17 results on '"Zoltán Bochdanovits"'
Search Results
2. Resequencing three candidate genes for major depressive disorder in a Dutch cohort.
- Author
-
Eva C Verbeek, Marianna R Bevova, Zoltán Bochdanovits, Patrizia Rizzu, Ingrid M C Bakker, Tiny Uithuisje, Eco J De Geus, Johannes H Smit, Brenda W Penninx, Dorret I Boomsma, Witte J G Hoogendijk, and Peter Heutink
- Subjects
Medicine ,Science - Abstract
Major depressive disorder (MDD) is a psychiatric disorder, characterized by periods of low mood of more than two weeks, loss of interest in normally enjoyable activities and behavioral changes. MDD is a complex disorder and does not have a single genetic cause. In 2009 a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. Many of the top signals of this GWAS mapped to a region spanning the gene PCLO, and the non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became genome wide significant after post-hoc analysis. We performed resequencing of PCLO, GRM7, and SLC6A4 in 50 control samples from the GAIN-MDD cohort, to detect new genomic variants. Subsequently, we genotyped these variants in the entire GAIN-MDD cohort and performed association analysis to investigate if rs2522833 is the causal variant or simply in linkage disequilibrium with a more associated variant. GRM7 and SLC6A4 are both candidate genes for MDD from literature. We aimed to gather more evidence that rs2522833 is indeed the causal variant in the GAIN-MDD cohort or to find a previously undetected common variant in either PCLO, GRM7, or SLC6A4 with a higher association in this cohort. After next generation sequencing and association analysis we excluded the possibility of an undetected common variant to be more associated. For neither PCLO nor GRM7 we found a more associated variant. For SLC6A4, we found a new SNP that showed a lower P-value (P = 0.07) than in the GAIN-MDD GWAS (P = 0.09). However, no evidence for genome-wide significance was found. Although we did not take into account rare variants, we conclude that our results provide further support for the hypothesis that the non-synonymous coding SNP rs2522833 in the PCLO gene is indeed likely to be the causal variant in the GAIN-MDD cohort.
- Published
- 2013
- Full Text
- View/download PDF
3. Modulatory effects of the piccolo genotype on emotional memory in health and depression.
- Author
-
Saskia Woudstra, Marie-José van Tol, Zoltán Bochdanovits, Nic J van der Wee, Frans G Zitman, Mark A van Buchem, Esther M Opmeer, André Aleman, Brenda W Penninx, Dick J Veltman, and Witte J Hoogendijk
- Subjects
Medicine ,Science - Abstract
Major depressive disorder (MDD) has been associated with biased memory formation for mood-congruent information, which may be related to altered monoamine levels. The piccolo (PCLO) gene, involved in monoaminergic neurotransmission, has previously been linked to depression in a genome-wide association study. Here, we investigated the role of the PCLO risk allele on functional magnetic resonance imaging (MRI) correlates of emotional memory in a sample of 89 MDD patients (64 PCLO risk allele carriers) and 29 healthy controls (18 PCLO risk allele carriers). During negative word encoding, risk allele carriers showed significant lower activity relative to non-risk allele carriers in the insula, and trend-wise in the anterior cingulate cortex and inferior frontal gyrus. Moreover, depressed risk allele carriers showed significant lower activity relative to non-risk allele carriers in the striatum, an effect which was absent in healthy controls. Finally, amygdalar response during processing new positive words vs. known words was blunted in healthy PCLO+ carriers and in MDD patients irrespective of genotype, which may indicate that signalling of salient novel information does not occur to the same extent in PCLO+ carriers and MDD patients. The PCLO risk allele may increase vulnerability for MDD by modulating local brain function with regard to responsiveness to salient stimuli (i.e. insula) and processing novel negative information. Also, depression-specific effects of PCLO on dorsal striatal activation during negative word encoding and the absence of amygdalar salience signalling for novel positive information further suggest a role of PCLO in symptom maintenance in MDD.
- Published
- 2013
- Full Text
- View/download PDF
4. A fine-mapping study of 7 top scoring genes from a GWAS for major depressive disorder.
- Author
-
Eva C Verbeek, Ingrid M C Bakker, Marianna R Bevova, Zoltán Bochdanovits, Patrizia Rizzu, David Sondervan, Gonneke Willemsen, Eco J de Geus, Johannes H Smit, Brenda W Penninx, Dorret I Boomsma, Witte J G Hoogendijk, and Peter Heutink
- Subjects
Medicine ,Science - Abstract
Major depressive disorder (MDD) is a psychiatric disorder that is characterized--amongst others--by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f.>0.1, r(2)>0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at P = 6.8E-7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at P = 1.2E-6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to P = 9.9E-7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833.
