Suicidal behavior (SB) has a complex etiology involving genes and environment. One of the genetic components in SB could be copy number variations (CNVs), as CNVs are implicated in neurodevelopmental disorders. However, a recently published genome-wide and case-control study did not observe any significant role of CNVs in SB. Here we complemented these initial observations by instead using a family-based trio-sample that is robust to control biases, having severe suicide attempt (SA) in offspring as main outcome (n = 660 trios). We first tested for CNV associations on the genome-wide Illumina 1M SNP-array by using FBAT-CNV methodology, which allows for evaluating CNVs without reliance on CNV calling algorithms, analogous to a common SNP-based GWAS. We observed association of certain T-cell receptor markers, but this likely reflected inter-individual variation in somatic rearrangements rather than association with SA outcome. Next, we used the PennCNV software to call 385 putative rare (<1%) and large (>100 kb) CNVs, observed in n = 225 SA offspring. Nine SA offspring had rare CNV calls in a set of previously schizophrenia-associated loci, indicating the importance of such CNVs in certain SA subjects. Several additional, very large (>1MB) sized CNV calls in 15 other SA offspring also spanned pathogenic regions or other neural genes of interest. Overall, 45 SA had CNVs enriched for 65 medically relevant genes previously shown to be affected by CNVs, which were characterized by a neurodevelopmental biology. A neurodevelopmental implication was partly congruent with our previous SNP-based GWAS, but follow-up analysis here indicated that carriers of rare CNVs had a decreased burden of common SNP risk-alleles compared to non-carriers. In conclusion, while CNVs did not show genome-wide association by the FBAT-CNV methodology, our preliminary observations indicate rare pathogenic CNVs affecting neurodevelopmental functions in a subset of SA, who were distinct from SA having increased SNP risk-allele burden. These observations may open up new avenues in the genetic etiology of SB.

Suicidal behaviors represent a fatal dimension of mental ill-health, involving both environmental and heritable (genetic) influences. The putative genetic components of suicidal behaviors have until recent years been mainly investigated by hypothesis-driven research (of "candidate genes"). But technological progress in genotyping has opened the possibilities towards (hypothesis-generating) genomic screens and novel opportunities to explore polygenetic perspectives, now spanning a wide array of possible analyses falling under the term Genome-Wide Association Study (GWAS). Here we introduce and discuss broadly some apparent limitations but also certain developing opportunities of GWAS. We summarize the results from all the eight GWAS conducted up to date focused on suicidality outcomes; treatment emergent suicidal ideation (3 studies), suicide attempts (4 studies) and completed suicides (1 study). Clearly, there are few (if any) genome-wide significant and reproducible findings yet to be demonstrated. We then discuss and pinpoint certain future considerations in relation to sample sizes, the units of genetic associations used, study designs and outcome definitions, psychiatric diagnoses or biological measures, as well as the use of genomic sequencing. We conclude that GWAS should have a lot more potential to show in the case of suicidal outcomes, than what has yet been realized.