Moderators of gene-outcome associations following traumatic brain injury

Carmichael, Jai; Hicks, Amelia J.; Spitz, Gershon; Gould, Kate Rachel; Ponsford, Jennie

doi:10.1016/j.neubiorev.2021.08.015

Cited by 7 publications

(7 citation statements)

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“…The lower allelic frequencies of G may be one of reasons why there were no significant changes of circadian rhythm/sleep-related behavioral data between AA and AG group. Furthermore, previous studies have found that several gene polymorphism frequency varies depending on both region and ethnicity in healthy and clinical diseases populations (81)(82)(83)(84). In addition, the genotype distribution of PER1 in the present study was identified in a small sample of 77.…”

Section: Discussionsupporting

confidence: 48%

Per1 gene polymorphisms influence the relationship between brain white matter microstructure and depression risk

et al. 2022

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BackgroundCircadian rhythm was involved in the pathogenesis of depression. The detection of circadian genes and white matter (WM) integrity achieved increasing focus for early prediction and diagnosis of major depressive disorder (MDD). This study aimed to explore the effects of PER1 gene polymorphisms (rs7221412), one of the key circadian genes, on the association between depressive level and WM microstructural integrity.Materials and methodsDiffusion tensor imaging scanning and depression assessment (Beck Depression Inventory, BDI) were performed in 77 healthy college students. Participants also underwent PER1 polymorphism detection and were divided into the AG group and AA group. The effects of PER1 genotypes on the association between the WM characteristics and BDI were analyzed using tract-based spatial statistics method.ResultsCompared with homozygous form of PER1 gene (AA), more individuals with risk allele G of PER1 gene (AG) were in depression state with BDI cutoff of 14 (χ2 = 7.37, uncorrected p = 0.007). At the level of brain imaging, the WM integrity in corpus callosum, internal capsule, corona radiata and fornix was poorer in AG group compared with AA group. Furthermore, significant interaction effects of genotype × BDI on WM characteristics were observed in several emotion-related WM tracts. To be specific, the significant relationships between BDI and WM characteristics in corpus callosum, internal capsule, corona radiata, fornix, external capsule and sagittal stratum were only found in AG group, but not in AA group.ConclusionOur findings suggested that the PER1 genotypes and emotion-related WM microstructure may provide more effective measures of depression risk at an early phase.

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Section: Discussionsupporting

confidence: 48%

Per1 gene polymorphisms influence the relationship between brain white matter microstructure and depression risk

et al. 2022

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“…A recent review by our research group identified that associations between genetic factors, including COMT Val158 and BDNF 66Met, and outcomes after TBI may vary as a function of other factors such as age, biological sex, and injury severity. 36 Further, we recently demonstrated the utility of accounting for potential moderating factors on gene-outcome associations after TBI in a study of the association between the apolipoprotein E (APOE) ɛ4 SNP and emotional distress. We found that the contribution of the APOE ɛ4 SNP to post-TBI emotional distress varied across the age of the participants, representing a risk factor only among older TBI survivors.…”

Section: Introductionmentioning

confidence: 99%

“… 31 , 38–41 It is possible that biological sex also moderates the associations of the COMT Val158 and BDNF 66Met SNPs with emotional distress, given that the expression of both SNPs are impacted by sex hormones. 20 , 28 , 36 Lastly, TBI severity may moderate these gene-outcome associations, because of the involvement of these genes in neural repair and recovery in brain areas important for emotional regulation.…”

Section: Introductionmentioning

confidence: 99%

“… The association between COMT Val158 and emotional distress would be moderated by age, sex, and injury severity. Based on the literature, 36 we hypothesized that the COMT Val158 SNP would be most strongly associated with higher levels of emotional distress among female participants, older adult participants, and participants with a longer duration of post-traumatic amnesia (PTA). Adults with moderate-severe TBI carrying one or more copies of the BDNF 66Met SNP would report greater levels of emotional distress 1 year post-injury, as measured by the total score on the HADS.…”

Section: Introductionmentioning

confidence: 99%

“… The association between BDNF 66Met and emotional distress would be moderated by age, sex, and injury severity. Based on the literature, 36 we hypothesized that the BDNF 66Met SNP would be most strongly associated with higher levels of emotional distress among younger adult participants, and participants with a longer duration of PTA. No specific direction was hypothesised regarding an interaction between BDNF 66Met and sex on emotional distress, due to mixed findings in the extant literature.…”

Section: Introductionmentioning

confidence: 99%

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COMT Val158Met and BDNF Val66Met Single-Nucleotide Polymorphisms Are Not Associated With Emotional Distress One Year After Moderate-Severe Traumatic Brain Injury

Anderson

Hicks

Carmichael

et al. 2023

Neurotrauma Reports

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Emotional distress is a common, but poorly addressed, feature of moderate-severe traumatic brain injury (TBI). Previously identified sociodemographic, psychological, and injury-related factors account for only a small proportion of the variability in emotional distress post-TBI. Genetic factors may help to further understand emotional distress in this population. The catechol- O -methyltransferase (COMT) Val158 and brain-derived neurotrophic factor (BDNF) 66Met single-nucleotide polymorphisms (SNPs) have been identified as possible contributory factors to outcomes after TBI. We investigated whether the COMT Val158 and BDNF 66Met SNPs were associated with emotional distress 1 year after moderate-severe TBI, and whether these associations were moderated by age, sex, and TBI severity (as measured by the duration of post-traumatic amnesia [PTA]). Moderate-severe TBI survivors (COMT, n = 391; BDNF, n = 311) provided saliva samples after admission to a TBI rehabilitation hospital. At a follow-up interview ∼1 year after injury, participants completed a self-report measure of emotional distress (Hospital Anxiety and Depression Scale; HADS). Multiple linear regression models were constructed for each SNP to predict total scores on the HADS. Neither COMT Val158 nor BDNF 66Met carriage status (carrier vs. non-carrier) significantly predicted emotional distress (COMT, p = 0.49; BDNF, p = 0.66). Interactions of SNP × age (COMT, p = 0.90; BDNF, p = 0.93), SNP × sex (COMT, p = 0.09; BDNF, p = 0.60), SNP × injury severity (COMT, p = 0.53; BDNF, p = 0.87), and SNP × sex × age (COMT, p = 0.08; BDNF, p = 0.76) were also non-significant. Our null findings suggest that COMT Val158 and BDNF 66Met SNPs do not aid the prediction of emotional distress 1 year after moderate-severe TBI, neither in isolation nor in interaction with age, sex and injury severity. The reporting of null findings such as ours is important to avoid publication bias and prompt researchers to consider the challenges of single-gene candidate studies in understanding post-TBI outcomes. Analyses in larger samples that incorporate multiple genetic factors and their relevant moderating factors may provide a greater understanding of the role of genetics in post-TBI emotional distress.

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