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International Journal of Genetics and Genomics

2014; 2(2): 19-29


Published online May 30, 2014 (http://wwws!ien!epublishin""#oup!o$/%/i%"")
doi: 1011&4'/%i%""2014020212


Genetic variations associated with brain disorders: Focus
on synaptic plasticity and apoptosis regulatory genes in
schizophrenia, posttraumatic stress disorder and
ischemic stroke
Anna Boyajyan, Ani Stepanyan, Diana Avetyan, Hovsep Ghazaryan, Sofi Atshemyan,
Roksana Zakharyan, Kristina Pirumyan, Gohar Tsakanova
(abo#ato#y o) *u$an +eno$i!s and ,$$uno$i!s, -epa#t$ent o) .pplied Mole!ula# /iolo"y, ,nstitute o) Mole!ula# /iolo"y 0.1 2.,
3e#e4an, .#$enia
mai! a""ress#
aboya%yan5s!ia$ (. /oya%yan), a6stepanyan5$bs!ia$ (. 1tepanyan), i$b5s!ia$ (- .4etyan),
h6"ha7a#yan5$bs!ia$ (* +ha7a#yan), s6atshe$yan5$bs!ia$ (1 .tshe$yan), #67a8ha#yan5$bs!ia$ (2 9a8ha#yan),
86pi#u$yan5$bs!ia$ (: Pi#u$yan), natdep5s!ia$ (+ ;sa8ano4a)
To $ite this arti$!e#
.nna /oya%yan, .ni 1tepanyan, -iana .4etyan, *o4sep +ha7a#yan, 1o)i .tshe$yan, 2o8sana 9a8ha#yan, :#istina Pi#u$yan, +oha#
;sa8ano4a +eneti! <a#iations .sso!iated with /#ain -iso#de#s: =o!us on 1ynapti! Plasti!ity and .poptosis 2e"ulato#y +enes in
1!hi7oph#enia, Postt#au$ati! 1t#ess -iso#de# and ,s!he$i! 1t#o8e International Journal of Genetics and Genomics.
<ol 2, 0o 2, 2014, pp 19-29 doi: 1011&4'/%i%""2014020212

