Genome‐wide analyses of psychological resilience in U.S. Army soldiers

Abstract

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genome-wide association studies (GWASs) of self-assessed (by questionnaire) and outcome-based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self-assessed resilience (N = 11,492) was found to have significant common-variant heritability (h 2 = 0.162, se = 0.050, p = 5.37 × 10 −4 ), and to be significantly negatively genetically correlated with neuroticism (r g = −0.388, p = .0092). GWAS results from the EUR soldiers revealed a genome-wide significant locus on an intergenic region on Chr 4 upstream from doublecortin-like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [p = 5.65 × 10 −9 ] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch-like family member 36 (KLHL36) was detected at gene-wise genomewide significance [p = 1.89 × 10 −6 ]. A polygenic risk score derived from the self-assessed resilience GWAS was not significantly associated with outcome-based resilience. In very

Genetics of resilience: Implications from genome‐wide association studies and candidate genes of the stress response system in posttraumatic stress disorder and depression

“…Nevertheless, there is no doubt that resilience is partly influenced by genetic factors. The heritability of resilience was repeatedly demonstrated in twin studies, although the proportion of the genetic impact between these studies varied markedly (Connor & Davidson, ; Kim‐Cohen et al, ), as well as in the so far only GWAS on resilience in which SNP‐based heritability was estimated at 16% (Stein et al, ).…”

“…An interesting candidate among the significant hits was DCLK2 , a member of the doublecortin family of kinases that promote survival and regeneration of neurons (Nawabi et al, ). Stein et al () additionally discussed the possibility of DCLK2 being an expression quantitative trait locus in the frontal cortex that could alter brain structure or cognitive function and thus resilience. Interestingly, the top hit is located approximately 0.4 Mbp downstream from the neighboring gene, the NR3C2 gene, which is also discussed in the context of resilience in this review (Vinkers et al, ).…”

“…To date there is only one GWAS on resilience, which was published recently by Stein et al (). Since PTSD in particular, but also MDD, can occur frequently due to trauma, stress a result of a lack of resilience, these phenotypes are useful to identify new potential loci that can then be further investigated to assess possible effects on resilience.…”

“…The analyses of prospective outcome‐based resilience were performed in a smaller sample ( N = 1,939), with no SNP reaching genome‐wide significance. However, if only those participants who had experienced high stress exposure ( N = 581) were considered, a genome‐wide significant polymorphism was detected less than 0.1 Mbp downstream from SLC15A5 (Solute Carrier Family 15 Member 5; Stein et al, ).…”

Association between resilience and a functional polymorphism in the serotonin transporter (SLC6A4) gene: A meta-analysis

“…These results suggest that specific genes could be playing an important role in this psychological process. A genome-wide association study (GWAS) has identified that in European soldiers four Single Nucleotide Polymorphisms (SNPs) in DCLK2 gene are related to self-assessed resilience, in addition to variants in the KLHL36 gene (Stein et al, 2019[ 43 ]). On the other hand, studies focused in evaluating candidate genes have found that some polymorphisms in genes involved in synaptic plasticity, such as SLC6A4, BDNF, DRD4 and COMT, have been associated with resilience levels in people with or without diseases (Carli et al, 2011[ 7 ]; Kang et al, 2013[ 25 ]; La Greca et al, 2013[ 28 ]; Niitsu et al, 2019[ 33 ]).…”