An association study of suicide and candidate genes in the serotonergic system.

INTRODUCTION: Strong evidence demonstrates a genetic susceptibility to suicidal behaviour and a relationship between suicide and mental disorders. The aim of this study was to test for association between suicide and five selected genetic variants, which had shown association with suicide in other populations. METHOD: We performed a nationwide case-control study on all suicide cases sent for autopsy in Denmark between the years 2000 and 2007. The study comprised 572 cases and 1049 controls and is one of the largest genetic studies in completed suicide to date. The analysed markers were located within the Serotonin Transporter (SLC6A4), Monoamine Oxidase-A (MAOA) and the Tryptophan Hydroxylase I and II (TPH1 and TPH2) genes. RESULTS: None of the genetic markers within SLC6A4, MAOA, TPH1 and TPH2 were significantly associated with completed suicide or suicide method in the basic association tests. Exploratory interaction test showed that the minor allele of rs1800532 in TPH1 has a protective effect for males younger than 35 years and females older than 50 years, whereas for the oldest male subjects, it tended to be a risk factor. We also observed a significant interaction between age-group and the 5-HTTLPR genotype (with and without rs25531) in SLC6A4. The long allele or high expression allele tends to have a protective effect in the middle age-group. LIMITATION: We only analysed a limited number of genetic variants. CONCLUSION: None of the analysed variants are strong risk factors. To reveal a better understanding of the genes involved in suicide, we suggest future studies should include both genetic and non-genetic factors.

Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk.

N-methyl-D-aspartate (NMDA) receptors are very important for proper brain development and several lines of evidence support that hypofunction of the NMDA receptors are involved in the pathophysiology of schizophrenia. Gene variation and gene-environmental interactions involving the genes encoding the NMDA receptors are therefore likely to influence the risk of schizophrenia. The aim of this study was to determine (1) whether SNP variation in the genes (GRIN1, GRIN2A, GRIN2B, GRIN2C, and GRIN2D) encoding the NMDA receptor were associated with schizophrenia; (2) whether GRIN gene variation in the offspring interacted with maternal herpes simplex virus-2 (HSV-2) seropositivity during pregnancy influencing the risk of schizophrenia later in life. Individuals from three independently collected Danish case control samples were genotyped for 81 tagSNPs (in total 984 individuals diagnosed with schizophrenia and 1,500 control persons) and antibodies against maternal HSV-2 infection were measured in one of the samples (365 cases and 365 controls). Nine SNPs out of 30 in GRIN2B were significantly associated with schizophrenia. One SNP remained significant after Bonferroni correction (rs1806194, P(nominal) = 0.0008). Significant interaction between maternal HSV-2 seropositivity and GRIN2B genetic variation in the offspring were observed for seven SNPs and two remained significant after Bonferroni correction (rs1805539, P(nominal) = 0.0001 and rs1806205, P(nominal) = 0.0008). The significant associations and interactions were located at the 3' region of GRIN2B suggesting that genetic variation in this part of the gene may be involved in the pathophysiology of schizophrenia.

Meta-analysis of heterogeneous data sources for genome-scale identification of risk genes in complex phenotypes.

Meta-analyses of large-scale association studies typically proceed solely within one data type and do not exploit the potential complementarities in other sources of molecular evidence. Here, we present an approach to combine heterogeneous data from genome-wide association (GWA) studies, protein-protein interaction screens, disease similarity, linkage studies, and gene expression experiments into a multi-layered evidence network which is used to prioritize the entire protein-coding part of the genome identifying a shortlist of candidate genes. We report specifically results on bipolar disorder, a genetically complex disease where GWA studies have only been moderately successful. We validate one such candidate experimentally, YWHAH, by genotyping five variations in 640 patients and 1,377 controls. We found a significant allelic association for the rs1049583 polymorphism in YWHAH (adjusted P = 5.6e-3) with an odds ratio of 1.28 [1.12-1.48], which replicates a previous case-control study. In addition, we demonstrate our approach's general applicability by use of type 2 diabetes data sets. The method presented augments moderately powered GWA data, and represents a validated, flexible, and publicly available framework for identifying risk genes in highly polygenic diseases. The method is made available as a web service at www.cbs.dtu.dk/services/metaranker.

Support for a bipolar affective disorder susceptibility locus on chromosome 12q24.3.

OBJECTIVE: Linkage and association studies of bipolar affective disorder (BAD) point out chromosome 12q24 as a region of interest. METHODS: To investigate this region further, we conducted an association study of 22 DNA markers within a 1.14 Mb region in a Danish sample of 166 patients with BAD and 311 control individuals. Two-hundred and four Danish patients with schizophrenia were also included in the study. RESULTS: We observed highly significant allelic and genotypic association between BAD and two highly correlated markers. The risk allele of both markers considered separately conferred an odds ratio of 2 to an individual carrying one risk allele and an odds ratio of 4 for individuals carrying both risk alleles assuming an additive genetic model. These findings were supported by the haplotype analysis. In addition, we obtained a replication of four markers associated with BAD in an earlier UK study. The most significantly associated marker was also analyzed in a Scottish case-control sample and was earlier associated with BAD in the UK cohort. The association of that particular marker was strongly associated with BAD in a meta-analysis of the Danish, Scottish and UK sample (P=0.0003). The chromosome region confined by our most distant markers is gene-poor and harbours only a few predicted genes. This study implicates the Slynar locus. We confirmed one annotated Slynar transcript and identified a novel transcript in human brain cDNA. CONCLUSION: This study confirms 12q24.3 as a region of functional importance in the pathogenesis of BAD and highlights the importance of focused genotyping.

Search for a shared segment on chromosome 10q26 in patients with bipolar affective disorder or schizophrenia from the Faroe Islands.

Previous linkage studies have suggested a new locus for bipolar affective disorder and possibly also for schizophrenia on chromosome 10q26. We searched for allelic association and chromosome segment and haplotype sharing on chromosome 10q26 among distantly related patients with bipolar affective disorder or schizophrenia and controls from the relatively isolated population of the Faroe Islands by investigating 22 microsatellite markers from a 35 cM region. We used a combined approach with both assumption free tests and tests based on genealogical relationships. The 6.5 cM region between D10S1230 and D10S2322, which has been implied in previous linkage analyses, received some support. A search for segment sharing yielded empirical P-values around 0.02 among patients with bipolar affective disorder and around 0.03 for patients with schizophrenia. For both disorders combined allelic association yielded empirical P-values around 0.003 at marker D10S1723. A haplotype data mining approach supported haplotype sharing in this region. In another, more distal, 11.5 cM region between markers D10S214 and D10S505, which has received support in previous linkage studies, increased haplotype sharing in patients with bipolar affective disorder was supported by Fisher's exact test, tests based on genealogy and by haplotype data mining. Our findings yield some support for a risk gene for bipolar affective disorder and possibly also for schizophrenia.