A%stra$t# >pide$iolo"i!, !lini!al and e?pe#i$ental data indi!ates that a $a%o#ity o) b#ain diso#de#s in!ludin"
s!hi7oph#enia (1@9), postt#au$ati! st#ess diso#de# (P;1-), and is!he$i! st#o8e (,1) a#e $ulti)a!to#ial diso#de#s with
st#on" and !o$ple? "eneti! !o$ponent ,denti)i!ation o) all "eneti! 4a#iations asso!iated with these diso#de#s $ay
su))i!iently !ont#ibute to unde#standin" o) thei# basi! patho$e!hanis$s and en!ou#a"e de4elop$ent o) new inno4ati4e
app#oa!hes to thei# ea#ly dia"nosis and t#eat$ent ;he ai$ o) this #e4iew a#ti!le is to p#o4ide o4e#4iew o) ou# #e!ent studies
on e4aluation o) potential asso!iation o) 1@9, P;1- and ,1 with )un!tional sin"le nu!leotide poly$o#phis$s (10Ps) o)
synapti! plasti!ity and apoptosis #e"ulato#y "enes in .#$enian population *e#e, ou# attention was )o!used on "enes
en!odin" net#in +1 (NTNG1), b#ain-de#i4ed neu#ot#ophi! )a!to# (BDNF), !o$ple?in-2 (CPLX2), ne#4e "#owth )a!to# (NGF)
and its #e!epto# (NGFR), anne?in )a$ily p#oteins - anne?in .A and anne?in .11 (NX!, NX11), and /-!ell ly$pho$a
2 (/!l-2) )a$ily p#oteins - /!l-2 p#ope# and /!l-2-asso!iated B p#otein (BCL2, BX) +eno$i! -0. sa$ples o) diseased
and healthy indi4iduals we#e "enotyped )o# a nu$be# o) 10Ps o) the $entioned "enes usin" poly$e#ase !hain #ea!tion
with seCuen!e-spe!i)i! p#i$e#s (P@2-11P) ;he si"ni)i!an!e o) di))e#en!es in "enotype and allele )#eCuen!ies and $ino#
allele !a##ia"e between patients and healthy !ont#ol sub%e!ts was dete#$ined usin" Pea#sonDs @hi-sCua#e test P-4alues less
than 00A we#e !onside#ed statisti!ally si"ni)i!ant 1i"ni)i!ant asso!iations we#e )ound between: (1) 1@9 and BDNF #s&2&A,
CPLX2 #s13&&11&, #s3'92909, NGF #s&330, #s4'3943A, NGFR #sE34194, #s114&&1AA, #s20E244&, NX< #s11AEA94A,
BX #s10AE3&9 10Ps; (2) P;1- and CPLX2 #s13&&11&, BCL2 #s9A&AE2 10Ps; (3) ,1 and NTNG1 #s&2'11E, CPLX2
#s13&&11&, NX! #s11AEA94A 10Ps ;he obtained #esults indi!ated the in4ol4e$ent o) "eneti!ally dete#$ined alte#ations
in synapti! plasti!ity and apoptosis in patho$e!hanis$s o) 1@9, P;1- and ,1 ;he $ino# ; allele o) the CPLX2 "ene
#s13&&11& poly$o#phis$ #ep#esents #is8 )a!to# )o# all studied diseased !onditions indi!atin" i$po#tant )un!tional
si"ni)i!an!e o) this "eneti! 4a#iation in $aintenan!e o) synapti! plasti!ity .nothe# i$po#tant !on!lusion o) these studies is
that $ino# alleles o) so$e poly$o#phi! 4a#iants o) "enes, en!odin" synapti! plasti!ity and apoptosis #e"ulato#y p#oteins,
$ay play a p#ote!ti4e #ole #elati4e to 1@9 de!#easin" the #is8 )o# de4elop$ent o) this diso#de# ,n su$$a#y, ou# studies
e$phasi7e the i$po#tant !ont#ibution o) !han"es in synapti! plasti!ity and apoptosis #e"ulation to patho$e!hanis$s o)
1@9, P;1-, and ,1 as well as si"ni)i!ant input o) "eneti! )a!to#s to these !han"es
Key&or"s# 1!hi7oph#enia, Postt#au$ati! 1t#ess -iso#de#, ,s!he$i! 1t#o8e, 1ynapti! Plasti!ity, .poptosis,
2e"ulato#y +enes, 1in"le 0u!leotide Poly$o#phis$s, +enotypin", .sso!iation

20 .nna /oya%yan et al.: +eneti! <a#iations .sso!iated with /#ain -iso#de#s: =o!us on 1ynapti! Plasti!ity and
.poptosis 2e"ulato#y +enes in 1!hi7oph#enia, Postt#au$ati! 1t#ess -iso#de# and ,s!he$i! 1t#o8e

