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. Author manuscript; available in PMC: 2019 Nov 1.
Published in final edited form as: Psychiatry Res. 2018 Jul 17;269:64–69. doi: 10.1016/j.psychres.2018.07.017

A Genome-Wide Association Study of Suicide Attempts and Suicidal Ideation In U.S. Military Veterans

Nathan A Kimbrel a,b,c,*, Melanie E Garrett d, Michelle F Dennis a,c; VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroupb, Michael A Hauser d,e, Allison E Ashley-Koch d,e, Jean C Beckham a,b,c
PMCID: PMC6207450  NIHMSID: NIHMS980942  PMID: 30145303

Abstract

Death by suicide and suicidal behavior are major concerns among U.S. military veterans; however, no genome-wide association studies (GWAS) studies of suicidal behavior have been conducted among U.S. military veterans to date, despite the elevated rate of suicidal behavior observed within this population. Accordingly, the primary objective of the present research was to conduct the first GWAS of suicide attempts and suicidal ideation in a large and well-characterized sample of U.S. military veterans. The gene most significantly associated (p=9.28×10−7) with suicide attempts was the Potassium Calcium-Activated Channel Subfamily M Regulatory Beta Subunit 2 (KCNMB2) gene, which plays a key role in neuronal excitability. In addition, replication analyses provided additional support for the potential role of the ABI Family Member 3 Binding Protein (ABI3BP) gene in the pathogenesis of suicidal behavior, as numerous nominal associations were found between this gene and both suicide attempts and suicidal ideation. Additional work aimed at replicating and extending these findings is needed.

1. Introduction

Death by suicide and suicidal behavior (i.e., suicide attempts, plans, or ideation) are major concerns among veterans (US Department of Veterans Affairs, 2016). While military veterans only comprise 8.5% of the U.S. adult population, they account for a disproportionately high percentage (18%) of deaths by suicide (US Department of Veterans Affairs, 2016). After adjusting for age and gender, risk for suicide is still 21% higher among veterans than civilians (US Department of Veterans Affairs, 2016). Moreover, recent estimates suggest that, on average, 20 veterans die by suicide each day in the U.S. (US Department of Veterans Affairs, 2016), highlighting the need for improved understanding of the genetic and biological basis of suicide and suicidal behavior within this population.

Family and twin studies indicate that genetic factors play a significant role in the pathogenesis of both suicide (Brent et al., 1996; Tidemalm et al., 2011) and suicide risk factors (e.g., posttraumatic stress disorder (PTSD) and depression; True et al., 1993; Koenen et al., 2008); however, the genetic basis of death by suicide and suicidal behavior is largely unknown at the present time (Mirkovic et al., 2016). To date, there have been more than 100 candidate-gene studies of suicidal behavior, examining over 200 genetic variants, with serotonergic, dopaminergic, and adrenergic genes among the most widely studied genes in relation to suicidal behavior (Clayden et al., 2012; Mirkovic et al., 2016); however, very few candidate single nucleotide polymorphisms (SNPs) have been reliably associated with suicidal behavior to date (Clayden et al., 2012; Mirkovic et al., 2016). Other candidate gene studies have focused on identifying the genetic basis of risk factors and endophenotypes for suicide, such as posttraumatic stress disorder (PTSD; e.g., Kimbrel, Hauser et al., 2015; Liu et al., 2015), depression (Kimbrel, Morissette et al., 2015; Caspi et al., 2002), and hopelessness (Serafini et al., 2012; Lazary et al., 2012); however, these studies have also failed to identify specific SNPs that are reliably associated with suicide. As a result, there has been increasing attention focused on more atheoretical (i.e., non-hypothesis driven) approaches to gene discovery in relation to suicidal behavior, such as genome-wide association studies (GWAS).

