Unravelling the interaction between the DRD2 and DRD4 genes, personality traits and concussion risk

Abstract

Background
Concussion occurs when biomechanical forces transmitted to the head result in neurological deficits. Personality may affect the balance between safe and dangerous play potentially influencing concussion risk. Dopamine receptor D2 ( DRD2 ) and dopamine receptor D4 ( DRD4 ) genetic polymorphisms were previously associated with personality traits.

Objectives
This case–control genetic association study investigated the associations of (1) DRD2 and DRD4 genotypes with concussion susceptibility and personality, (2) personality with concussion susceptibility and (3) the statistical model of genotype, personality and concussion susceptibility.

Methods
In total, 138 non-concussed controls and 163 previously concussed cases were recruited from high school (n=135, junior), club and professional rugby teams (n=166, senior). Participants were genotyped for DRD2 rs12364283 (A>G), DRD2 rs1076560 (C>A) and DRD4 rs1800955 (T>C) genetic variants. Statistical analyses including structural equation modelling were performed using the R environment and STATA.

Results
The rs1800955 CC genotype (p=0.014) and inferred DRD2 (rs12364283–rs1076560) –DRD4 (rs1800955) A–C–C allele combination (p=0.019) were associated with decreased concussion susceptibility in juniors. The rs1800955 TT and CT genotypes were associated with low reward dependence in juniors (p<0.001) and seniors (p=0.010), respectively. High harm avoidance was associated with decreased concussion susceptibility in juniors (p=0.009) and increased susceptibility in seniors (p=0.001). The model showed that a genetic variant was associated with personality while personality was associated with concussion susceptibility.

Conclusion
These findings highlight the linear relationship between genetics, personality and concussion susceptibility. Identifying a genetic profile of ‘high risk’ behaviour, together with the development of personalised behavioural training, can potentially reduce concussion risk.

Full text

AbrahamsS, etal. BMJ Open Sport Exerc Med 2019;5:e000465. doi:10.1136/bmjsem-2018-000465 1
Open access Original article
Unravelling the interaction between the
DRD2 and DRD4 genes, personality
traits and concussion risk
Shameemah Abrahams,1,2 Sarah McFie,1 Miguel Lacerda,3 Jon Patricios,4,5,6
Jason Suter,7 Alison V September,1 Michael Posthumus1
To cite: AbrahamsS,
McFieS, LacerdaM, etal.
Unravelling the interaction
between the DRD2 and DRD4
genes, personality traits and
concussion risk. BMJ Open
Sport & Exercise Medicine
2019;5:e000465. doi:10.1136/
bmjsem-2018-000465
►Additional material is
published online only. To view
please visit the journal online
(http:// dx. doi. org/ 10. 1136/
bmjsem- 2018- 000465).
Accepted 8 December 2018
For numbered afliations see
end of article.
Correspondence to
Dr Michael Posthumus;
mposthumus@ me. com
© Author(s) (or their
employer(s)) 2019. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published by
BMJ.
ABSTRACT
Background Concussion occurs when biomechanical
forces transmitted to the head result in neurological
decits. Personality may affect the balance between safe
and dangerous play potentially inuencing concussion risk.
Dopamine receptor D2 (DRD2) and dopamine receptor D4
(DRD4) genetic polymorphisms were previously associated
with personality traits.
Objectives This case–control genetic association study
investigated the associations of (1) DRD2 and DRD4
genotypes with concussion susceptibility and personality,
(2) personality with concussion susceptibility and (3) the
statistical model of genotype, personality and concussion
susceptibility.
Methods In total, 138 non-concussed controls and 163
previously concussed cases were recruited from high
school (n=135, junior), club and professional rugby teams
(n=166, senior). Participants were genotyped for DRD2
rs12364283 (A>G), DRD2 rs1076560 (C>A) and DRD4
rs1800955 (T>C) genetic variants. Statistical analyses
including structural equation modelling were performed
using the R environment and STATA.
Results The rs1800955 CC genotype (p=0.014)
and inferred DRD2 (rs12364283–rs1076560)–DRD4
(rs1800955) A–C–C allele combination (p=0.019) were
associated with decreased concussion susceptibility
in juniors. The rs1800955 TT and CT genotypes were
associated with low reward dependence in juniors
(p<0.001) and seniors (p=0.010), respectively. High harm
avoidance was associated with decreased concussion
susceptibility in juniors (p=0.009) and increased
susceptibility in seniors (p=0.001). The model showed that
a genetic variant was associated with personality while
personality was associated with concussion susceptibility.
