Introduction: Panic disorder (PD) has many comorbidities such as depression, bipolar disorder (BPD), and agoraphobia (AG). PD is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Recently, a tri-allelic serotonin transporter (5-HTTLPR/rs25531) polymorphism was reported to be more sensitive to personality traits compared to the bi-allelic 5-HTTLPR polymorphism. We hypothesized that the 5-HTTLPR/rs25531 polymorphism may lead to a pathological anxious state depending on the presence or absence of a comorbidity in PD. Methods: In this study, we investigated the relationship between comorbidities in PD and tri-allelic 5-HTTLPR polymorphisms. A total of 515 patients with PD (148 males, 367 females) were genotyped, and the Revised NEO Personality Inventory as well as anxiety-related psychological tests were administered. Depression, BPD, and AG were diagnosed as comorbidities. Results: For the tri-allele 5-HTTLPR genotype, a significant interaction effect was found between openness to experience and comorbid depression. Examination of the interaction between AG and the tri-allelic 5-HTTLPR genotype revealed that L’ allele carriers are associated with higher trait anxiety than the S’S’ genotype group in PD without AG. Conclusion: Some anxiety and personality traits can be characterized by the tri-allelic gene effect of 5-HTTLPR. These results suggest that tri-allelic 5-HTTLPR genotypes have genetic effects on the presence of comorbidities of PD.

1.
American Psychiatric Association
.
Diagnostic and statistical manual of mental disorders
. 4th ed.
Washington (DC)
:
American Psychiatric Press
;
1994
.
2.
Brown
TA
,
Campbell
LA
,
Lehman
CL
,
Grisham
JR
,
Mancill
RB
.
Current and lifetime comorbidity of the DSM-IV anxiety and mood disorders in a large clinical sample
.
J Abnorm Psychol
.
2001
Nov
;
110
(
4
):
585
99
.
[PubMed]
0021-843X
3.
Chen
YH
,
Lin
HC
.
Patterns of psychiatric and physical comorbidities associated with panic disorder in a nationwide population-based study in Taiwan
.
Acta Psychiatr Scand
.
2011
Jan
;
123
(
1
):
55
61
.
[PubMed]
0001-690X
4.
Kaufman
J
,
Charney
D
.
Comorbidity of mood and anxiety disorders
.
Depress Anxiety
.
2000
;
12
(
S1
Suppl 1
):
69
76
.
[PubMed]
1091-4269
5.
Kessler
RC
,
Chiu
WT
,
Jin
R
,
Ruscio
AM
,
Shear
K
,
Walters
EE
.
The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication
.
Arch Gen Psychiatry
.
2006
Apr
;
63
(
4
):
415
24
.
[PubMed]
0003-990X
6.
Sugaya
N
,
Yoshida
E
,
Yasuda
S
,
Tochigi
M
,
Takei
K
,
Otani
T
, et al
Prevalence of bipolar disorder in panic disorder patients in the Japanese population
.
J Affect Disord
.
2013
May
;
147
(
1-3
):
411
5
.
[PubMed]
0165-0327
7.
American Psychiatric Association
.
Diagnostic and statistical manual of mental disorders
. 3rd ed.
Washington (DC)
:
American Psychiatric Press
;
1980
.
8.
American Psychiatric Association
.
Diagnostic and statistical manual of mental disorders
. 5th ed.
Washington (DC)
:
American Psychiatric Press
;
2013
.
9.
Asmundson
GJ
,
Taylor
S
,
Smits
JA
.
Panic disorder and agoraphobia: an overview and commentary on DSM-5 changes
.
Depress Anxiety
.
2014
Jun
;
31
(
6
):
480
6
.
[PubMed]
1091-4269
10.
Cosci
F
,
Mansueto
G
.
Biological and clinical markers in panic disorder
.
Psychiatry Investig
.
2019
Jan
;
16
(
1
):
27
36
.
[PubMed]
1738-3684
11.
MacKinnon
DF
,
Zamoiski
R
.
Panic comorbidity with bipolar disorder: what is the manic-panic connection?
Bipolar Disord
.
2006
Dec
;
8
(
6
):
648
64
.
[PubMed]
1398-5647
12.
