A genome-wide association study of attempted suicide

Abstract

The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. While 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 1,201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1,497 BP subjects without a history of suicide attempts. 2,507 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 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.

Response to the letter from Dr. Maher and colleagues Re. Linkage on suicidality

“…In females with bipolar disorder, evidence was detected at rs10170138 (P < 1eÀ06) which lies in intron 3 of the LRRTM4 gene and near D2S1777 [Willour et al 2011]. Perlis et al [2010] analyzed all bipolar cases (unstratified by sex), and showed some evidence for association (P ¼ 4eÀ05) at rs17014915, located 1.2 Mb from the previous finding.…”

Assessment of Whole-Exome Sequence Data in Attempted Suicide within a Bipolar Disorder Cohort

“…Additionally, the examined pathways are not all-inclusive representations of the genes that may be important to the given processes, and may be missing key genes that would help explain that pathway's role in suicidal behavior. For example, one of the primary pathways we assessed, the KEGG [51] glutamatergic synapse pathway, did not include several key synaptic structural proteins such as NRXN or LRRTM family genes which have been implicated in suicidal behavior [19]. Furthermore, analyses geared toward any single pathway may fail to capture a signal that crosses several potentially associated pathways.…”

“…Table S1). For example, GWAS techniques have had success identifying nominally associated sites throughout the genome as well as 2 potential genome-wide significant associations ( p ∼ 5.0 × 10 -8 ) with common variants in at least 1 population each within the 2p25 region [19] and the ABI3BP gene [17]. Genome-wide gene expression investigation efforts have similarly implicated pathways of potential importance such as polyamine regulation [6], general nervous system development [10], and glutamatergic and GABAergic synaptic signaling [11].…”

“…These subjects overlapped with our prior GWAS study (91% overlap) [19]. Briefly, subjects were diagnosed as BP type 1 (942 subjects), schizoaffective disorder bipolar type (75 subjects), or BP not otherwise specified (1 subject) in accordance with research diagnostic criteria, Diagnostic Statistical Manual (DSM)-III-R, or DSM-IV criteria.…”

“…The diversity and number of these findings underscore the complexity of suicidal behavior genetic risk and make follow-up efforts in the framework of individual candidate gene studies inefficient. This has led to the use of broad hypothesis-free investigation methods in many recent studies, including gene expression [6,7,8,9,10,11,12], linkage [13,14,15,16], and genome-wide association studies (GWAS) of common variants [17,18,19,20,21,22,23,24]. These studies have identified additional targets that may contribute to the risk of suicidal behavior, but very few implicated sites have been replicated [25,26].…”