Conclusion These ndings highlight the linear
relationship between genetics, personality and concussion
susceptibility. Identifying a genetic prole of ‘high risk’
behaviour, together with the development of personalised
behavioural training, can potentially reduce concussion
risk.
INTRODUCTION
Concussions are brain injuries resulting from
biomechanical forces transmitting to the
head and causing altered neurological func-
tion.1 Concussions are common in rugby with
an incidence of 3.9 concussions/1000 play-
er-hours reported.2
An individual’s personality traits have been
implicated in modulating sport concussion
susceptibility.3–5 Specifically, high impulsivity
scores were reported in rugby players with an
increased concussion risk.3 Both impulsivity
and aggression were associated with a concus-
sion history in former athletes4; however,
aggression was not associated with concus-
sion susceptibility in soldiers.5 Theoretically,
unchecked aggressive behaviour can exacer-
bate pre-existing concussion symptoms and
increase the likelihood of severe concussions.
High novelty-seeking (NS) or a ‘risk-taking’
personality trait was previously correlated with
genetic variants within genes encoding dopa-
mine receptors.6 7 These dopamine receptors,
including D2 and D4 receptor subtypes, are
involved in dopamine neurotransmission and
may modulate memory, behaviour and execu-
tive functions.8 9 The DRD2 gene encodes for
the dopamine D2 receptor, and several func-
tional genetic variants within the DRD2 gene
were previously associated with personality
traits.7 10 11 The DRD2 promoter rs12364283
(−844 A>G) variant was associated with D2
receptor transcription and density in post-
mortem brain tissue.11 The rs12364283 AA
genotype was associated with personality
changes including improved avoidance-based
Key messages
►The C allele of rs1800955 variant within the dopa-
mine receptor encoding gene, DRD4, was correlated
with a reduction in concussion susceptibility as not-
ed in junior rugby players.
►The DRD4 rs1800955 T allele was associated with
socially detached behaviour in both junior and senior
players.
►A risk model of genetic, personality and injury pro-
les showed that the DRD4 rs1800955 variant was
associated with personality, while personality was
associated with concussion susceptibility.
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Open access
decisions, poorer behavioural inhibition and increased
impulsivity.7 10 Furthermore, the DRD2 intronic rs1076560
(C>A) variant was shown to be associated with splicing
and mRNA expression of the D2 receptor,11 while the A
allele was associated with impaired avoidance learning
behaviour.10
The DRD4 gene encodes the dopamine D4 receptor
and is expressed in the cognitive and emotional areas
of the limbic system.12 13 The functional DRD4 promoter
rs1800955 (−521 T>C) variant was shown to influence
DRD4 transcriptional activity14; however, this was not
reproduced in two independent studies.15 16 The CC
genotype was associated with high NS trait, while the C
allele was previously over-represented in schizophrenia
sufferers.6 14 Collectively, the supporting evidence
from expression studies and associations with person-
ality implicates the DRD2 rs12364283, DRD2 rs1076560
and DRD4 rs1800955 variants in modifying personality
possibly via inhibition of neurotransmission. Therefore,
the investigation of the underlying physiology involved in
personality-associated pathways may explain the role of
personality in concussion susceptibility. To the authors’
knowledge, no studies have investigated all three func-
tional dopamine receptor variants (DRD2 rs12364283,
DRD2 rs1076560 and DRD4 rs1800955) independently
and collectively, in a haplotype, with concussion suscepti-
bility and personality.
The aims of this novel, case–control genetic association
study were to independently investigate the associations
of (1) DRD2 (rs12364283: A>G, rs1076560: C>A) and
DRD4 (rs1800955: T>C) genotypes with concussion
susceptibility, (2) DRD2 and DRD4 genotypes with person-
ality and (3) personality with concussion susceptibility.
An additional aim was to statistically model the collec-
tive interaction of concussion susceptibility, personality
dimensions and genotype profile.
METHODS
Participant recruitment
This case–control genetic association study was conducted
according to the STrengthening the REporting of
Genetic Association Studies guidelines17 and Decla-
ration of Helsinki. Details on concussion definition,
participant recruitment, concussion history and sports
participation for this cohort were previously described.18
Concussions were defined according to the Concussion
in Sport Group1 and symptoms were selected from the
validated list in the Sports Concussion Assessment Tool
V.2, which was the latest version in use at the time of diag-
nosis as participants were recruited during 2013–2015.19
Briefly, concussed cases were defined as individuals who
sustained a concussion while playing rugby, with one
or more of the following inclusion criteria: (1) diag-
nosis confirmed by a medical professional (physicians,
physiotherapists, paramedics regardless of concussion
diagnosis/management training), (2) sustained one or
more symptoms and (3) the diagnosis may have included
scores from computerised cognitive tests (eg, ImPACT).