'( )ntro"u$tion
>pide$iolo"i!, !lini!al and e?pe#i$ental data indi!ates
that a $a%o#ity o) b#ain diso#de#s a#e $ulti)a!to#ial diso#de#s
with st#on" and !o$ple? "eneti! !o$ponent F1-3G .$on"
those diso#de#s a#e s!hi7oph#enia (1@9) F4G, postt#au$ati!
st#ess diso#de# (P;1-) FAG, and is!he$i! st#o8e (,1) F&G .ll
th#ee diso#de#s a#e se4e#e diseased !onditions and !ont#ibute
si"ni)i!antly to disability and $o#tality o) the hu$an
population wo#ldwide FE-9G Mole!ula# patho$e!hanis$s
#esponsible )o# "ene#ation, p#o"#ession and un)a4o#able
!lini!al out!o$e o) 1@9, P;1- and ,1 a#e only be"innin" to
be unde#stood, and !u##ently a4ailable p#o"nosti!, dia"nosti!
and t#eat$ent $easu#es #elated to these diso#de#s a#e not
4e#y e))i!ient ,denti)i!ation o) all "eneti! 4a#iations
asso!iated with these diso#de#s $ay su))i!iently !ont#ibute to
unde#standin" o) thei# basi! patho$e!hanis$s and
en!ou#a"e de4elop$ent o) new inno4ati4e app#oa!hes to
thei# ea#ly dia"nosis and t#eat$ent 1e4e#al studies, in!ludin"
ou# own, su""est i$pli!ation o) alte#ations in synapti!
neu#onal plasti!ity and apoptosis to pathophysiolo"y o) 1@9,
P;1-, and ,1 F10-19G ;his #e4iew p#o4ides o4e#4iew o) ou#
#e!ent studies (in!ludin" published F20-33G and unpublished
data) on e4aluation o) potential asso!iation o) 1@9, P;1-
and ,1 with )un!tional sin"le nu!leotide poly$o#phis$s
(10Ps) o) synapti! plasti!ity and apoptosis #e"ulato#y "enes
*e#e, ou# attention was )o!used on "enes en!odin" net#in +1
(NTNG1), b#ain-de#i4ed neu#ot#ophi! )a!to# (BDNF),
!o$ple?in-2 (CPLX2), ne#4e "#owth )a!to# (NGF) and its
#e!epto# (NGFR), anne?in )a$ily p#oteins - anne?in .A and
anne?in .11 (NX!, NX11"# and /-!ell ly$pho$a 2
(/!l-2) )a$ily p#oteins - /!l-2 p#ope# and /!l-2-asso!iated
B p#otein (BCL2# BX) +eno$i! -0. sa$ples o) diseased
and healthy indi4iduals we#e "enotyped )o# a nu$be# o)
10Ps o) the $entioned "enes usin" poly$e#ase !hain
#ea!tion with seCuen!e-spe!i)i! p#i$e#s (P@2-11P) /#ie)
!ha#a!te#isti!s o) sele!ted "enes and 10Ps a#e "i4en in ;able
1
Table 1. Brief c$aracteristics of selected %enes and &NPs.
Gene S*P
*ame )D +o$ation )D Su%stitution
,
Position +o$ation -type.
NTNG1 22'A4 1p133 #s&2'11E .H+ 10E99E10& int#oni!
BDNF &2E 11p13 #s&2&A +H. 2E&E991& e?oni! ($issense)
CPLX2 10'14 AC3A2
#s13&&11& @H; 1EA29EA31 int#oni! (AI nea# "ene)
#s3'92909 @H; 1EA30AA91 int#oni!
0+= 4'03 1p131
#s&330 +H. 11A'29313 e?oni! ($issense)
#s4'3943A +H. 11A'A'104 int#oni!
NGFR 4'04 1EC21-C22
#s114&&1AA @H; 4494299' e?oni! (synony$ous)
#s20E244& @H; 4EA'E'19 $issense
#sE34194 ;H+ 4EA91&09 3I-J;2
NX! 30' 4C2E #s11AEA94A -1@H; 122&1EE4A :o7a8 seCuen!e
NX11 311 10C21-23 #s1049AA0 +H. '191&&'2 $issense
BX A'1 19C1333 #s10AE3&9 .H+ 494&4'&& int#oni!
BCL2 A9& 1'C2133
#s9A&AE2 +H. &0'20AE1 int#oni!
#s1'0101' .H+ &09'A'E9 e?oni! (synony$ous)
K
on )o#wa#d st#and
/( 0etho"o!o1y
2.1. Study Population
1tudy sub%e!ts we#e !h#oni! patients with pa#anoid )o#$
o) 1@9 and with P;1- o) !o$bat o#i"in, patients with
a!ute ,1, and healthy indi4iduals (*,) with no )a$ily o#
past histo#y o) any $ental, !e#eb#o4as!ula# o#
!a#dio4as!ula# diso#de#s, as well as diso#de#s !ha#a!te#i7ed
by alte#ations in apoptosis and synapti! plasti!ity .ll
sub%e!ts we#e .#$enians bo#n and li4in" in .#$enia /oth,
the in)o#$ed !onsents )#o$ all study sub%e!ts and the
app#o4al o) the >thi!s @o$$ittee o) the ,nstitute o)
Mole!ula# /iolo"y (,2/ L000040E9) we#e #e!ei4ed )o#
these studies
2.2. Methods
.bout A $l o) pe#iphe#al 4enous blood was !olle!ted
)#o$ ea!h study sub%e!t and t#ans)e##ed to >-;.-!on-
tainin" tubes +eno$i! -0. sa$ples we#e isolated )#o$
)#esh blood a!!o#din" to a standa#d phenol-!hlo#o)o#$
$ethod F34G and sto#ed at -30M@ until use Jsin" P@2-11P
$ethod F3AG -0. sa$ples we#e "enotyped )o# NTNG1
#s&2'11E, BDNF #s&2&A, CPLX2 #s13&&11&, #s3'92909,
NGF #s&330, #s4'3943A, NGFR #s114&&1AA, #s20E244&,
#sE34194, NX! #s11AEA94A, NX11 #s1049AA0, BX
#s10AE3&9, BCL2 #s9A&AE2, #s1'0101' )un!tional 10Ps
;he 10Ps we#e sele!ted based on eithe# thei# )un!tionality
a!!o#din" to the 0ational @ente# o) /iote!hnolo"y
,n)o#$ation (0@/,) databases
(http://wwwn!binl$nih"o4/) o# ta""in" #esults obtained
usin" the ,nte#national *apMap P#o%e!t database
(http://hap$apn!binl$nih"o4) .ll p#i$e#s )o# P@2-11P
we#e desi"ned usin" the "eno$i! seCuen!es in the
+en/an8 nu!leotide seCuen!e database
(https://wwwn!binl$ nih"o4/"enban8/) and a#e indi!ated
,nte#national Nou#nal o) +eneti!s and +eno$i!s 2014; 2(2): 19-29 21

