Zoltán Bochdanovits

Genome-wide association study confirms extant PD risk loci among the Dutch.

In view of the population-specific heterogeneity in reported genetic risk factors for Parkinsons 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=1.63 × 10−5, OR=1.325 and BST1, rs12502586: P=1.63 × 10−3, 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=1.22 × 10−4, OR=1.51; HLA, rs4248166: P=4.39 × 10−5, OR=1.36; and MAPT, rs3785880: P=1.9 × 10−3, OR=1.19).

The role of the brain-derived neurotrophic factor (BDNF) val66met variant in the phenotypic expression of obsessive-compulsive disorder (OCD)

Evidence suggests that the Val66Met variant of the brain‐derived neurotrophic factor (BDNF) gene may play a role in the etiology of Obsessive‐Compulsive Disorder (OCD). In this study, the role of the BDNF Val66Met variant in the etiology and the phenotypic expression of OCD is investigated. Associations between the BDNF Val66Met variant and OCD, obsessive‐compulsive symptom dimensions, Yale‐Brown Obsessive Compulsive Scale (YBOCS) severity scores, age of onset and family history of obsessive‐compulsive symptoms were assessed. The BDNF Val66Met variant was genotyped in 419 patients with sub‐/clinical OCD and 650 controls. No differences in allele or genotype frequency were observed between cases and controls. In females with OCD, the Met66Met genotype was associated with later age of onset and a trend for a negative family history, whereas the Val66Val genotype was associated with a trend for lower YBOCS severity scores. Item‐level factor analysis revealed six factors: 1) Contamination/cleaning; 2) Aggressive obsessions/checking; 3) Symmetry obsessions, counting, ordering and repeating; 4) Sexual/religious obsessions; 5) Hoarding and 6) Somatic obsessions/checking. A trend was found for a positive association between Factor 4 (Sexual/religious obsessions) and the BDNF Val66Val genotype. The results suggest that BDNF function may be implicated in the mediation of OCD. We found that for the BDNF Met66Met genotype may be associated with a milder phenotype in females and a possible role for the BDNF Val66Val genotype and the BDNF Val66 allele in the sexual/religious obsessions.

Probing the roles of LRR RLK genes in Arabidopsis thaliana roots using a custom T-DNA insertion set.

Leucine-rich repeat receptor-like protein kinases (LRR RLKs) represent the largest group of Arabidopsis RLKs with approximately 235 members. A minority of these LRR RLKs have been assigned to diverse roles in development, pathogen resistance and hormone perception. Using a reverse genetics approach, a collection of homozygous T-DNA insertion lines for 69 root expressed LRR RLK genes was screened for root developmental defects and altered response after exposure to environmental, hormonal/chemical and abiotic stress. The obtained data demonstrate that LRR RLKs play a role in a wide variety of signal transduction pathways related to hormone and abiotic stress responses. The described collection of T-DNA insertion mutants provides a valuable tool for future research into the function of LRR RLK genes.

Modulatory Effects of the Piccolo Genotype on Emotional Memory in Health and Depression

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.

Joint reanalysis of 29 correlated SNPs supports the role of PCLO/Piccolo as a causal risk factor for major depressive disorder.

Joint reanalysis of 29 correlated SNPs supports the role of PCLO/ Piccolo as a causal risk factor for major depressive disorder

The Role of the COMT Val(158)Met Polymorphism in the Phenotypic Expression of Obsessive-Compulsive Disorder

Obsessive‐Compulsive Disorder (OCD) is characterized by the presence of obsessions and compulsions, and shows considerable phenotypic variability. Family and twin studies have indicated a genetic component in the etiology of OCD, and the catechol‐O‐methyl transferase (COMT) gene is an important candidate gene for OCD. This study investigates the influence of the functional COMT Val158Met polymorphism on the phenotypic expression of OCD, using an item‐level factor‐analytic approach in a large sample. The COMT Val158Met variant was genotyped in 373 patients and 462 controls. It was tested whether there was an association between the COMT Val158Met polymorphism and OCD or dimensional phenotypes such as YBOCS severity score, age of onset of obsessive‐compulsive symptoms and six symptom dimensions recently found in a large item‐level factor‐analytic study [Katerberg et al., submitted]. We further investigated possible sex‐specific associations between the COMT Val158Met polymorphism and OCD or dimensional phenotypes. There was a trend for an association of the COMT 158Met allele with OCD in males, and an interaction between the COMT Val158Met genotype and sex on the somatic and sensory phenomena symptom dimension, with females showing lower scores. In conclusion, a dimensional approach seems fruitful in detecting genes of importance for OCD.

Comprehensive mRNA Expression Profiling Distinguishes Tauopathies and Identifies Shared Molecular Pathways

Background Understanding the aetiologies of neurodegenerative diseases such as Alzheimers disease (AD), Picks 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-ε 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.

Variation at GRN 3 '-UTR rs5848 Is Not Associated with a Risk of Frontotemporal Lobar Degeneration in Dutch Population

Background 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). Methodology/Principal Findings 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. Fishers exact test, failed to find any significant association between rs5848 and a subset of 23 pathology confirmed FTLD-TDP cases. Conclusions/Significance The evidence presented here suggests that variation at rs5848 does not contribute to the etiology of FTLD in the Dutch population.

A Fine-Mapping Study of 7 Top Scoring Genes from a GWAS for Major Depressive Disorder

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, r2>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.

Use of support vector machines for disease risk prediction in genome-wide association studies: concerns and opportunities.

The success of genome‐wide association studies (GWAS) in deciphering the genetic architecture of complex diseases has fueled the expectations whether the individual risk can also be quantified based on the genetic architecture. So far, disease risk prediction based on top‐validated single‐nucleotide polymorphisms (SNPs) showed little predictive value. Here, we applied a support vector machine (SVM) to Parkinson disease (PD) and type 1 diabetes (T1D), to show that apart from magnitude of effect size of risk variants, heritability of the disease also plays an important role in disease risk prediction. Furthermore, we performed a simulation study to show the role of uncommon (frequency 1–5%) as well as rare variants (frequency <1%) in disease etiology of complex diseases. Using a cross‐validation model, we were able to achieve predictions with an area under the receiver operating characteristic curve (AUC) of ∼0.88 for T1D, highlighting the strong heritable component (∼90%). This is in contrast to PD, where we were unable to achieve a satisfactory prediction (AUC ∼0.56; heritability ∼38%). Our simulations showed that simultaneous inclusion of uncommon and rare variants in GWAS would eventually lead to feasible disease risk prediction for complex diseases such as PD. The used software is available at http://www.ra.cs.uni‐tuebingen.de/software/MACLEAPS/. Hum Mutat 33:1708–1718, 2012.