A ‘diagnosed concussion’ was categorised as concussions
diagnosed by a medical professional with one or more
concussion symptoms reported; while a ‘self-reported
concussion’ was categorised as concussions not diag-
nosed by a medical professional but self-reporting one or
more symptoms.
In total, 420 participants were included in this study
after completing the consent and study questionnaire.
Participants were excluded based on self-reporting
ancestry, sporting activity and brain-related disorders
(online supplementary figure S1). After all exclusions, a
final total of 301 white, male Rugby Union players (aged
12–39 years) were analysed, with 138 participants self-re-
porting no concussion history (control group) and 163
participants with a history of clinically diagnosed and
self-reported concussions (all cases group). A subgroup,
of the all cases group, comprised participants with a
history of clinically diagnosed concussions and sepa-
rately analysed as clinically diagnosed subgroup (n=140).
Participants were collectively analysed and stratified by
playing level into juniors (n=135, high school/youth
rugby players aged 12–18 years) and seniors (19–39
years; amateur-level club, n=116, and professional rugby
players, n=50), and independently analysed. The partici-
pants were analysed by playing level to identify potential
differences in genetic susceptibility. For example, junior
players are vulnerable to adverse complications following
concussion20 21 while senior players have a higher expo-
sure to potentially pathology-induced, repetitive head
impacts.22 23 In addition, the differences in life experi-
ence and intellect development between juniors and
seniors may also influence personality scores.24 25 All
participants completed a study questionnaire detailing
their concussion, sporting and medical histories, as well
as a psychometric personality questionnaire.
DNA extraction and genotyping
DNA was extracted from either a buccal swab26 27 or
venous blood sample.28 The selected variants, rs12364283
(−844 A>G) and rs1076560 (C>A) within the DRD2 gene
(online supplementary figure S2) and rs1800955 (−521
T>C) within the DRD4 gene (online supplementary
figure S2), had minor allele frequencies >5% in the white
population (NCBI, https://www. ncbi. nlm. nih. gov/).
The rs12364283, rs1076560 and rs1800955 variants were
genotyped as previously described,18 at the Division of
Exercise Science and Sports Medicine biochemistry labo-
ratory, using fluorescence-based TaqMan real-time PCR
assays and the StepOnePlus real-time PCR machine with
software V.2.2.2 (Applied Biosystems, USA).
Personality questionnaire
Cloninger’s 96-item true/false, validated Tri-dimen-
sional Questionnaire (TPQ) was used to measure the
three personality dimensions.29 The personality dimen-
sions evaluated were NS, which responds to novelty and
reward, harm avoidance (HA), which responds to aver-
sive stimulus, and reward dependence (RD) for reward
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anticipation and reinforced behaviour.29 30 True and false
answers were scored with one and zero, respectively, and
a total was determined for each personality dimension
and subscale. Individuals with a higher score would have
a heightened behavioural response while the inverse for
a lower score (online supplementary table S1).
Statistical analysis
Statistical analysis was performed using STATA statis-
tical software release V.14 (College Station) and the R
language and environment for statistical computing.31 A
logistic regression model was fitted on concussion history
(case–control) as a function of personality traits (NS,
HA and RD) as well as a separate analysis where person-
ality was tested as a function of genotypes (rs12364283,
rs1076560, rs1800955) using genetics, SNPassoc and
haplo. stats packages, and Fisher’s exact test in R.32 33
These analyses were adjusted for age as a confounding
covariate. Generalised structural equation modelling
was performed using STATA to collectively investigate
the interactions between concussion history, personality
and genotypes. Concussion history was coded within the
model with the all cases group and clinically diagnosed
subgroup compared relative to the control group, and
the major homozygous genotype used as the reference
genotype for each variant (rs12364283: A/A, rs1076560:
C/C, rs1800955: T/T). Concussion history was compared
between personality and genotypes, while personality
was compared between genotypes. A hypothesis-driven
approach was adopted with three biologically relevant
variants (two of which were positioned on a single gene,
DRD2 rs12364283 and rs1076560; D′=0.030, r2=0.0004),
thus correcting for multiple testing would be too conser-
vative for this study.34 Statistical significance was set at
p<0.05.