- Published
- 2012
- Full Text
- View/download PDF
5. Comprehensive mRNA expression profiling distinguishes tauopathies and identifies shared molecular pathways.
- Author
-
Iraad F Bronner, Zoltán Bochdanovits, Patrizia Rizzu, Wouter Kamphorst, Rivka Ravid, John C van Swieten, and Peter Heutink
- Subjects
Medicine ,Science - Abstract
BACKGROUND:Understanding the aetiologies of neurodegenerative diseases such as Alzheimer's disease (AD), Pick's disease (PiD), Progressive Supranuclear Palsy (PSP) and Frontotemporal dementia (FTD) is often hampered by the considerable clinical and molecular overlap between these diseases and normal ageing. The development of high throughput genomic technologies such as microarrays provide a new molecular tool to gain insight in the complexity and relationships between diseases, as they provide data on the simultaneous activity of multiple genes, gene networks and cellular pathways. METHODOLOGY/PRINCIPAL FINDINGS:We have constructed genome wide expression profiles from snap frozen post-mortem tissue from the medial temporal lobe of patients with four neurodegenerative disorders (5 AD, 5 PSP, 5 PiD and 5 FTD patients) and 5 control subjects. All patients were matched for age, gender, ApoE-epsilon and MAPT (tau) haplotype. From all groups a total of 790 probes were shown to be differently expressed when compared to control individuals. The results from these experiments were then used to investigate the correlations between clinical, pathological and molecular findings. From the 790 identified probes we extracted a gene set of 166 probes whose expression could discriminate between these disorders and normal ageing. CONCLUSIONS/SIGNIFICANCE:From genome wide expression profiles we extracted a gene set of 166 probes whose expression could discriminate between neurological disorders and normal ageing. This gene set can be further developed into an accurate microarray-based classification test. Furthermore, from this dataset we extracted a disease specific set of genes and identified two aging related transcription factors (FOXO1A and FOXO3A) as possible drug targets related to neurodegenerative disease.
- Published
- 2009
- Full Text
- View/download PDF
6. Variation at GRN 3'-UTR rs5848 is not associated with a risk of frontotemporal lobar degeneration in Dutch population.
- Author
-
Javier Simón-Sánchez, Harro Seelaar, Zoltán Bochdanovits, Dorly J H Deeg, John C van Swieten, and Peter Heutink
- Subjects
Medicine ,Science - Abstract
A single nucleotide polymorphism (rs5848) located in the 3'- untranslated region of GRN has recently been associated with a risk of frontotemporal lobar degeneration (FTLD) in North American population particularly in pathologically confirmed cases with neural inclusions immunoreactive for ubiquitin and TAR DNA-binding protein 43 (TDP-43), but negative for tau and alpha-synuclein (FTLD-TDP).In an effort to replicate these results in a different population, rs5848 was genotyped in 256 FTLD cases and 1695 controls from the Netherlands. Single SNP gender-adjusted logistic regression analysis revealed no significant association between variation at rs5848 and FTLD. Fisher's exact test, failed to find any significant association between rs5848 and a subset of 23 pathology confirmed FTLD-TDP cases.The evidence presented here suggests that variation at rs5848 does not contribute to the etiology of FTLD in the Dutch population.
- Published
- 2009
- Full Text
- View/download PDF
7. Genome-wide prediction of functional gene-gene interactions inferred from patterns of genetic differentiation in mice and men.