At least 12 genome wide association studies (GWAS) have attempted to identify novel variants associated with suicidal behavior (Mirkovic et al., 2016; Perlis et al., 2010; Stein et al., 2017; Willour et al., 2012). Of these studies, only three have identified genome-wide significant results (i.e., 5 × 10−8) (Perlis et al., 2010; Willour et al., 2012; Stein et al., 2017). Perlis et al. found an association between suicide attempts and a single nucleotide polymorphism (SNP; rs2576377, p=2.55×10−8) in the ABI Family Member 3 Binding Protein (ABI3BP) gene among civilians with major depression. Willour et al. conducted a GWAS of suicide attempts in two samples of patients with bipolar disorder. No genome-wide significant hits were identified when the samples were examined separately; however, meta-analysis of the samples revealed an association (p=5.07×10−8) between suicide attempts and rs300774, located in an intergenic region of chromosome 2. Most recently, Stein et al. (2017) conducted a GWAS of suicide attempts among active-duty military personnel. This important study identified a region near the Melanocortin 2 Receptor Accessory Protein 2 (MRAP2) gene in which multiple SNPS were genome-wide significant. Notably, the present sample served as a replication site for Stein et al. (2017) and found that a proxy SNP (rs17187076) in complete LD with the top hit (rs12524136) had a nominally significant association with suicide attempts; however, no other SNPs from the present sample have been examined in relation to suicide attempts to date.

1.3. Study Objectives

The primary objective of the present research was to use GWAS to identify additional novel variants associated with suicidal behavior in a well-characterized sample of military veterans containing a large proportion of cases of PTSD, depression, and suicidal behavior (Ashley-Koch et al., 2015; Kimbrel et al., 2014; Kimbrel et al., 2015). Our secondary objective was to attempt to replicate previous GWAS findings associating rs3300774 (intergenic) and rs2576377 (ABI3BP) with suicidal behavior, given prior work associating these SNPs with suicide attempts in other samples (Willour et al., 2012 and Perlis et al., 2010, respectively).

2. Methods

2.1. Participants

Study procedures have been described in detail previously (Brancu et al., 2017; Ashley-Koch et al., 2015; Kimbrel et al., 2014; Kimbrel et al., 2015). To be eligible for inclusion in the present study, participants had to have served in the U.S. military on or after September 11, 2001. Exclusion criteria included primary language other than English, difficulty comprehending the informed consent form or process, and/or inability to travel to a data-collection site. Participants were recruited via mailings, advertisements, and referrals at four VA hospitals in the Southeastern U.S. The local institutional review boards at each participating hospital approved the study protocol. Written informed consent was obtained from all participants prior to enrollment. Following informed consent procedures, participants were administered the Structured Clinical Interview for DSM-IV-TR (First et al., 1994) along with a battery of self-report measures (Beck and Steer, 1991; Keane, 1989; Kubany et al., 2000), which included the Beck Scale for Suicide Ideation (BSI; Beck and Steer, 1991). The final study sample included in the present analyses consisted of 1571 U.S. veterans of the wars in Iraq and Afghanistan, many of whom met lifetime criteria for PTSD (46.8%) or major depression (40.2%), diagnoses that are associated with increased risk for death by suicide and suicidal behavior (Bullman and Kang, 1994; Kimbrel et al., 2014, 2016). Sample characteristics are provided in Table 1.

Table 1.

Participant Characteristics by Suicidal Behavior Status.

Suicidal Ideation Suicide Attempt
Variable Absent Present p-value Absent Present p-value
N 1433 138 1447 122
% 91.22% 8.78% 92.10% 7.77%
Age 37.46 36.11 0.1252 37.55 34.74 0.0025
Gender (% F) 20.66% 19.57% 0.762 18.80% 41.80% <0.0001
Race (% NHW) 45.64% 57.25% 0.009 46.99% 42.62% 0.3527
Combat Exposure Scale 11.36 16.78 <0.0001 11.81 12.15 0.7332
Childhood Sexual Trauma 19.05% 26.81% 0.0287 17.28% 49.18% <0.0001
Lifetime PTSD 43.68% 78.99% <0.0001 44.16% 78.69% <0.0001
Lifetime MDD 37.06% 72.46% <0.0001 37.94% 66.39% <0.0001
PTSD/MDD Composite <0.0001 <0.0001
Neither 44.10% 7.97% 43.75% 7.38%
PTSD or MDD 31.05% 32.61% 30.41% 40.16%
PTSD and MDD 24.84% 59.42% 25.85% 52.46%
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2.2. Phenotyping Procedures