RESULTS
Participant characteristics
Only the findings for junior and senior groups will be
discussed while the findings for all participants collec-
tively can be found in the online supplementary material
1 (online supplementary tables S2, S3, S4, S5 and S6, and
figure S3).
When only the juniors were analysed, no significant
differences were noted between groups for age, height,
weight, body mass index, rugby exposure and non-rugby
collision sport exposure (online supplementary table
S2). When only the seniors were analysed, the control
group (n=66) was significantly younger than the all cases
group (n=100) (p=0.038; control: 21.7±3.3 years; all
cases: 22.9±3.9 years).
DRD2 rs12364283, DRD2 rs1076560 and DRD4 rs1800955
genotype and allele frequency distribution
For juniors (figure 1C), the rs1800955 CC genotype
was significantly over-represented in the control group
(n=11) compared with the all cases group (n=2) and
the clinically diagnosed subgroup (n=0) (CC vs TT+CT;
control vs all cases: p=0.014, control, 19% and all cases,
4%; OR 0.18, 95% CI 0.04 to 0.87; control vs clinically
diagnosed: p=0.003, clinically diagnosed, 0%). All three
variants (rs12364283, rs1076560 and rs1800955) were in
Hardy-Weinberg equilibrium (HWE) for the control and
case groups (p>0.05), with the exception of the rs1800955
variant which was not in HWE for the clinically diagnosed
subgroup (p=0.016; figure 1).
For seniors, the rs12364283, rs1076560 and rs1800955
genotypes (figure 1) and allele frequency distributions
(online supplementary table S4) were not significantly
different between groups. All three variants were in HWE
for the control and case groups (p>0.05; figure 1).
Inferred DRD2 rs12364283-rs1076560-DRD4 rs1800955 allele
combination distribution
The inferred DRD2 and DRD4 allele combination was
constructed using the genotype data [DRD2 rs12364283
(A>G), DRD2 rs1076560 (C>A), DRD4 rs1800955 (T>C)].
In total, four inferred allele combinations, above a
frequency of 4%, were identified (figure 2). The A–C–C
and A–C–T allele combinations were noted as the most
frequent (25%–51%), while the A–A–C and A–A–T were
the least frequent (3%–11%) for the control and case
groups (figure 2). No significant differences were noted
for the inferred DRD2 rs12364283–rs1076560–DRD4
rs1800955 allele combination between groups, when only
seniors were analysed (figure 2B).
For juniors (figure 2A), the A–C–C allele combina-
tion was significantly over-represented in the control
group (n=19, 32%) compared with the all cases group
(n=12, 25%) and compared with the clinically diagnosed
subgroup (n=11, 28%) (recessive model, control vs all
cases: p=0.019, hap. score=−2.34; control vs clinically diag-
nosed: p=0.039, hap. score=−2.06).
Genotype and personality dimensions
For juniors (table 1), the mean RD score was significantly
lower in individuals with the rs1800955 TT genotype
(n=24) compared with the combined CC and CT geno-
types (n=39) (TT vs CC+CT: p<0.001, TT, 15.5±4.2;
CC+CT, 20.0±3.5). Furthermore, the RD1, RD3 and RD4
subscales were significantly lower in individuals with the
TT genotype (TT vs CC+CT, RD1: p<0.001, TT, 2.8±1.0,
n=27; CC+CT, 3.9±1.0, n=41; RD3: p=0.002, TT, 5.4±2.5,
n=24; CC+CT, 7.3±2.2, n=42; RD4: p=0.002, TT, 2.0±1.1,
n=27; CC+CT, 2.8±1.1, n=42).
For seniors (table 1), the mean RD score was signifi-
cantly lower in individuals with the rs1800955 CT
genotype (n=73) compared with the combined TT
and CC genotypes (n=66) (CT vs TT+CC: p=0.010,
CT, 18.4±3.9; TT+CC, 20.2±4.2). However, none of the
RD subscales were significantly different between the
rs1800955 genotypes (RD1: p=0.122, RD2: p=0.053, RD3:
p=0.499, RD4: p=0.237).