- Author
-
Zoltán Bochdanovits, David Sondervan, Sophie Perillous, Toos van Beijsterveldt, Dorret Boomsma, and Peter Heutink
- Subjects
Medicine ,Science - Abstract
The human genome encodes a limited number of genes yet contributes to individual differences in a vast array of heritable traits. A possible explanation for the capacity our genome to generate this virtually unlimited range of phenotypic variation in complex traits is to assume functional interactions between genes. Therefore we searched two mammalian genomes to identify potential epistatic interactions by looking for co-adapted genes marked by excess two-locus genetic differentiation between populations/lineages using publicly available SNP genotype data. The practical motivation for this effort is to reduce the number of pair-wise tests that need to be performed in genome-wide association studies aimed at detecting GxG interactions, by focusing on pairs predicted to be more likely to jointly affect variation in complex traits. Hence, this approach generates a list of candidate interactions that can be empirically tested. In both the mouse and human data we observed two-locus genetic differentiation in excess of what can be expected from chance alone based on simulations. In an attempt to validate our hypothesis that pairs of genes showing excess genetic divergence represent potential functional interactions, we selected a small set of gene combinations postulated to be interacting based on our analyses and looked for a combined effect of the selected genes on variation in complex traits in both mice and man. In both cases the individual effect of the genes were not significant, instead we observed marginally significant interaction effects. These results show that genome wide searches for gene-gene interactions based on population genetic data are feasible and can generate interesting candidate gene pairs to be further tested for their contribution to phenotypic variation in complex traits.
- Published
- 2008
- Full Text
- View/download PDF
8. Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease
- Author
-
Mina Ryten, Daniah Trabzuni, J. Ding, Bart Post, Albert Hofman, Jean-Charles Lambert, Olaf Riess, Michele T.M. Hu, Andrew B. Singleton, Stephen Sawcer, X. Huang, Caroline H. Williams-Gray, H. R. Zielke, C Smith, Peter Lichtner, B.P.C. van de Warrenburg, Bernard Ravina, F. Durif, Ellen Sidransky, Mike A. Nalls, Karen E. Morrison, J. R. Gibbs, Robert L. Johnson, Peter Heutink, David J. Burn, Michael Bonin, Sarah Edkins, T. Gasser, Luigi Ferrucci, H. Chau, Sampath Arepalli, Chris C. A. Spencer, Yoav Ben-Shlomo, Honglei Chen, Caroline M. Tanner, Zoltán Bochdanovits, Ruth Chia, Heiko Huber, Kari Stefansson, Dena G. Hernandez, Jean-Marc Taymans, Veerle Baekelandt, Iakov N. Rudenko, Evy Lobbestael, Huw R. Morris, A. Goate, C. Moorby, Lois E. Greene, Manu Sharma, Emma Gray, Ira Shoulson, Janet Brooks, Juan C. Troncoso, K. Shaw, Laura Civiero, Alessandra Biffi, Hans Scheffer, Matthew Moore, Alan B. Zonderman, S. Sveinbjornsdottir, Avazeh Tashakkori-Ghanbaria, Jean-Christophe Corvol, Vincent Plagnol, H. Petursson, Alice Kaganovich, M M Wickremaratchi, Nigel Williams, Thomas Foltynie, Henk W. Berendse, P. Damier, A. Strange, J. M. Cooper, Simon C. Potter, Patricia Limousin, Jiali Gao, Sophie Winder-Rhodes, M. Van Der Brug, Marie Vidailhet, Elisa Greggio, Nicholas W. Wood, Kevin Talbot, M. R. Cookson, Johanna Huttenlocher, J.J. van Hilten, Dan L. Longo, Alisdair McNeill, François Tison, K.D. van Dijk, David N. Hauser, Allissa Dillman, Suneil K. Kalia, Lorraine V. Kalia, Patrick F. Chinnery, Alexis Brice, Kelechi Ndukwe, J. F. Dartigues, M. Gardner, Mohamad Saad, Palmi V. Jonsson, Kailash P. Bhatia, Roger A. Barker, André G. Uitterlinden, Maria Martinez, R. Walker, Elisa Majounie, Fernando Rivadeneira, Joel S. Perlmutter, Panagiotis Deloukas, Bryan J. Traynor, Ese E. Mudanohwo, Grisel Lopez, UM Sheerin, Joanne D. Stockton, Thomas Illig, Andres M. Lozano, Rita Guerreiro, David T. Dexter, Andrew J. Lees, Sean Chong, Gavin Hudson, Cordelia Langford, Günther Deuschl, Ravindran Kumaran, Janice L. Holton, Tamas Revesz, B.R. Bloem, Alexandra Beilina, Clare Elizabeth Harris, Daniela Berg, Anthony H.V. Schapira, Suzanne Lesage, Sean S. O'Sullivan, Albert R. Hollenbeck, James A. Pearson, R. M. A. de Bie, Delia Lorenz, Sarah E. Hunt, Richard O'Brien, Gavin Charlesworth, Maciej B. Olszewski, Stacy Steinberg, Kathrin Brockmann, Carl E Clarke, Patrizia Rizzu, Claudia Schulte, Hreinn Stefansson, Daan C. Velseboer, Omar Gustafsson, Jonathan R. Evans, Alexandra Durr, Javier Simón-Sánchez, Pierre Pollak, H. Z. Munchen, Jose Bras, Carl Counsell, John Hardy, ANS - Amsterdam Neuroscience, Neurology, and Graduate School
