A powerful and efficient two-stage method for detecting gene-to-gene interactions in GWAS.

For over a decade functional gene-to-gene interaction (epistasis) has been suspected to be a determinant in the "missing heritability" of complex traits. However, searching for epistasis on the genome-wide scale has been challenging due to the prohibitively large number of tests which result in a serious loss of statistical power as well as computational challenges. In this article, we propose a two-stage method applicable to existing case-control data sets, which aims to lessen both of these problems by pre-assessing whether a candidate pair of genetic loci is involved in epistasis before it is actually tested for interaction with respect to a complex phenotype.

Resequencing three candidate genes for major depressive disorder in a Dutch cohort.

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.

Accurate prediction of a minimal region around a genetic association signal that contains the causal variant.

In recent years, genome-wide association studies have been very successful in identifying loci for complex traits. However, typically these findings involve noncoding and/or intergenic SNPs without a clear functional effect that do not directly point to a gene. Hence, the challenge is to identify the causal variant responsible for the association signal.

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).

Cervical dystonia and genetic common variation in the dopamine pathway.

Cervical dystonia, a late onset focal dystonia, has a complex genetic background. Multiple lines of evidence point to a role for aberrant dopamine levels in dystonia. We assessed whether common variation within genes that regulate brain dopamine levels and in key genes of the dopamine metabolic pathway, modulate the risk for cervical dystonia.

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.

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.

Extended kindred with recessive late-onset Alzheimer disease maps to locus 8p22-p21.2: a genome-wide linkage analysis.

Late-onset Alzheimer disease (LOAD) is a complex genetic disorder. Although genes involved in early-onset forms were discovered more than a decade ago, LOAD research has only been able to point out small effect loci, with the exception of APOE. We mapped the gene predisposing to LOAD in an extended inbred family coming from a genetically isolated region (24 sampled individuals, 12 of whom are affected), completing a genome-wide screen with an Affymetrix10 K single nucleotide polymorphism microarray.

The complete automation of cell culture: improvements for high-throughput and high-content screening.

Genomic approaches provide enormous amounts of raw data with regard to genetic variation, the diversity of RNA species, and protein complement. High-throughput (HT) and high-content (HC) cellular screens are ideally suited to contextualize the information gathered from other "omic" approaches into networks and can be used for the identification of therapeutic targets. Current methods used for HT-HC screens are laborious, time-consuming, and prone to human error.

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.

Transcriptional plasticity of a soil arthropod across different ecological conditions.

Ecological functional genomics, dealing with the responses of organisms to their natural environment is confronted with a complex pattern of variation and a large number of confounding environmental factors. For gene expression studies to provide meaningful information on conditions deviating from normal, a baseline or normal operating range (NOR) response needs to be established which indicates how an organism's transcriptome reacts to naturally varying ecological factors. Here we determine the transcriptional plasticity of a soil arthropod, Folsomia candida, exposed to various natural environments, as part of a first attempt in establishing such a NOR.

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 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.

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.

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.

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.

Comprehensive mRNA expression profiling distinguishes tauopathies and identifies shared molecular pathways.

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.

Adaptive differences in gene expression associated with heavy metal tolerance in the soil arthropod Orchesella cincta.

Field-selected tolerance to heavy metals has been reported for Orchesella cincta (Arthropoda: Collembola) populations occurring at metal-contaminated mining sites. This tolerance correlated with heritable increase in metal excretion efficiency, less pronounced cadmium (Cd)-induced growth reduction and overexpression of the metallothionein gene. We applied transcriptomics to determine differential gene expression caused by this abiotic stress in reference and Cd-tolerant populations.

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 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.

Global similarity with local differences in linkage disequilibrium between the Dutch and HapMap-CEU populations.

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.

Glucocorticoid receptor gene polymorphisms and childhood adversity are associated with depression: New evidence for a gene-environment interaction.

The hypothalamic-pituitary-adrenal (HPA)-axis regulates the response to stressful events and is expected to be involved in the pathogenesis of depression. The glucocorticoid receptor (GR) regulates the activity of the HPA-axis. Both GR gene polymorphisms and childhood adversity are known to be associated with increased risk for depression.

A Functional polymorphism under positive evolutionary selection in ADRB2 is associated with human intelligence with opposite effects in the young and the elderly.

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.

Testing replication of a 5-SNP set for general cognitive ability in six population samples.

A 5-single nucleotide polymorphism (SNP) set has been associated with general cognitive ability in 5000 7-year-old children from the Twins Early Development Study (TEDS). Four of these SNPs were identified through a 10 K microarray analysis and one was identified through a targeted analysis of brain-expressed genes. The present study tested this association with general cognitive ability in six population samples of varying size and age from Australia, the UK (Scotland and England) and the Netherlands.

Genome-wide prediction of functional gene-gene interactions inferred from patterns of genetic differentiation in mice and men.

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.

Empirical assessment of the validity of the 'fundamental theorem of the HapMap' in the light of 'cryptic' tagging of multiple susceptibility loci.

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.

Latitudinal clines in Drosophila melanogaster: body size, allozyme frequencies, inversion frequencies, and the insulin-signalling pathway.

Many latitudinal clines exist in Drosophila melanogaster: in adult body size, in allele frequency at allozyme loci, and in frequencies of common cosmopolitan inversions. The question is raised whether these latitudinal clines are causally related. This review aims to connect data from two very different fields of study, evolutionary biology and cell biology, in explaining such natural genetic variation in D.