Rao
S
,
Han
X
,
Shi
M
,
Siu
CO
,
Waye
MM
,
Liu
G
, et al
Associations of the serotonin transporter promoter polymorphism (5-HTTLPR) with bipolar disorder and treatment response: A systematic review and meta-analysis
.
Prog Neuropsychopharmacol Biol Psychiatry
.
2019
Mar
;
89
:
214
26
.
[PubMed]
0278-5846
13.
Schumacher
J
,
Deckert
J
.
Serotonin transporter polymorphisms and panic disorder
.
Genome Med
.
2010
Jun
;
2
(
6
):
40
.
[PubMed]
1756-994X
14.
Yohn
CN
,
Gergues
MM
,
Samuels
BA
.
The role of 5-HT receptors in depression
.
Mol Brain
.
2017
Jun
;
10
(
1
):
28
.
[PubMed]
1756-6606
15.
Schloss
P
,
Williams
DC
.
The serotonin transporter: a primary target for antidepressant drugs
.
J Psychopharmacol
.
1998
;
12
(
2
):
115
21
.
[PubMed]
0269-8811
16.
Mynett-Johnson
L
,
Kealey
C
,
Claffey
E
,
Curtis
D
,
Bouchier-Hayes
L
,
Powell
C
, et al
Multimarkerhaplotypes within the serotonin transporter gene suggest evidence of an association with bipolar disorder
.
Am J Med Genet
.
2000
Dec
;
96
(
6
):
845
9
.
[PubMed]
0148-7299
17.
Rao
S
,
Leung
CS
,
Lam
MH
,
Wing
YK
,
Waye
MM
,
Tsui
SK
.
Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese
.
Gene
.
2017
Mar
;
603
:
34
41
.
[PubMed]
0378-1119
18.
Shi
M
,
Hu
J
,
Dong
X
,
Gao
Y
,
An
G
,
Liu
W
, et al
Association of unipolar depression with gene polymorphisms in the serotonergic pathways in Han Chinese
.
Acta Neuropsychiatr
.
2008
Jun
;
20
(
3
):
139
44
.
[PubMed]
0924-2708
19.
Nakamura
M
,
Ueno
S
,
Sano
A
,
Tanabe
H
.
The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants
.
Mol Psychiatry
.
2000
Jan
;
5
(
1
):
32
8
.
[PubMed]
1359-4184
20.
Heils
A
,
Teufel
A
,
Petri
S
,
Stöber
G
,
Riederer
P
,
Bengel
D
, et al
Allelic variation of human serotonin transporter gene expression
.
J Neurochem
.
1996
Jun
;
66
(
6
):
2621
4
.
[PubMed]
0022-3042
21.
Lesch
KP
,
Bengel
D
,
Heils
A
,
Sabol
SZ
,
Greenberg
BD
,
Petri
S
, et al
Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region
.
Science
.
1996
Nov
;
274
(
5292
):
1527
31
.
[PubMed]
0036-8075
22.
Wendland
JR
,
Martin
BJ
,
Kruse
MR
,
Lesch
KP
,
Murphy
DL
.
Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531
.
Mol Psychiatry
.
2006
Mar
;
11
(
3
):
224
6
.
[PubMed]
1359-4184
23.
Chang
HA
,
Fang
WH
,
Liu
YP
,
Tzeng
NS
,
Shyu
JF
,
Wan
FJ
, et al
Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety disorder
.
J Psychiatry Neurosci
.
2020
Nov
;
45
(
6
):
379
86
.
[PubMed]
1180-4882
24.
Porcelli
S
,
Fabbri
C
,
Serretti
A
.
Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy
.
Eur Neuropsychopharmacol
.
2012
Apr
;
22
(
4
):
239
58
.
[PubMed]
0924-977X
25.
Collier
DA
,
Stöber
G
,
Li
T
,
Heils
A
,
Catalano
M
,
Di Bella
D
, et al
A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders
.
Mol Psychiatry
.
1996
Dec
;
1
(
6
):
453
60
.
[PubMed]
1359-4184
26.
Oo
KZ
,
Aung
YK
,
Jenkins
MA
,
Win
AK
.