Concussion history and personality dimensions
For juniors (table 2), the HA dimension was significantly
higher in the control group (n=44) compared with all
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Figure 1 The genotypes frequencies of DRD2 rs12364283, rs1076560 and DRD4 rs1800955. The genotype frequencies
(%) between the control group (controls), all clinically diagnosed and self-reported concussed cases (all cases) and clinically
diagnosed concussed cases only (clinically diagnosed); for the (A) DRD2 rs12364283 (A>G), (B) rs1076560 (C>A) and (C) DRD4
rs1800955 (T>C) variants in juniors (left panel, n=125) and seniors (right panel, n=165). Signicant differences between groups
are indicated (p<0.05). The rs12364283 GG genotype is missing in seniors.
cases group (n=40) and clinically diagnosed subgroup
(n=33) (control vs all cases: p=0.009, control, 12.9±5.9,
all cases, 9.7±5.0; control vs clinically diagnosed: p=0.006,
clinically diagnosed, 9.5±4.8). Furthermore, HA1 and
HA2 of the four HA subscales were significantly higher in
the control group compared with the concussed groups
(HA1: control vs all cases, p=0.024; control, 4.1±2.2,
n=47, all cases, 3.0±1.9, n=41; control vs clinically diag-
nosed, p=0.012; clinically diagnosed, 2.9±1.7, n=33; HA2:
control vs all cases, p=0.017; control, 3.0±2.0, n=46, all
cases, 2.1±1.5, n=40; control vs clinically diagnosed,
p=0.009; clinically diagnosed, 1.9±1.4, n=32).
For seniors (table 2), the HA dimension was signifi-
cantly lower in the control group (n=56) compared with
all cases group (n=86) and clinically diagnosed subgroup
(n=74) (control vs all cases: p=0.001, control, 8.1±4.9, all
cases, 11.2±6.1; control vs clinically diagnosed: p=0.002,
clinically diagnosed, 11.1±6.0). Furthermore, HA1,
HA3 and HA4 of the four HA subscales were signifi-
cantly lower in the control group compared with the
concussed groups (HA1: control vs all cases, p=0.003;
control, 2.1±1.7, n=57, all cases, 3.1±2.1, n=89; control
vs clinically diagnosed, p=0.004; clinically diagnosed,
3.1±2.1, n=76; HA3: control vs all cases, p=0.018; control,
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Figure 2 The frequencies of the inferred DRD2 rs12364283–rs1076560–DRD4 rs1800955 allele combination. The frequencies
(%) between the control group (controls), all clinically diagnosed and self-reported concussed cases (all cases) and clinically
diagnosed concussed cases only (clinically diagnosed) for the inferred DRD2 rs12364283 (A>G), DRD2 rs1076560 (C>A) and
DRD4 rs1800955 (T>C) allele combinations; in (A) juniors (n=107) and (B) seniors (n=163). Signicant differences between
groups are indicated (p<0.05, recessive model).
1.8±1.7, n=59, all cases, 2.6±2.1, n=89; control vs clinically
diagnosed, p=0.038; clinically diagnosed, 2.6±2.1, n=77;
HA4: control vs all cases, p=0.004; control, 2.1±2.1, n=58,
all cases, 3.0±2.4, n=90; control vs clinically diagnosed,
p=0.004; clinically diagnosed, 3.1±2.3, n=77).
Modelling the collective relationship between concussion
history, personality and genotype scores
The interplay between concussion susceptibility, person-
ality dimensions and DRD2 and DRD4 genotypes was
investigated using a generalised structural equation
model (figure 3, online supplementary table S7).
When the juniors were evaluated (figure 3), personality
and genotype were collectively correlated and specifi-
cally the RD score was significantly associated with the
rs1800955 genotype for the all cases group (TT vs CT:
p<0.0001, coefficient=4.45, SE=1.04; TT vs CC: p=0.028,
coefficient=3.06, SE=1.39), and the clinically diagnosed
subgroup (TT vs CT: p<0.0001, coefficient=5.01, SE=1.05;
TT vs CC: p=0.007, coefficient=3.95, SE=1.46).
When seniors were evaluated (figure 3), the person-
ality dimensions were found to be significantly correlated
with concussion susceptibility. In particular, the HA score
was significantly different between control and all cases
groups (p=0.007, coefficient=0.10, SE=0.04), as well
as between control and clinically diagnosed subgroup
(p=0.008, coefficient=0.11, SE=0.04). When the clini-
cally diagnosed subgroup was analysed, personality and
genotype were significantly correlated, with the RD score
significantly associated with the rs1800955 genotype (TT
vs CT: p=0.004, coefficient=−2.30, SE=0.80).
