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. 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.

Figure 1

The Manhattan plot for the primary attempted suicide analysis. The chromosomes are presented in order (pter to qter) and color-coded for ease of identification. The individual SNPs are represented by open circles and their corresponding p-values are graphed according to the −log10(p-value).

Figure 2

The 2p25 candidate region - shown are the chromosomal location, genotyped SNPs from the primary analysis, gene structure for each of the candidate genes in the region, and linkage disequilibrium structure for the region based on the HapMap CEU population (UCSC Genome Browser, March 2006).

Figure 3

Top association signals for the secondary analyses - shown are the chromosomal locations, genotyped SNPs, gene structures, and linkage disequilibrium structures for each of the top association signals (UCSC Genome Browser, March 2006). A-male-specific results; B-female-specific results; C-substance abuse/dependence-specific results; and D-substance free results.

Figure 3

Top association signals for the secondary analyses - shown are the chromosomal locations, genotyped SNPs, gene structures, and linkage disequilibrium structures for each of the top association signals (UCSC Genome Browser, March 2006). A-male-specific results; B-female-specific results; C-substance abuse/dependence-specific results; and D-substance free results.

Figure 3

Top association signals for the secondary analyses - shown are the chromosomal locations, genotyped SNPs, gene structures, and linkage disequilibrium structures for each of the top association signals (UCSC Genome Browser, March 2006). A-male-specific results; B-female-specific results; C-substance abuse/dependence-specific results; and D-substance free results.

Figure 3

Top association signals for the secondary analyses - shown are the chromosomal locations, genotyped SNPs, gene structures, and linkage disequilibrium structures for each of the top association signals (UCSC Genome Browser, March 2006). A-male-specific results; B-female-specific results; C-substance abuse/dependence-specific results; and D-substance free results.