in ;able 2 ;he p#esen!e/absen!e o) allele-spe!i)i!
a$pli!ons in the P@2 p#odu!ts was 4isuali7ed in 2O
a"a#ose "el stained with ethidiu$ b#o$ide )luo#es!ent dye
usin" -0. $ole!ula# wei"ht $a#8e#s as a #e)e#en!e ;o
!he!8 the #ep#odu!ibility o) #esults, #ando$ly sele!ted
-0. sa$ples (10O o) total) we#e "enotyped twi!e
2.3. Data Analysis
;he dist#ibutions o) "enotypes )o# all in4esti"ated 10Ps
we#e !he!8ed )o# !o##esponden!e to the *a#dy-Peinbe#"
(*-P) eCuilib#iu$ ,n o#de# to )ind potential #ele4an!e o)
the sele!ted 10Ps to 1@9, thei# "enotype and allele
)#eCuen!ies and $ino# allele !a##ia"e #ates in patients and
*, we#e !o$pa#ed ;he si"ni)i!an!e o) di))e#en!es in
"enotype and allele )#eCuen!ies and $ino# allele !a##ia"e
between patients and *, was dete#$ined usin" Pea#sonDs
@hi-sCua#e test P-4alues less than 00A we#e !onside#ed
statisti!ally si"ni)i!ant P-4alues ad%usted by /on)e##oni
$ultiple !o$pa#ison !o##e!tion a#e )u#the# indi!ated as
P
!o##e!ted
, and those not ad%usted - as P
no$inal