DISCUSSION
The main findings of this study were (1) the indepen-
dent DRD4 rs1800955 genotype and inferred DRD2
(rs12364283–rs1076560)–DRD4 (rs1800955) allele
combination were associated with concussion suscepti-
bility in juniors, (2) the rs1800955 variant was associated
with RD scores in both junior and senior groups, (3) HA
scores were associated with concussion susceptibility in
both junior and senior groups and (4) the model showed
that a genetic variant was associated with personality
while personality was associated with concussion suscepti-
bility in white male rugby players.
Distribution of the DRD2 rs12364283, DRD2 rs1076560
and DRD4 rs1800955 genotype, allele and inferred allele
combination
In this study, the DRD4 rs1800955 CC genotype and
the inferred DRD2 (rs12364283–rs1076560)-DRD4
(rs1800955) A–C–C allele combination were over-repre-
sented in the control group. These findings implicate the
rs1800955 C allele in reduced concussion susceptibility.
The C allele, compared with the T allele, was previously
associated with higher DRD4 expression.14 The pref-
erential binding of dopamine to D4 receptors inhibits
adenylyl cyclase,8 thereby suppressing neurotransmission,
particularly modulating decision-making and cogni-
tive behaviour.35 36 We hypothesise that the C allele may
stimulate DRD4 expression, increasing the D4 receptor
availability to dopamine and directing the dopaminergic
activity towards an overall inhibition of decision-making
and cognitive behaviour. Tentatively, therefore, the C
allele acts as a neuro-protective response against concus-
sion injury by inhibiting ‘risk-taking’ behaviour (online
supplementary figure S4).
Genotype and personality dimensions
The rs1800955 TT and CT genotypes were associated with
a low RD score in juniors and seniors, respectively. In this
study, juniors with the TT genotype presented with socially
detached behaviour (low RD).29 37 In seniors, socially
detached behaviour was associated with the CT genotype.
The theory proposed is that in response to a reward stim-
ulus the TT genotype, in juniors, and the CT genotype,
in seniors, may elicit a change in D4 receptor expression
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Table 1 The mean scores for the Tri-dimensional Personality Questionnaire (TPQ) dimensions; novelty seeking (NS), harm avoidance (HA) and reward dependence (RD),
between the DRD2 rs12364283 (A>G), DRD2 rs1076560 (C>A) and DRD4 rs1800955 (T>C) genotypes
TPQ
dimensions
DRD2 rs12364283
P value
DRD2 rs1076560
P value
DRD4 rs1800955
P value AA AG GG CC CA AA TT CT CC
Junior
N (66) (8) (2) (55) (23) (3) (27) (28) (11)
NS 15.7±4.4
(66)
13.1±3.6 (8) 13.5±6.4 (2) 0.240 15.0±4.2
(54)
16.1±4.9
(20)
14.7±4.9 (3) 0.589 16.8±3.8
(26)
16.1±4.2
(26)
14.1±5.0
(11)
0.201
HA 11.3±5.8
(66)
10.4±5.5 (8) 11.5±5.0 (2) 0.908 11.5±5.5
(52)
11.0±5.7
(23)
15.7±8.6 (3) 0.442 11.0±5.4
(25)
9.9±6.1 (28) 12.6±4.6
(11)
0.401
RD† 18.1±4.4
(66)
15.9±4.4 (8) 22.5±2.1 (2) 0.079 17.7±4.3
(55)
18.2±4.7
(20)
18.7±3.2 (3) 0.859 15.5±4.2
(24)
20.4±3.6
(28)
18.9±3.1
(11)
<0.001
(<0.001)*
RD1 2.8±1.0 (27) 4.1±0.8 (30) 3.3±1.0 (11) <0.001
(<0.001)*
RD2 5.6±2.1 (27) 6.0±1.6 (28) 6.1±2.0 (11) 0.629
RD3 5.4±2.5 (24) 7.6±2.2 (31) 6.6±1.9 (11) 0.003
(0.002)*
RD4 2.0±1.1 (27) 2.8±1.1 (31) 2.9±1.1 (11) 0.005
(0.002)*
Senior
N (116) (26) (102) (31) (5) (40) (73) (26)
NS 16.4±5.6
(113)
14.6±4.0
(26)
– 0.068 15.9±4.9
(100)
16.6±6.5
(31)
19.3±8.6 (4) 0.405 15.9±4.7
(39)
16.0±5.7
(72)
17.2±5.2
(26)
0.710
HA 10.0±6.0
(116)
10.0±4.9
(25)
– 0.864 10.7±6.0
(101)
8.6±5.3 (31) 8.0±2.6 (5) 0.158 8.5±5.3 (40) 10.6±6.4
(73)
10.5±4.6
(26)
0.170
RD† 19.0±4.2
(116)
20.2±4.0
(25)
– 0.208 19.0±4.2
(102)
20.0±4.2
(30)
21.6±2.7 (5) 0.233 20.0±4.2
(40)
18.4±3.9
(73)
20.6±4.2
(26)
0.030
(0.010)**
RD1 3.7±1.2 (42) 3.5±1.1 (73) 4.0±1.1 (27) 0.122
RD2 6.3±1.4 (40) 5.8±2.0 (76) 6.7±1.6 (28) 0.053
RD3 7.0±2.3 (41) 6.5±2.4 (75) 6.5±2.5 (26) 0.499
RD4 3.1±1.3 (42) 2.7±1.3 (76) 3.2±1.3 (27) 0.237
The means±SD are presented with total number (N) of participants given in parentheses. Signicant differences between genotypes are highlighted in bold (p<0.05, age-adjusted, generalised
linear model).