The Beck Scale for Suicide Ideation (BSI; Beck & Steer, 1991) was used to phenotype suicidal behavior. The BSI is a self-report questionnaire designed to assess suicidal ideation and plans during the past week. Respondents are asked to rate items on a Likert scale where higher values indicate greater severity of ideation. Following our previously established methods (Kimbrel et al., 2014), item 20 from the BSI was used to identify participants with a lifetime history of suicide attempts (n=122; 7.8%), whereas a total score of 3 or higher (Brown et al., 2000) was used to identify participants with clinically-significant levels of current suicidal ideation (n=138; 8.8%).

2.3. Genotyping Procedures

The genotyping, QC pipeline, and imputation of genotypes used in the present research have been described previously (Ashley-Koch et al., 2015). Whole blood samples were obtained via venipuncture. DNA was extracted from whole blood and genotyped in three different batches on three different bead chips, including the HumanHap650 BeadChip, the Human1M-Duo BeadChip, and the HumanOmni2.5 BeadChip (Illumina, San Diego, CA). These batches were then merged and imputed using a global reference panel from 1000Genomes (Ashley-Koch et al., 2015). Imputed SNPs were required to have 90% certainty or better and were removed if the call rate was below 97%. Imputed probes were also removed if deviations from Hardy Weinberg Equilibrium expectations were observed (p < 10−6) in the controls or if the minor allele frequency was below 1%. After applying these quality control procedures, 2,711,511 SNPs were available for the present analyses.

2.4. Statistical Analysis Plan

Logistic regression was used to test for associations between SNPs and lifetime suicide attempts and current suicidal ideation after controlling for age, race, combat exposure (Keane, 1989), childhood sexual trauma (Kubany et al., 2000), PTSD, and depression (see Table 1). A composite lifetime PTSD-depression variable (“0” = no lifetime history of PTSD or depression; “1” = a lifetime history of PTSD or depression; “2” = a lifetime history of PTSD and depression) was used as a covariate in the analyses due to recent findings indicating that co-occurring PTSD-depression is a particularly strong risk factor for suicide attempts and suicidal ideation in veterans (Kimbrel et al., 2014; Kimbrel et al., 2016). Childhood sexual trauma and combat exposure were also included as covariates in the model given previous associations between these variables and psychopathology in general (e.g., Chen et al., 2010; Kimbrel et al., 2015) as well as suicidal behavior, specifically (e.g., Chen et al., 2010; Dillon et al., in press; Kimbrel et al., 2016). Race was genetically estimated using previously reported procedures (Ashley-Koch et al., 2015) and was also included as a covariate. False-discovery rate (FDR) q-values were generated to control for Type I error. Given previous findings indicating that different genetic and environmental factors may be involved in the pathogenesis of suicide attempts and suicidal ideation (Beck and Steer, 1991; Brent et al., 1996; Galfalvy et al., 2015), the suicide attempt and suicidal ideation phenotypes were examined separately.

3. Results

The top hit for suicide attempts was rs11762112 (OR=2.16; p=7.58×10−7; FDR=0.32; Table 2), which lies within an intergenic region on chromosome 7. The next most significant SNP was rs79324256 (OR=2.98; p=9.28×10−7; FDR=0.32) in the Potassium Calcium-Activated Channel Subfamily M Regulatory Beta Subunit 2 (KCNMB2) gene, located on chromosome 3. Two additional SNPs from KCNMB2 (rs6788360, rs7861880) were also in the top five hits (FDR=0.32) for suicide attempts. The next most significant SNP residing in a gene was rs7931096 from the Leucine Zipper Protein 2 (LUZP2) gene on chromosome 11. The SNP most strongly associated with suicidal ideation was rs2613142, which lies in an intergenic region on chromosome 4 (OR=2.92; p=1.88×10−7; FDR=0.21; Table 2). Nearly all of the strongest associations (p<10−6) for suicidal ideation fell within intergenic regions, with the majority falling into a linkage disequilibrium (LD) block with rs2613142 on chromosome 4.