Associations of 5HTTLPR polymorphism with major depressive disorder and alcohol dependence: A systematic review and meta-analysis
.
Aust N Z J Psychiatry
.
2016
Sep
;
50
(
9
):
842
57
.
[PubMed]
0004-8674
27.
Goenjian AK, Bailey JN, Walling DP, Steinberg AM, Schmidt D, Dandekar U, et al. Association of TPH1, TPH2, and 5HTTLPR with PTSD and depressive symptoms. J Affect Disord. 2012 Nov;140(3):244–52.
28.
Schiele
MA
,
Kollert
L
,
Lesch
KP
,
Arolt
V
,
Zwanzger
P
,
Deckert
J
, et al
Hypermethylation of the serotonin transporter gene promoter in panic disorder-Epigenetic imprint of comorbid depression?
Eur Neuropsychopharmacol
.
2019
Oct
;
29
(
10
):
1161
7
.
[PubMed]
0924-977X
29.
Chang
CC
,
Chang
HA
,
Fang
WH
,
Chang
TC
,
Huang
SY
.
Gender-specific association between serotonin transporter polymorphisms (5-HTTLPR and rs25531) and neuroticism, anxiety and depression in well-defined healthy Han Chinese
.
J Affect Disord
.
2017
Jan
;
207
:
422
8
.
[PubMed]
0165-0327
30.
Munafò
MR
,
Freimer
NB
,
Ng
W
,
Ophoff
R
,
Veijola
J
,
Miettunen
J
, et al
5-HTTLPR genotype and anxiety-related personality traits: a meta-analysis and new data
.
Am J Med Genet B Neuropsychiatr Genet
.
2009
Mar
;
150B
(
2
):
271
81
.
[PubMed]
1552-4841
31.
Otsubo
T
,
Tanaka
K
,
Koda
R
,
Shinoda
J
,
Sano
N
,
Tanaka
S
, et al
Reliability and validity of Japanese version of the mini-international neuropsychiatric interview
.
Psychiatry Clin Neurosci
.
2005
Oct
;
59
(
5
):
517
26
.
[PubMed]
1323-1316
32.
Bollini
P
,
Pampallona
S
,
Tibaldi
G
,
Kupelnick
B
,
Munizza
C
.
Effectiveness of antidepressants. Meta-analysis of dose-effect relationships in randomised clinical trials
.
Br J Psychiatry
.
1999
Apr
;
174
(
4
):
297
303
.
[PubMed]
0007-1250
33.
Zung
WW
.
A self-rating depression scale
.
Arch Gen Psychiatry
.
1965
Jan
;
12
(
1
):
63
70
.
[PubMed]
0003-990X
34.
Spielberger
CD
,
Gorsuch
RL
,
Lushene
R
,
Vagg
PR
,
Jacobs
GA
.
Manual for the State-Trait Anxiety Inventory (Form Y)
.
Palo Alto (CA)
:
Consulting Psychologists Press
;
1983
.
35.
Reiss
S
,
Peterson
RA
,
Gursky
DM
,
McNally
RJ
.
Anxiety sensitivity, anxiety frequency and the prediction of fearfulness
.
Behav Res Ther
.
1986
;
24
(
1
):
1
8
.
[PubMed]
0005-7967
36.
Costa
PT
 Jr
,
McCrae
RR
.
Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) professional manual
.
Odessa (FL)
:
Psychological Assessment Resources, Inc
;
1992
.
37.
Gudayol-Ferré
E
,
Guàrdia-Olmos
J
,
Peró-Cebollero
M
,
Herrera-Guzmán
I
,
Camarena
B
,
Cortés-Penagos
C
, et al
Prediction of the time-course pattern of remission in depression by using clinical, neuropsychological, and genetic variables
.
J Affect Disord
.
2013
Sep
;
150
(
3
):
1082
90
.
[PubMed]
0165-0327
38.
Bonferroni
CE
.
Teoria statistica delle classi e calcolo delle probabilità
.
Pub R Ist Superiore Sci Econ Commerc Firenze.
1936
;
8
:
3
62
.
39.
Gelernter
J
.
SLC6A4 polymorphism, population genetics, and psychiatric traits
.