- Subjects
Candidate gene ,autophagy ,Blotting, Western ,Golgi Apparatus ,Genome-wide association study ,Protein Serine-Threonine Kinases ,Biology ,Leucine-rich repeat ,Cell Fractionation ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Mass Spectrometry ,Commentaries ,Protein Interaction Mapping ,Humans ,Immunoprecipitation ,Genetic Predisposition to Disease ,Transport Vesicles ,Gene ,Adaptor Proteins, Signal Transducing ,DNA Primers ,Genetics ,Analysis of Variance ,Microscopy, Confocal ,Multidisciplinary ,Kinase ,HEK 293 cells ,BAG5 ,Intracellular Signaling Peptides and Proteins ,Brain ,rab7 GTP-Binding Proteins ,Signal transducing adaptor protein ,Parkinson Disease ,Biological Sciences ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,GAK ,LRRK2 ,nervous system diseases ,HEK293 Cells ,Genetic Loci ,rab GTP-Binding Proteins ,Multiprotein Complexes ,trans-Golgi ,Genome-Wide Association Study ,Plasmids - Abstract
Item does not contain fulltext Mutations in leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson disease (PD), and common variants around LRRK2 are a risk factor for sporadic PD. Using protein-protein interaction arrays, we identified BCL2-associated athanogene 5, Rab7L1 (RAB7, member RAS oncogene family-like 1), and Cyclin-G-associated kinase as binding partners of LRRK2. The latter two genes are candidate genes for risk for sporadic PD identified by genome-wide association studies. These proteins form a complex that promotes clearance of Golgi-derived vesicles through the autophagy-lysosome system both in vitro and in vivo. We propose that three different genes for PD have a common biological function. More generally, data integration from multiple unbiased screens can provide insight into human disease mechanisms.
- Published
- 2014
- Full Text
- View/download PDF
9. Global similarity with local differences in linkage disequilibrium between the Dutch and HapMap–CEU populations
- Author
-
Patrick F. Sullivan, Luba M. Pardo, Brenda W.J.H. Penninx, Jouke J. Hottenga, Peter Heutink, Zoltán Bochdanovits, Danielle Posthuma, Eco J. C. de Geus, Dorret I. Boomsma, Human genetics, Psychiatry, NCA - Anxiety & Depression, Biological Psychology, and Neuroscience Campus Amsterdam - Anxiety & Depression
- Subjects
HAPLOTYPE BLOCKS ,Netherlands Twin Register (NTR) ,Linkage disequilibrium ,Dutch population ,INFORMATION ,Genotype ,Population ,GENETIC-ASSOCIATION ,Genome-wide association study ,Single-nucleotide polymorphism ,Biology ,Population stratification ,Polymorphism, Single Nucleotide ,HapMap-CEU ,Article ,Linkage Disequilibrium ,White People ,03 medical and health sciences ,Gene Frequency ,Genetics ,Humans ,natural sciences ,International HapMap Project ,GENOME-WIDE ASSOCIATION ,WORLDWIDE SURVEY ,education ,Genetics (clinical) ,030304 developmental biology ,Genetic association ,pair-wise LD ,Netherlands ,Linkage (software) ,0303 health sciences ,education.field_of_study ,SNP DATA ,COMPLEX TRAITS ,030305 genetics & heredity ,TAGSNP TRANSFERABILITY ,Genetics, Population ,Evolutionary biology ,SAMPLE-SIZE ,PATTERNS ,bootstrapping ,LD blocks ,Genome-Wide Association Study - Abstract
