Detecting significant genotype-phenotype association rules in bipolar disorder: market research meets complex genetics.

Background: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive.

Genome-wide association study reveals two new risk loci for bipolar disorder.

Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci.

Longer telomere length in patients with schizophrenia.

Previous studies have reported an association between shorter leukocyte telomere length and schizophrenia (SCZ). The aim of the present study was to replicate this finding in a large sample of SCZ patients (n=539) and population-based controls (n=519). In addition, the possible influence of SCZ severity on telomere length - as measured by age of onset, mode of onset, and course of the disorder - was investigated.

Copy number variants in German patients with schizophrenia.

Large rare copy number variants (CNVs) have been recognized as significant genetic risk factors for the development of schizophrenia (SCZ). However, due to their low frequency (1∶150 to 1∶1000) among patients, large sample sizes are needed to detect an association between specific CNVs and SCZ. So far, the majority of genome-wide CNV analyses have focused on reporting only CNVs that reached a significant P-value within the study cohort and merely confirmed the frequency of already-established risk-carrying CNVs.

Implication of a rare deletion at distal 16p11.2 in schizophrenia.

Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication.

Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples.

Studies in humans and mice implicate neurocan in the etiology of mania.

Objective: Genome-wide association has been reported between the NCAN gene and bipolar disorder. The aims of this study were to characterize the clinical symptomatology most strongly influenced by NCAN and to explore the behavioral phenotype of Ncan knockout (Ncan(-/-)) mice.

Method: Genotype/phenotype correlations were investigated in patients with bipolar disorder (N=641) and the genetically related disorders major depression (N=597) and schizophrenia (N=480).

Genome-wide association data provide further support for an association between 5-HTTLPR and major depressive disorder.

Background: Dysfunctions of serotonergic neurotransmission are supposed to be involved in the pathogenesis of psychiatric disorders such as major depressive disorder (MDD). The concentration of serotonin (5-hydroxytryptamine, 5-HT) in the synaptic cleft is essentially regulated by the 5-HT transporter (5-HTT). A length polymorphism repeat in the 5-HTT promoter region, termed 5-HTTLPR, has been commonly investigated for an association with psychiatric disorders.

Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder.

Linkage and fine mapping studies have established that the neuregulin 3 gene (NRG3) is a susceptibility locus for schizophrenia. Association studies of this disorder have implicated NRG3 variants in both psychotic symptoms and attention performance. Psychotic symptoms and cognitive deficits are also frequent features of bipolar disorder.

Segment-wise genome-wide association analysis identifies a candidate region associated with schizophrenia in three independent samples.

Recent studies suggest that variation in complex disorders (e.g., schizophrenia) is explained by a large number of genetic variants with small effect size (Odds Ratio ≈ 1.

Association between schizophrenia and common variation in neurocan (NCAN), a genetic risk factor for bipolar disorder.

A recent study found genome-wide significant association between common variation in the gene neurocan (NCAN, rs1064395) and bipolar disorder (BD). In view of accumulating evidence that BD and schizophrenia partly share genetic risk factors, we tested this single-nucleotide polymorphism for association with schizophrenia in three independent patient-control samples of European ancestry, totaling 5061 patients and 9655 controls. The rs1064395 A-allele, which confers risk for BD, was significantly over-represented in schizophrenia patients compared to controls (p=2.

A mega-analysis of genome-wide association studies for major depressive disorder.

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.

Molecular genetic overlap in bipolar disorder, schizophrenia, and major depressive disorder.

Objectives: Genome-wide association studies (GWAS) in complex phenotypes, including psychiatric disorders, have yielded many replicated findings, yet individual markers account for only a small fraction of the inherited differences in risk. We tested the performance of polygenic models in discriminating between cases and healthy controls and among cases with distinct psychiatric diagnoses.

Methods: GWAS results in bipolar disorder (BD), major depressive disorder (MDD), schizophrenia (SZ), and Parkinson's disease (PD) were used to assign weights to individual alleles, based on odds ratios.

Gene-based analysis of regionally enriched cortical genes in GWAS data sets of cognitive traits and psychiatric disorders.

Background: Despite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain.

Association between copy number variants in 16p11.2 and major depressive disorder in a German case-control sample.

The majority of genetic risk factors for major depressive disorder (MDD) still await identification. Since copy number variants (CNVs) have been implicated in various neuropsychiatric disorders, the question arises as to whether CNVs also play a role in MDD. We performed a genome-wide CNV study using Illumina's SNP array data from 604 MDD patients and 1,643 controls.

Common variants at VRK2 and TCF4 conferring risk of schizophrenia.

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.

The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia.

Background: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia.

Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder.

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls.

Resequencing and follow-up of neurexin 1 (NRXN1) in schizophrenia patients.

Large rare deletions in NRXN1 increase the risk for schizophrenia. The aim of the present study was to determine whether small rare sequence changes in exons and splice sites contribute to the development of schizophrenia in a high-penetrance manner. Complete coding regions and splice sites were resequenced in 94 patients and 94 controls.

Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.

Background: Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression.

Methods: We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects.

The catechol-O-methyl transferase (COMT) gene and its potential association with schizophrenia: findings from a large German case-control and family-based sample.

The aim of the present study was to investigate possible associations between schizophrenia and 13 SNP markers in COMT. No association was observed in 631 cases, 207 nuclear families, and 776 controls. A cognitive performance phenotype (Trail Marking Test) was available for a subgroup of the patients.

A reappraisal of the association between Dysbindin (DTNBP1) and schizophrenia in a large combined case-control and family-based sample of German ancestry.

Background: Dysbindin (DTNBP1) is a widely studied candidate gene for schizophrenia (SCZ); however, inconsistent results across studies triggered skepticism towards the validity of the findings. In this HapMap-based study, we reappraised the association between Dysbindin and SCZ in a large sample of German ethnicity.

Method: Six hundred thirty-four cases with DSM-IV SCZ, 776 controls, and 180 parent-offspring trios were genotyped for 38 Dysbindin SNPs.

Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1.

The major mood disorders, which include bipolar disorder and major depressive disorder (MDD), are considered heritable traits, although previous genetic association studies have had limited success in robustly identifying risk loci. We performed a meta-analysis of five case-control cohorts for major mood disorder, including over 13,600 individuals genotyped on high-density SNP arrays. We identified SNPs at 3p21.

Common variants conferring risk of schizophrenia.

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms.

Dissection of phenotype reveals possible association between schizophrenia and Glutamate Receptor Delta 1 (GRID1) gene promoter.

Recent linkage and association data have implicated the Glutamate Receptor Delta 1 (GRID1) locus in the etiology of schizophrenia. In this study, we sought to test whether variants in the promoter region are associated with this disorder. The distribution of CpG islands, which are known to be relevant for transcriptional regulation, was computationally determined at the GRID1 locus, and the putative transcriptional regulatory region at the 5'-terminus was systematically tagged using HapMap data.