*Post-hocp value:rs1800955 TT vsCC+CT. ** Post-hocp value:rs1800955 CT vsTT+CC.
†TheRD main dimension is signicantly different, thus the RD subscales (RD1–RD4) are alsodisplayed.
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AbrahamsS, etal. BMJ Open Sport Exerc Med 2019;5:e000465. doi:10.1136/bmjsem-2018-000465
Open access
Table 2 The mean scores of the Tri-dimensional Personality Questionnaire (TPQ) dimensions; novelty seeking (NS), harm
avoidance (HA) and reward dependence (RD), between the control group (controls) and all clinically diagnosed and self-
reported concussed cases (all cases) and clinically diagnosed concussed cases only (clinically diagnosed)
TPQ dimensions Controls All cases P value* Clinically diagnosed P value**
Junior
N (44) (40) (33)
NS 15.3±4.8 (44) 15.3±3.9 (37) 0.961 15.2±3.9 (30) 0.879
HA† 12.9±5.9 (44) 9.7±5.0 (39) 0.009 9.5±4.8 (31) 0.006
HA1 4.1±2.2 (47) 3.0±1.9 (41) 0.024 2.9±1.7 (33) 0.012
HA2 3.0±2.0 (46) 2.1±1.5 (40) 0.017 1.9±1.4 (32) 0.009
HA3 3.0±2.2 (47) 2.3±2.0 (42) 0.071 2.4±2.1 (34) 0.108
HA4 3.0±2.3 (47) 2.5±2.3 (41) 0.321 2.5±2.3 (33) 0.294
RD 17.8±3.9 (43) 18.2±4.9 (40) 0.799 18.7±4.9 (33) 0.447
Senior
N (56) (87) (76)
NS 16.6±5.6 (54) 15.7±5.3 (85) 0.481 16.0±5.2 (73) 0.651
HA† 8.1±4.9 (56) 11.2±6.1 (86) 0.001 11.1±6.0 (74) 0.002
HA1 2.1±1.7 (57) 3.1±2.1 (89) 0.003 3.1±2.1 (76) 0.004
HA2 2.0±1.9 (58) 2.5±1.7 (91) 0.103 2.4±1.6 (78) 0.263
HA3 1.8±1.7 (59) 2.6±2.1 (89) 0.018 2.6±2.1 (77) 0.038
HA4 2.1±2.1 (58) 3.0±2.4 (90) 0.004 3.1±2.3 (77) 0.004
RD 19.5±4.0 (55) 19.1±4.2 (87) 0.654 19.5±4.0 (76) 0.955
The means±SD are presented with total number (N) of participants given in parentheses.
*P values for the control group compared to all clinically diagnosed and self-reported concussed cases (all cases). **Clinically diagnosed
concussed cases (clinically diagnosed), with signicant differences highlighted in bold (p<0.05, age-adjusted).
†The HA main dimension is signicantly different, thus the HA subscales (HA1–HA4) are displayed.
and availability thereby increasing excitatory nerve signals
and stimulating socially indifferent behaviour. This indif-
ferent behaviour may promote callousness leading to
dangerously tackling another player and increase a rugby
player’s risk of injuring themselves or others. Reckless
tackling techniques are cited as common mechanisms of
rugby-related concussions.38 39 Furthermore, in seniors,
the C or T allele may act on different biological pathways
and both still contribute to eliciting a low RD behaviour. It
is possible that the heterozygosity (or heterosis) observed
may be due to (1) participant selection or (2) a true
effect of heterosis. First, all participant demographics
were normally distributed. Second, heterosis of a genetic
marker was previously shown to associate with increased
risk for neurodegenerative diseases40 and may be a plau-
sible genotype–personality association in seniors in this
study.