The HapMap project has facilitated the selection of tagging single nucleotide polymorphisms (tagSNPs) for genome-wide association studies (GWAS) under the assumption that linkage disequilibrium (LD) in the HapMap populations is similar to the populations under investigation. Earlier reports support this assumption, although in most of these studies only a few loci were evaluated. We compared pair-wise LD and LD block structure across autosomes between the Dutch population and the CEU-HapMap reference panel. The impact of sampling distribution on the estimation of LD blocks was studied by bootstrapping. A high Pearson correlation (genome-wide; 0.93) between pair-wise r(2) for the Dutch and the CEU populations was found, indicating that tagSNPs from the CEU-HapMap panel capture common variation in the Dutch population. However, some genomic regions exhibited, significantly lower correlation than the genome-wide estimate. This might decrease the validity of HapMap tagSNPs in these regions and the power of GWAS. The LD block structure differed considerably between the Dutch and CEU-HapMap populations. This was not explained by demographic differences between the CEU and Dutch samples, as testing for population stratification was not significant. We also found that sampling variation had a large effect on the estimation of LD blocks, as shown by the bootstrapping analysis. Thus, in small samples, most of the observed differences in LD blocks between populations are most likely the result of sampling variation. This poor concordance in LD block structure suggests that large samples are required for robust estimations of local LD block structure in populations. European Journal of Human Genetics (2009) 17, 802-810; doi: 10.1038/ejhg.2008.248; published online 7 January 2009
- Published
- 2009
- Full Text
- View/download PDF
10. Determining the genome-wide kinship coefficient seems unhelpful in distinguishing consanguineous couples with a high versus low risk for adverse reproductive outcome
- Author
-
Peter Heutink, Fowzan S. Alkuraya, Eamonn Sheridan, Lidewij Henneman, Martina C. Cornel, Piet J. Kostense, A. van Haeringen, Patrizia Rizzu, Wided Kelmemi, Jan-Maarten Cobben, Amira Masri, M. Hashem, Hülya Kayserili, Zoltán Bochdanovits, Charlotte J. Dommering, Sander Ouburg, Marieke Teeuw, Marianne A. Jonker, L. P. ten Kate, H. Bouhamed-Chaabouni, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Quality of Care, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Amsterdam Neuroscience, Other Research, Human Genetics, Paediatric Genetics, Human genetics, Medical Microbiology and Infection Prevention, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Quality of care, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Kelmemi, W., Teeuw, M. W., Bochdanovits, Z., Ouburg, S., Jonker, M. A., Alkuraya, F., Hashem, M., Kayserili, H., Haeringen, van A., Sheridan, E., Masri, A., Cobben, J. M., Rizzu, P., Kostense, P. J., Dommering, C. J., Henneman, L., Bouhamed-Chaabouni, H., Heutink, P., Cornel, L. P. ten Kate and M. C., School of Medicine, and Department of Medical Genetics
- Subjects
Male ,Linkage disequilibrium ,Genotype ,genetics [Congenital Abnormalities] ,Population ,Inbreeding coefficient ,Single-nucleotide polymorphism ,Genes, Recessive ,Consanguinity ,Biology ,Relatedness ,Autosomal recessive disorder ,Polymorphism, Single Nucleotide ,Statistics, Nonparametric ,Congenital Abnormalities ,03 medical and health sciences ,Kinship ,Genetics ,Humans ,Genetics(clinical) ,ddc:610 ,genetics [Genome, Human] ,education ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Base Sequence ,Genome, Human ,Medical genetics ,030305 genetics & heredity ,Case-control study ,Regression analysis ,Sequence Analysis, DNA ,Pedigree ,Case-Control Studies ,Mann–Whitney U test ,Female ,Research Article - Abstract
Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case–control status and genomic kinship coefficient. In this case–control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents., NA
- Published
- 2015
- Full Text
- View/download PDF
11. Resequencing Three Candidate Genes for Major Depressive Disorder in a Dutch Cohort
- Author
-
Marianna R. Bevova, Zoltán Bochdanovits, Tiny Uithuisje, Johannes H. Smit, I. Bakker, Eva C. Verbeek, Patrizia Rizzu, Eco J. C. de Geus, Brenda W.J.H. Penninx, Dorret I. Boomsma, Witte J.G. Hoogendijk, Peter Heutink, Functional Genomics, Biological Psychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Clinical Genetics, Psychiatry, Human genetics, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, and NCA - Brain imaging technology
- Subjects
