A genome-wide association study of attempted suicide

Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
Molecular Psychiatry (Impact Factor: 14.5). 03/2011; 17(4):433-44. DOI: 10.1038/mp.2011.4
Source: PubMed


The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10(-8)). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.

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Available from: Jordan W Smoller, Jun 18, 2014
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    • "Another attempted suicide GWAS that compared the SNP genotypes of 1,201 BD subjects with a history of suicide attempts to the genotypes of 1,497 BD subjects without a history of suicide attempts was performed by Willour et al.85 The authors found 2,507 SNPs with evidence for association with suicide attempts at P<0.001, but these associations were not significantly associated in the replication sample after correcting for multiple testing. "
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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.
    Full-text · Article · Oct 2013 · Neuropsychiatric Disease and Treatment
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    • "Please cite this article as: Singh, P.K., et al., High rate of suicide attempt and associated psychological traits in an isolated tribal population of North-East India. Journal of Affective Disorders (2013), (Willour et al., 2012; Perlis et al., 2010; Mann et al., 2011 "
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    ABSTRACT: Background: Cases of suicide documented earlier all over the world reflect the presence of suicide behavior in primitive world at a higher rate compared to general urban population. The cause of such behavior is thought to be different among tribes and mental health was rarely presumed to be associated. In India, several ethnographic narratives described instances of suicides among several tribes, but evaluation of psychological traits were lacking. The present study on Idu Mishmi is an attempt to further validate earlier report of high rate of suicides among them and to evaluate psychological traits. Interview and administration of Patient Health Questionnaire (PHQ) on 218 individuals comprised the data. Bi-variate analyses and linear multiple regression were done to evaluate psychological traits in suicide behavior. In the Idu Mishmi Population suicide attempt (14.22%) was higher than urban population in general (0.4-4.2%) and females were at higher risk. Depression (8.26%) was comparable with earlier reports, whereas anxiety syndrome (6.42%), alcohol abuse (36.24%) and eating disorder like Binge eating (6.42%), Bulimia nervosa (1.38%) were also recorded in the population. Absence of psychiatry clinic and mechanism of recording suicide occurrences in remote tribal area is the basic limitation of the study. Depression and gender turned out to be significant determinants of suicide attempt in the studied population, whereas alcohol abuse was not a significant factor.
    Full-text · Article · Aug 2013 · Journal of Affective Disorders
    • "Candidate gene approaches often produce conflicting results and technical improvements have led to genome-wide association (GWAS) studies in order to locate candidate genes from the whole genome. However, results to date from GWAS studies are unsatisfactory with most studies showing no evidence of association at a genome-wide significant level (Schosser et al., 2011) or only marginally (Willour et al., 2011). In addition, the genetic loci that emerge from GWAS studies are often hard to replicate (Perlis et al., 2010). "
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    ABSTRACT: Suicide is one of the leading causes of death in the world. Its aetiology is complex and diverse, however, epidemiological studies show that suicidal behavior is partly heritable. Neurobiological evidence implicates serotonergic dysfunction in suicidality, stimulating genetic research to focus on genes related to the serotonergic system. In this paper, we review evidence from studies examining the association between various serotonergic genes (Tryptophan Hydroxylase genes: TPH1; TPH2, Serotonin Transporter gene: 5-HTTLPR in SLC6A4, Serotonin Receptor genes: HTR1A, HTR2A, HTR1B, HTR2C and Monoamine Oxidase A gene: MAOA) and suicidal behavior. The data show associations between variation on the TPH1 gene and 5-HTTLPR gene and violent suicidal behavior in Caucasian populations, with the least inconsistencies. Results are mixed for the TPH2 gene and serotonin receptor genes, but for some genes, studies that include haplotypic analyses or that examine a larger coding region of the genes tend to provide more reliable results. Findings on endophenotypes of suicidality, such as aggression and impulsivity traits, show positive associations for the TPH1, HTR2A, and MAOA genes, but need further replication, since negative associations are also occasionally reported. Since genes can only partially explain suicidal risk, several studies during the past decade have tried to incorporate environmental factors in the susceptibility model. Studies to date show that variation on the 5-HTTLPR, MAOA and HTR2A gene can interact with stressful life events to increase risk for suicidal behavior. Limitations of case-control studies are discussed and future considerations are put forward with regard to endophenotypic measurements and gene-environment interactions.
    No preview · Article · Jun 2013 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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