Table 2.

SNPs Most Significantly Associated with Suicidal Behavior in Veterans.

Results of the GWAS of Suicide Attempts
Chromosome Probe Risk Allele Odds Ratio p-value FDR p-value Gene
7 rs11762112 A 2.16 7.582E-07 0.32
3 rs79324256 C 2.98 9.282E-07 0.32 KCNMB2
3 rs112504494 A 2.98 9.282E-07 0.32
3 rs6788360 A 2.98 9.282E-07 0.32 KCNMB2
3 rs76861880 G 2.98 0.000000938 0.32 KCNMB2
3 rs61606793 G 2.96 0.000001361 0.32
11 rs10898553 C 0.47 0.000001892 0.32
21 rs2834789 C 2.40 0.000002489 0.32
21 rs2834778 A 2.38 0.000002593 0.32
21 rs9977375 G 2.37 0.000002885 0.32
11 rs7931096 A 2.23 0.000003155 0.32 LUZP2
21 rs9808623 T 2.36 0.000003405 0.32
21 rs2409588 T 2.36 0.000003405 0.32
21 rs2409587 T 2.36 0.000003405 0.32
21 rs2094870 C 2.36 0.000003509 0.32
11 11-19226162 A 3.36 0.000003787 0.32
4 rs10488889 A 3.47 0.000004291 0.32
4 rs10488888 C 3.47 0.000004291 0.32
3 rs77075415 G 3.38 0.000004744 0.32
3 rs1520042 C 3.38 0.000004744 0.32
21 rs9983537 T 2.34 0.000004772 0.32
9 rs4745426 G 3.01 0.000004902 0.32
11 rs7928862 T 2.20 0.000005081 0.32 LUZP2
9 rs11144542 A 3.00 0.000005085 0.32
11 rs11028325 C 2.20 0.000005164 0.32
Results of the GWAS of Suicidal Ideation
Chromosome Probe Risk Allele Odds Ratio p-value FDR p-value Gene
4 rs2613142 A 2.92 1.877E-07 0.21
4 rs2715651 C 2.86 3.724E-07 0.21
4 rs1460608 G 2.86 3.782E-07 0.21
4 rs2722149 G 2.86 3.782E-07 0.21
4 rs2613149 A 2.86 3.859E-07 0.21
14 rs12100626 T 4.13 9.881E-07 0.34
4 rs2613155 G 2.76 0.000001228 0.34
4 rs2715640 A 2.75 0.000001368 0.34
4 rs2613152 C 2.77 0.000001607 0.34
4 rs13151415 G 2.62 0.000001629 0.34
4 rs2678763 G 2.74 0.000002012 0.34
4 rs2722152 A 2.72 0.0000022 0.34
4 rs2613150 A 2.10 0.000002352 0.34
4 rs2715650 G 2.10 0.000002352 0.34
4 rs2715652 A 2.71 0.00000243 0.34
14 rs17101543 A 4.02 0.000002551 0.34
8 rs17750193 C 3.26 0.000002592 0.34
4 rs2715653 G 2.70 0.00000272 0.34
4 rs2715654 G 2.70 0.00000272 0.34
4 rs2613151 C 2.70 0.00000272 0.34
4 rs1841397 T 2.70 0.000002766 0.34
4 rs1460607 C 2.70 0.000002766 0.34
4 rs2715662 T 2.72 0.000003756 0.44
22 rs2070889 A 1.97 0.000004079 0.46 OSM
4 rs2613143 C 2.21 0.000008084 0.81
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We also attempted to replicate previous GWAS findings associating rs3300774 (intergenic) (Willour et al., 2012) and rs2576377 (ABI3BP) (Perlis et al., 2010) with suicidal behavior. No association was found between rs3300774 and either suicide attempts (OR=0.86; p=0.45; FDR=0.98) or suicidal ideation (OR=1.04; p=0.81; FDR=0.99). rs2576377 of the ABI3BP gene was also unassociated with suicide attempts (OR=1.13; p=0.57; FDR=0.98) and suicidal ideation (OR=0.91; p=0.64; FDR=0.99); however, further probing of the ABI3BP gene revealed that 22 of the 357 SNPs examined in ABI3BP had nominally significant (i.e., p<0.05) associations with suicide attempts, whereas 110 had nominally significant associations with suicidal ideation. The top hit for attempts was rs6441552 (OR=1.66; p=0.0062; FDR=0.95), whereas the top hit for ideation was rs975536 (OR=0.68; p=0.013; FDR=0.95.