Netherlands Twin Register (NTR) ,Linkage disequilibrium ,Candidate gene ,lcsh:Medicine ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Receptors, Metabotropic Glutamate ,Polymorphism, Single Nucleotide ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,mental disorders ,SNP ,Humans ,lcsh:Science ,Promoter Regions, Genetic ,030304 developmental biology ,Genetic association ,Netherlands ,Genetics ,Serotonin Plasma Membrane Transport Proteins ,0303 health sciences ,Depressive Disorder, Major ,Multidisciplinary ,lcsh:R ,Neuropeptides ,Epistasis, Genetic ,Cytoskeletal Proteins ,Haplotypes ,Cohort ,lcsh:Q ,030217 neurology & neurosurgery ,Imputation (genetics) ,Research Article ,Genome-Wide Association Study - Abstract
Major depressive disorder (MDD) is a psychiatric disorder, characterized by periods of low mood of more than two weeks, loss of interest in normally enjoyable activities and behavioral changes. MDD is a complex disorder and does not have a single genetic cause. In 2009 a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. Many of the top signals of this GWAS mapped to a region spanning the gene PCLO, and the non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became genome wide significant after post-hoc analysis. We performed resequencing of PCLO, GRM7, and SLC6A4 in 50 control samples from the GAIN-MDD cohort, to detect new genomic variants. Subsequently, we genotyped these variants in the entire GAIN-MDD cohort and performed association analysis to investigate if rs2522833 is the causal variant or simply in linkage disequilibrium with a more associated variant. GRM7 and SLC6A4 are both candidate genes for MDD from literature. We aimed to gather more evidence that rs2522833 is indeed the causal variant in the GAIN-MDD cohort or to find a previously undetected common variant in either PCLO, GRM7, or SLC6A4 with a higher association in this cohort. After next generation sequencing and association analysis we excluded the possibility of an undetected common variant to be more associated. For neither PCLO nor GRM7 we found a more associated variant. For SLC6A4, we found a new SNP that showed a lower P-value (P = 0.07) than in the GAIN-MDD GWAS (P = 0.09). However, no evidence for genome-wide significance was found. Although we did not take into account rare variants, we conclude that our results provide further support for the hypothesis that the non-synonymous coding SNP rs2522833 in the PCLO gene is indeed likely to be the causal variant in the GAIN-MDD cohort. © 2013 Verbeek et al.
- Published
- 2013
- Full Text
- View/download PDF
12. Piccolo genotype modulates neural correlates of emotion processing but not executive functioning
- Author
-
D.J. Veltman, Brenda W.J.H. Penninx, M.A. van Buchem, Zoltán Bochdanovits, M-J van Tol, Saskia Woudstra, Frans G. Zitman, N.J. van der Wee, Liliana Ramona Demenescu, Esther M. Opmeer, Witte J.G. Hoogendijk, André Aleman, Psychiatry, Human genetics, Anatomy and neurosciences, NCA - Anxiety & Depression, EMGO - Mental health, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Erasmus MC other, Neuroscience Campus Amsterdam - Anxiety & Depression, and EMGO+ - Mental Health
- Subjects
Male ,Neural substrate ,Emotions ,PCLO ,FACES ,Synaptic Transmission ,Developmental psychology ,AFFECTIVE FACIAL STIMULI ,EXPRESSIONS ,Monoaminergic ,LONDON TASK ,Serotonin transporter ,MAJOR DEPRESSIVE DISORDER ,medicine.diagnostic_test ,biology ,Genetic Carrier Screening ,Cognition ,Middle Aged ,Amygdala ,Magnetic Resonance Imaging ,neuroimaging genetics ,Facial Expression ,Psychiatry and Mental health ,medicine.anatomical_structure ,Pattern Recognition, Visual ,AMYGDALA ACTIVITY ,Major depressive disorder ,Original Article ,Female ,Psychology ,Adult ,MOOD DISORDERS ,Genotype ,behavioral disciplines and activities ,Cellular and Molecular Neuroscience ,ANTIDEPRESSANT TREATMENT ,Image Interpretation, Computer-Assisted ,medicine ,Humans ,Genetic Predisposition to Disease ,Dominance, Cerebral ,Biological Psychiatry ,Alleles ,Depressive Disorder, Major ,Polymorphism, Genetic ,emotion processing ,Neuropeptides ,medicine.disease ,Image Enhancement ,Oxygen ,Cytoskeletal Proteins ,executive function ,SEROTONIN TRANSPORTER ,biology.protein ,genome-wide association ,Functional magnetic resonance imaging ,Neuroscience ,Executive dysfunction ,Genome-Wide Association Study - Abstract