Concussion history and personality dimensions
In juniors, apprehensive and cautious behaviour (high
HA) was observed in the control group compared with
the case groups. Anticipatory worry and fear of uncer-
tainty (high HA1 and HA2 scores) were also noted in
the controls. These avoidant behavioural traits imply a
tendency to avoid dangerous playing techniques which
may result in reduced concussion susceptibility.41 In
seniors, however, the inverse relationship was observed
with carefree and confident behaviour (low HA) in
the controls. This contradictory relationship in seniors
could be explained by the fact that amateur club and
professional rugby players (senior group) have a greater
skill level and a higher self-confidence in their playing
ability.42 43 A greater self-confidence at the senior level
could lead to reduced concussion susceptibility, while
a less confident player may make more mistakes and
increase their susceptibility to concussion.
Concussion history, personality and genotype modelling
When investigating the collective effect of genetic vari-
ants and personality traits on concussion susceptibility
using a structural equation model, similar findings were
observed to the independent analyses performed. The
rs1800955 variant was associated with RD in both juniors
and seniors, while HA was associated with concussion
susceptibility in seniors only. The model highlighted that
genetics (rs1800955) explained personality changes (RD
dimension) while personality changes (HA dimension)
explained concussion susceptibility, without the direct
effect of genetics (figure 3).
This cohort represents a very narrow sample popula-
tion of white, young male rugby players and, therefore,
these results only provide a finite perspective of the
population and require investigation in a broader popu-
lation group. This study is also limited by the concussion
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8AbrahamsS, etal. BMJ Open Sport Exerc Med 2019;5:e000465. doi:10.1136/bmjsem-2018-000465
Open access
Figure 3 The generalised structural equation model of concussion susceptibility, personality traits and genetic variants.
The circles represent concussion susceptibility, consisting of non-concussed control and concussed case groups, as the
grouping variable, and personality (novelty seeking (NS), harm avoidance (HA), reward dependence (RD)) and genetics (DRD2
rs12364283: A>G, DRD2 rs1076560: C>A and DRD4 rs1800955: T>C) as the predictor variables. The dotted arrows indicate
the proposed relationship between variables. the solid arrows, connecting the black and grey coloured circles, indicate the
specic signicant associations displayed for junior and senior groups, where relevant (p<0.05).
diagnosis as not all medical professionals were trained
in concussion diagnosis/management and the inclusion
of self-reported concussion, which could result in misre-
porting of concussions.
In summary, these findings highlight that genetic
and personality pathways influence concussion risk
differently between juniors and seniors. In addition,
the findings highlight a linear relationship between
genetics, personality and concussion susceptibility in
rugby players. Future studies should compare junior and
senior groups in larger cohorts to further explore the
possible age effect on the relationship between genetics,
personality and concussion susceptibility. A future clin-
ical implication of these results is the identification of a
genetic profile which could highlight athletes susceptible
to ‘high concussion-risk’ behaviour.
Author afliations
1Division of Exercise Science and Sports Medicine, Department of Human Biology,
Faculty of Health Science, University of Cape Town, Cape Town, South Africa
2Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health
Sciences, Stellenbosch University, Cape Town, South Africa
3Department of Statistical Sciences, Faculty of Science, University of Cape Town,
Cape Town, South Africa
4Sports Concussion South Africa, Johannesburg, South Africa
5Section of Sports Medicine, University of Pretoria, Pretoria, South Africa
6Department of Emergency Medicine, University of the Witwatersrand,
Johannesburg, South Africa
7Cape Sports Medicine, Sports Science Institute, Cape Town, South Africa
Acknowledgements The authors thank all the participants and respective
authorities from the high schools, clubs, professional teams and medical practices
for their time, effort and participation in this study.
Funding This study and authors were funded by the South African National
Research Foundation (grant numbers: 90942, 93416, 85534), the Deutscher
Akademischer Austauschdienst (DAAD) and the University of Cape Town. Funders
had no involvement in the paper.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Ethical approval was obtained from the Human Research Ethics
Committee of the University of Cape Town.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the
use is non-commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.
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