4. Discussion

This study represents the first GWAS of suicide attempts and suicidal ideation in U.S. military veterans, a population at markedly elevated risk for death by suicide and suicidal behavior (US Department of Veterans Affairs, 2016). The most notable finding from this study was the novel association between multiple SNPs in KCNMB2 and suicide attempts. KCNMB2 encodes a regulatory subunit that acts as a negative regulator that confers rapid and complete inactivation of the potassium calcium-activated channel subfamily M Alpha 1 channel complex. Thus, it plays a key role in neuronal excitability (Beecham et al., 2014). It is also highly expressed in hippocampal pyramidal neurons and has been implicated in hippocampal sclerosis of the elderly (Beecham et al., 2014). The latter findings are intriguing given recent work demonstrating that individuals who attempt suicide show significant reductions in hippocampal volume (Colle et al., 2015) and that both chronic stress and major depression are associated with reductions in dendritic spines and synapses, dendritic arborisation, and hippocampal glial cells (Serafini et al., 2014).

LUZP2 was also associated with suicide attempts in the present study. LUZP2 is a leucine zipper protein coding gene that has recently been associated with Alzheimer’s Disease (Li et al., 2018; Lambert et al., 2013). LUZP2 has also been associated increased risk of atrophy of the right middle temporal gyrus (Li et al., 2018), which is considered to be a biomarker for the early stages of Alzheimer’s disease (Li et al., 2018; Frisoni et al., 2010). The association between LUZP2 and suicide attempts in a sample of Veterans with high rates of combat-related PTSD is particularly interesting given recent evidence that the ε4 allele of the apolipoprotein E (APOE) gene—a well-established genetic risk factor for AD—may also associated with increased risk for combat-related PTSD (e.g., Kimbrel et al., 2015; Roby et al., 2017) and death by suicide (Calderon-Garciduenas et al., 2018). Of course, while intriguing, the present findings associating KCNMB2 and LUZP2 with suicide attempts are still in need of replication, particularly since none of the present findings were FDR-significant.

Another important finding from the current study relates to our partial replication of previous findings associating ABI3BP with suicidal behavior among civilians with major depression. While we did not replicate the association between rs2576377 and suicide attempts in the present study, we did observe multiple variants in ABI3BP that were nominally-associated (i.e., p < 0.05) with suicidal behavior, providing additional support for the potential role of this gene in the pathogenesis of suicidal behavior. ABI3BP is expressed in multiple tissues throughout the body, including the brain. While its function is largely unknown at the present time, recent evidence suggests that ABI3BP may promote mesenchymal stem cell (MSC) differentiation and that knockout of ABI3BP leads to increases in MSC proliferation (Hodgkinson et al., 2014). ABI3BP may also play a role in apoptosis and senescence (Latini et al., 2008; Perlis et al., 2010). It is also noteworthy that Perlis et al. found an association between ABI3BP and suicide attempts in patients with major depression, since major depression was also quite common (~40% lifetime rate) in the present sample. Future work in this area should consider the possibility that ABI3BP might be a risk factor for suicidal behavior that is unique to patients with major depression.