Translational psychiatry 2012(2), e99 (2012). doi:10.1038/tp.2012.29, Published by Nature Publishing Group, London
- Published
- 2012
- Full Text
- View/download PDF
13. Genome-wide association study confirms extant PD risk loci among the Dutch
- Author
-
Sampath Arepalli, Zoltán Bochdanovits, Rob M.A. de Bie, Bart P.C. van de Warrenburg, Albert Hofman, Bart Post, Peter Heutink, Fernando Rivadeneira, Andrew B. Singleton, Dena G. Hernandez, Hans Scheffer, Jacobus J. van Hilten, Karin van Dijk, B.R. Bloem, Daan C. Velseboer, Henk W. Berendse, Patrizia Rizzu, André G. Uitterlinden, Javier Simón-Sánchez, Erasmus MC other, Internal Medicine, Epidemiology, Clinical Genetics, Human genetics, Neurology, Anatomy and neurosciences, NCA - Neurodegeneration, Neuroscience Campus Amsterdam - Neurodegeneration, ANS - Amsterdam Neuroscience, ACS - Amsterdam Cardiovascular Sciences, and Graduate School
- Subjects
Male ,Linkage disequilibrium ,Genome-wide association study ,Genomic disorders and inherited multi-system disorders Functional Neurogenomics [IGMD 3] ,0302 clinical medicine ,Gene Frequency ,Risk Factors ,Genotype ,MAPT ,Age of Onset ,Genetics (clinical) ,Netherlands ,Aged, 80 and over ,Genetics ,0303 health sciences ,Intracellular Signaling Peptides and Proteins ,Parkinson Disease ,Middle Aged ,HLA ,alpha-Synuclein ,PD ,Female ,Functional Neurogenomics [DCN 2] ,Adult ,Adolescent ,BST1 ,tau Proteins ,Single-nucleotide polymorphism ,Locus (genetics) ,Human leukocyte antigen ,Protein Serine-Threonine Kinases ,Biology ,GPI-Linked Proteins ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Antigens, CD ,Humans ,Genetic Predisposition to Disease ,GAK/DGKQ ,ADP-ribosyl Cyclase ,Allele frequency ,Aged ,030304 developmental biology ,Case-control study ,DNA Fingerprinting ,Genetic Loci ,Case-Control Studies ,SNCA ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
In view of the population-specific heterogeneity in reported genetic risk factors for Parkinson's disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514 799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P=1.63x10(-5), OR=1.325 and BST1, rs12502586: P=1.63x10(-3), OR=1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3' and 5' ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P=1.22x10(-4), OR=1.51; HLA, rs4248166: P=4.39x10(-5), OR=1.36; and MAPT, rs3785880: P=1.9x10(-3), OR=1.19). European Journal of Human Genetics (2011) 19, 655-661; doi:10.1038/ejhg.2010.254; published online 19 January 2011
- Published
- 2011
- Full Text
- View/download PDF
14. Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study
- Author
-
Peter Heutink, Zoltán Bochdanovits, Leo P. ten Kate, Martina C. Cornel, Marieke Teeuw, D.J. Kuik, Lidewij Henneman, Human genetics, Epidemiology and Data Science, EMGO - Quality of care, NCA - Integrative Analysis & Modeling, Neuroscience Campus Amsterdam - integrative Analysis & Modeling, and EMGO+ - Quality of Care
- Subjects
Male ,Parents ,lcsh:Internal medicine ,lcsh:QH426-470 ,Offspring ,Chromosome Disorders ,Genes, Recessive ,Consanguinity ,Ethnic origin ,Disease ,Identity by descent ,Risk Assessment ,Study Protocol ,SDG 3 - Good Health and Well-being ,Reference Values ,Genetic variation ,Prevalence ,Genetics ,Medicine ,Humans ,Genetics(clinical) ,lcsh:RC31-1245 ,Child ,Genetics (clinical) ,Stochastic Processes ,business.industry ,Case-control study ,Genetic Variation ,DNA ,Pedigree ,lcsh:Genetics ,Female ,business ,Risk assessment ,Demography - Abstract
Background The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only. Methods/Design This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis. Discussion This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous parents of affected children compared to the consanguineous parents of healthy children. If our hypothesis proves to be correct, further studies are needed to obtain different risk figure estimates for the different proportions of DNA identical-by-descent. With more precise information about their risk status, empowerment of couples can be improved when making reproductive decisions.