Hum Genet
.
2014
Apr
;
133
(
4
):
459
61
.
[PubMed]
0340-6717
40.
Homberg
JR
.
A mouse model to address unresolved antidepressant issues
.
Proc Natl Acad Sci USA
.
2011
Mar
;
108
(
9
):
3463
4
.
[PubMed]
0027-8424
41.
Kunugi
H
,
Hattori
M
,
Kato
T
,
Tatsumi
M
,
Sakai
T
,
Sasaki
T
, et al
Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder
.
Mol Psychiatry
.
1997
Oct-Nov
;
2
(
6
):
457
62
.
[PubMed]
1359-4184
42.
Asnaani
A
,
Gutner
CA
,
Hinton
DE
,
Hofmann
SG
.
Panic disorder, panic attacks and panic attack symptoms across race-ethnic groups: results of the collaborative psychiatric epidemiology studies
.
CNS Neurosci Ther
.
2009
;
15
(
3
):
249
54
.
[PubMed]
1755-5930
43.
Minelli
A
,
Bonvicini
C
,
Scassellati
C
,
Sartori
R
,
Gennarelli
M
.
The influence of psychiatric screening in healthy populations selection: a new study and meta-analysis of functional 5-HTTLPR and rs25531 polymorphisms and anxiety-related personality traits
.
BMC Psychiatry
.
2011
Mar
;
11
(
1
):
50
.
[PubMed]
1471-244X
44.
Beevers
CG
,
Wells
TT
,
Ellis
AJ
,
McGeary
JE
.
Association of the serotonin transporter gene promoter region (5-HTTLPR) polymorphism with biased attention for emotional stimuli
.
J Abnorm Psychol
.
2009
Aug
;
118
(
3
):
670
81
.
[PubMed]
0021-843X
45.
Kalbitzer
J
,
Frokjaer
VG
,
Erritzoe
D
,
Svarer
C
,
Cumming
P
,
Nielsen
FA
, et al
The personality trait openness is related to cerebral 5-HTT levels
.
Neuroimage
.
2009
Apr
;
45
(
2
):
280
5
.
[PubMed]
1053-8119
46.
Stoltenberg
SF
,
Twitchell
GR
,
Hanna
GL
,
Cook
EH
,
Fitzgerald
HE
,
Zucker
RA
, et al
Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism
.
Am J Med Genet
.
2002
Mar
;
114
(
2
):
230
4
.
[PubMed]
0148-7299
47.
Rahman
MS
,
Guban
P
,
Wang
M
,
Melas
PA
,
Forsell
Y
,
Lavebratt
C
.
The serotonin transporter promoter variant (5-HTTLPR) and childhood adversity are associated with the personality trait openness to experience
.
Psychiatry Res
.
2017
Nov
;
257
:
322
6
.
[PubMed]
0165-1781
48.
Demiralay
C
,
Husemann
J
,
Koelsch
W
,
Yassouridis
A
,
Wiedemann
K
,
Kellner
M
.
Does 5-HTTLPR genotype influence willingness to participate in panic challenges?
Depress Anxiety
.
2009
;
26
(
2
):
E68
70
.
[PubMed]
1091-4269
49.
Inoue
K
,
Kaiya
H
,
Hara
N
,
Okazaki
Y
.
A discussion of various aspects of panic disorder depending on presence or absence of agoraphobia
.
Compr Psychiatry
.
2016
Aug
;
69
:
132
5
.
[PubMed]
0010-440X
50.
Kessler
RC
,
Berglund
P
,
Demler
O
,
Jin
R
,
Merikangas
KR
,
Walters
EE
.
Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication
.
Arch Gen Psychiatry
.
2005
Jun
;
62
(
6
):
593
602
.
[PubMed]
0003-990X
51.
Roest
AM
,
de Vries
YA
,
Lim
CC
,
Wittchen
HU
,
Stein
DJ
,
Adamowski
T
, et al;
WHO World Mental Health Survey Collaborators
.
A comparison of DSM-5 and DSM-IV agoraphobia in the World Mental Health Surveys
.
Depress Anxiety
.
2019
Jun
;
36
(
6
):
499
510
.
[PubMed]
1091-4269
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