The frequency with which non-coding SNPs in intergenic regions of the genome were associated with suicidal behavior in the current study is also of considerable interest, as the vast majority of the top SNPs associated with suicidal behavior in the current study were located in non-coding regions (see Table 2). These findings are particularly interesting because Willour et al. also found non-coding regions to have the strongest associations with suicidal behavior. While it is unclear precisely why this might be the case, one potential explanation is that regulatory variation may exert considerable control over suicidal behavior. For schizophrenia and many other complex phenotypes, it is already clear that non-coding genetic variation contributes substantially to risk (Maurano et al., 2012; Roussos et al., 2014). The ongoing PsychENCODE project will provide more insight into the role of regulatory variation in psychiatric phenotypes (PsychENCODE Consortium et al., 2015).

Our findings also provide additional support for the hypothesis that the genetic basis for attempts is distinct from the genetic basis for ideation, as there was no overlap between the top hits identified for attempts and ideation in the current study. These findings are consistent with a prior GWAS study (Galfalvy et al., 2015) as well as prior family studies. For example, Brent et al. studied rates of suicidal behavior in first-degree relatives of suicide probands and found that the rate of attempts among relatives of probands was elevated, even after accounting for the effects of psychiatric disorders. In contrast, the increased rate of suicidal ideation in the relatives of probands was explained by higher rates of psychiatric disorders. Such findings suggest that future genomic investigations should continue to examine attempts and ideation separately; however, they also make our ABI3BP replication all the more intriguing, given that that ABI3BP was nominally associated with both attempts and ideation in the current study.

4.1. Limitations

The present findings should be interpreted in the context of several limitations. First, while we found multiple suggestive associations, it must be emphasized that no genome-wide significant results were identified in the current study. Second, while our sample size was relatively large for this type of research, it is likely that larger sample sizes (e.g., through the aggregation of multiple datasets) will be needed to detect genetic markers that are reliably associated with suicidal behavior. Third, our sample was restricted to veterans from the Iraq/Afghanistan-era. Thus, the degree to which findings from the present study might generalize to civilian populations is unknown, particularly given the high levels of combat exposure that veterans in the present sample reported. Fourth, our study was limited to examining associations between common genetic variants and suicidal behavior. Future work aimed at studying the association between suicidal behavior and other types of genetic (e.g., rare variants) and epigenetic variation (e.g., DNA methylation) is needed as well as research aimed at identifying how changes in gene expression might relate to changes in suicidal behavior.

4.2. Summary

The current study represents the first GWAS of suicidal behavior conducted among U.S. military veterans, a population known to be at markedly increased risk for death by suicide and suicidal behavior. While no genome-wide significant results were obtained, we did observe a novel association between suicide attempts and KCNMB2, a functional gene that appears to be relevant to the study of suicidal behavior. We also found additional support for the potential role of ABI3BP in the pathogenesis of suicidal behavior. Additional work aimed at replicating and extending these findings in larger samples of patients is needed.

Figure 1.

Figure 1.

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Manhattan Plot of Suicide Attempts GWAS Results.

Figure 2.

Figure 2.

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Manhattan Plot of Suicidal Ideation GWAS Results.

Acknowledgements

This work was supported by grant #I01BX002577 from the Biomedical and Laboratory Research and Development (BLR&D) Service of the Department of Veterans Affairs (VA) Office of Research and Development (ORD), grant #IK2CX000525 and #1IK2CX000718 from the Clinical Science Research and Development (CSR&D) Service of VA ORD, grant #1IK2RX000703, #1lK2RX000908, and #1lK2RX000908 from the Rehabilitation Research and Development (RR&D) Service of VA ORD, the Research and Development and Mental Health Services of the Durham VA Medical Center, and the VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center. J.C. Beckham was supported by a Research Career Scientist Award (#11S-RCS-009) from CSR&D. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the VA or the US government.

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