- Published
- 2010
- Full Text
- View/download PDF
15. A functional polymorphism under positive evolutionary selection in ADRB2 is associated with human intelligence with opposite effects in the young and the elderly
- Author
-
Dorret I. Boomsma, Linda M. van den Berg, Tinca J. C. Polderman, Michelle Luciano, Patrizia Rizzu, Zoltán Bochdanovits, John M. Starr, Peter Heutink, Sarah E. Harris, Ian J. Deary, Lorna M. Houlihan, Luba M. Pardo, Florencia M. Gosso, Eco J. C. de Geus, Danielle Posthuma, Biological Psychology, Neuroscience Campus Amsterdam - Attention & Cognition, Human genetics, and NCA - Attention & Cognition
- Subjects
Adult ,Male ,Primates ,Netherlands Twin Register (NTR) ,Candidate gene ,Aging ,Pan troglodytes ,Population ,Intelligence ,Single-nucleotide polymorphism ,Rodentia ,Biology ,Polymorphism, Single Nucleotide ,Evolution, Molecular ,Polymorphism (computer science) ,Genetics ,Animals ,Humans ,Family ,Allele ,Selection, Genetic ,education ,Child ,Gene ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,Genetic association ,Comparative genomics ,education.field_of_study ,Polymorphism, Genetic ,Genome, Human ,Brain ,Proteins ,Regression Analysis ,Female ,Receptors, Adrenergic, beta-2 - Abstract
Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior. © 2008 Springer Science+Business Media, LLC.
- Published
- 2009
- Full Text
- View/download PDF
16. Empirical assessment of the validity of the 'fundamental theorem of the HapMap' in the light of 'cryptic' tagging of multiple susceptibility loci
- Author
-
Zoltán Bochdanovits, A. W. van der Vaart, Peter Heutink, Human genetics, Neuroscience Campus Amsterdam 2008, Stochastics, and Mathematics
- Subjects
Genetics ,Linkage disequilibrium ,Linkage Disequilibrium Mapping ,Haplotype ,Chromosome Mapping ,Reproducibility of Results ,Locus (genetics) ,Genomics ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Bias ,Haplotypes ,Gene mapping ,Sample size determination ,Sample Size ,Genetic Predisposition to Disease ,International HapMap Project ,Genetics (clinical) ,Genetic association - Abstract
Underestimation of the sample size needed to detect genetic association may occur as a result of deviations from the 'fundamental theorem of the HapMap'. A biologically plausible mechanism that might cause this deviation is 'cryptic' tagging of multiple susceptibility loci by the same neutral marker. For complex disorders, the existence of multiple susceptibility loci on the same chromosome is probably the rule rather than the exception. Our results show that conditional on the known haplotype structure of the genome the probability that a tagging SNP that is in linkage disequilibrium (LD) with a susceptibility gene is also in LD with another susceptibility gene is not negligible. Consequently, we were able to estimate the extent and the prevalence of the bias in the necessary sample size to find association induced by 'cryptic' tagging. In general, the underestimation of the necessary sample size is modest: 5% of all association studies will underestimate the sample size by 5-30%. On the basis of our results, a safe bet is to use a sample that is 10% larger than otherwise deemed necessary.
- Published
- 2008
- Full Text
- View/download PDF
17. Antagonistic pleiotropy for life-history traits at the gene expression level.
- Author
-
Zoltán Bochdanovits and Gerdien de Jong
- Subjects
- *
GENE expression , *GENETIC regulation , *GENES , *METABOLISM - Abstract
Life-history trade-offs prevent different components of fitness from being maximized simultaneously. Although the existence of trade-offs has been clearly demonstrated, the 'classical' mechanism of adaptive resource allocation that should underlie them has recently received criticism. In this study, we explore the molecular mechanisms of life-history trade-offs by applying a quantitative genomic approach. Analysis of global gene expression in Drosophila melanogaster revealed 34 genes whose expression coincided with the genetic trade-off between larval survival and adult size. The joint expression of these candidate 'trade-off' genes explained 86.3% of the trade-off. Fourteen of these genes have known functions which suggest that the larval survival–adult size trade-off could be the result of resource allocation at the organismal level, but at the level of cellular metabolism the trade-off would reduce to a shift between energy metabolism versus protein biosynthesis, regulated by the RAS signalling pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.