub 2013 Sep 27.

Department of Neurology, University Hospital Schleswig Holstein, Kiel, Germany; Institute of Experimental Medicine, Christian-Albrechts University, Kiel, Germany.

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http://dx.doi.org/10.1016/j.parkreldis.2013.09.022DOI Listing
January 2014