Genome-Wide Association Study of Suicide Attempts in Mood Disorder Patients

Department of Psychiatry, VU University Amsterdam, Amsterdamo, North Holland, Netherlands
American Journal of Psychiatry (Impact Factor: 12.3). 11/2010; 167(12):1499-507. DOI: 10.1176/appi.ajp.2010.10040541
Source: PubMed

ABSTRACT Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts.
The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.
Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.
The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.

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Available from: Jordan W Smoller, Sep 27, 2015
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    • "From the meta-analysis, a candidate association study of 19 genes previously associated with suicide was also performed though no SNPs were significant after a Bonferroni correction was applied (Supplementary material). A SNP in ABI3BP had reached GWAS significance in a previous study of SA in depression, however the finding did not replicate in this analysis [Perlis et al., 2010]. "
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    ABSTRACT: Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2014; 165(5). DOI:10.1002/ajmg.b.32247 · 3.42 Impact Factor
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    • "Family and twin studies suggest that susceptibility for suicide attempts is heritable and distinct from mood disorder susceptibility, and the high resolution of the GWAS approach facilitates the detection of risk loci. The first GWAS performed for lifetime suicide attempts sub-phenotype was conducted by Perlis et al.84 BD subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the WTCCC bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network BD project and a German clinical cohort. "
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    ABSTRACT: Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data.
    Neuropsychiatric Disease and Treatment 10/2013; 9:1573-1582. DOI:10.2147/NDT.S28117 · 1.74 Impact Factor
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    • "In the case of BP, the presence of S allele-5HTTLPR polymorphism of the serotonin transporter (SERT) gene (SLC6A4) has been associated to violent suicide attempts among this group of patients (Neves et al., 2008; Neves et al., 2010). On the other hand, a Genome Wide Association Study (GWAS) carried out by Perlis et al. (2010) provide modest support of an association between FKBP5 and NGFR (p75NTR) genes and SB in BD. Nevertheless, it should be noted that this associations did not survive to multiple comparison correction. "
    European Neuropsychopharmacology 10/2013; 23:S370-S371. DOI:10.1016/S0924-977X(13)70585-6 · 4.37 Impact Factor
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