Table 2. Primers desi%ned for t$e selected &NPs.
S*P *u$!eoti"e se2uen$e of primers
#s&2'11E
standa#d allele: AQ .;@@;;++..;+...+@@@.
$ino# allele: AQ- .;@@;;++..;+...+@@@+
!onstant: AQ-;@.@;+@@@;@;+;+;+@.+;+
#s&2&A
standa#d allele: AQ- ++@;+.@.@;;;@+..@.@+
$ino# allele: AQ- ++@;+.@.@;;;@+..@.@.
!onstant: AQ- +;;.@@@.@;@.@;..;.@;+
#s13&&11&
standa#d allele: AQ-.;+;+;.++....;++@;;@+
$ino# allele: AQ-.;+;+;.++....;++@;;@.
!onstant: AQ- @..;++@@;@;+.@;++;+
#s3'92909
standa#d allele: AQ- ++;+.++@;+@;+;@;+@
$ino# allele: AQ-++;+.++@;+@;+;@;+;
S*P *u$!eoti"e se2uen$e of primers
!onstant: AQ-@;+@;;@.;+.@+..+;@@.
#s&330
standa#d allele: AQ-+@.;@;;+@;@;+;+@.+.;
$ino# allele: AQ-+.@.@.@@.;@@@@@..+@
!onstant: AQ-+.@.@.@@.;@@@@@..+;
#s4'3943A
standa#d allele: AQ-;+++;+@@.....+@;;++@
$ino# allele: AQ-;+++;+@@.....+@;;++;
!onstant: AQ-+@.+@;@@;+@..;;.;@@.
#s114&&1AA
standa#d allele: AQ-.++@;.;+;.++@@.@..++
$ino# allele: AQ-.++@;.;+;.++@@.@..+.
!onstant: AQ-@.+.+++@;@++.@.+@.@.
#s20E244&
standa#d allele: AQ-+;@@.@.@@@@@.+.+++@;@
$ino# allele: AQ-+;@@.@.@@@@@.+.+++@;;
!onstant: AQ-.+@.+@@.++.;++.+@..;
#sE34194
standa#d allele: AQ-+@;++.+@;++@+;@;+;@;
$ino# allele: AQ-+@;++.+@;++@+;@;+;@+
!onstant: AQ-@;.+.+@;+++.+...;@@@
#s11AEA94A
standa#d allele: AQ-@@;+.@@;+.+;.+;@+@ @
$ino# allele: AQ-@@;+.@@;+.+;.+;@+@;
!onstant: AQ-+@@.@+;@.@@.+@;+;;+@
#s1049AA0
standa#d allele: AI-@;+@@+@;+@;;+;;++.+@+
$ino# allele: AI-@;+@@+@;+@;;+;;++.+@.
!onstant: AI-@.@@@;@@.++.;+@@@;@.;.;
#s10AE3&9
standa#d allele: AI-.;@;;@;;@@.+.;++;+.+;
$ino# allele: AI-.;@;;@;;@@.+.;++;+.+@
!onstant: AI-;;.@.++;+;+.+@@.@@.;+
#s9A&AE2
standa#d allele: AI-.+.+++.+;@.;+.@;+..;@
$ino# allele: AI-.+.+++.+;@.;+.@;+..;;
!onstant: AI-@.+.;@;+;+@;;+..@@;@.
#s1'0101'
standa#d allele: AI.;@;@@@++;;.;@+;.@@@;
$ino# allele: AI-.;@;@@@++;;.;@+;.@@@@
!onstant: AI-+.;@@+...++..;;++..;.
3( Resu!ts an" Dis$ussion
;he #esults o) "enotypin" a#e p#esented sepa#ately )o#
ea!h diseased !ondition in ;ables 3-A

Table 3. Genot'(e# allele# and minor allele carria%e fre)uencies of t$e selected &NPs in (atients *it$ &C+ and ,I.
S*P )D Genotypes A!!e!es 4arria1e Ref(
#s&2'11E .. .+ ++ . + +
F20,22, 24G
1@9 (nR103) 32 A0 1' AE 43 &'
*, (nR10A) 34 41 2A AA 4A &&
P!o##e!tedR 0&'
a
0E3
b

#s&2&A ++ +. . . + . .
F20-22,24, 2'-30G
1@9 (nR103) 44 A0 & &9 31 AA
*, (nR10A) &A 33 2 ' 19 3A
P!o##e!tedR 0004
a
0003
b

#s13&&11& @@ @; ;; @ ; ;
F2&,30G
1@9 (nR2&0) 2& A0 24 A1 49 E4
*, (nR2&0) A3 3E 10 E1 29 4E
P!o##e!tedR 1>-49
a
2>-19
b

#s3'92909 @@ @; ;; @ ; ;
F2&,30G
1@9 (nR2&0) 33 A1 1& A' 42 &E
*, (nR2&0) 23 A0 2E 4' A2 EE
P!o##e!tedR 000
a
001
b

#s&330 ++ +. .. + . .
F2E,33G
1@9 (nR200) 43 4& 11 && 34 AE
*, (nR2A0) &A 29 & '0 20 3A
P!o##e!tedR 000
a
000
b

#s4'3943A ++ +. .. + . .
F2E,33G 1@9 (nR22A) 24 A& 20 A2 4' E&
*, (nR22A) A' 3E A E& 24 42
22 .nna /oya%yan et al.: +eneti! <a#iations .sso!iated with /#ain -iso#de#s: =o!us on 1ynapti! Plasti!ity and
.poptosis 2e"ulato#y +enes in 1!hi7oph#enia, Postt#au$ati! 1t#ess -iso#de# and ,s!he$i! 1t#o8e
S*P )D Genotypes A!!e!es 4arria1e Ref(
P!o##e!tedR 000
a
000
b

#s114&&1AA @@ @; ;; @ ; ;
F2E,2', 33G
1@9 (nR200) 39A 44 1&A &2 3' &0A
*, (nR22A) 20 A2 2' 4& A4 '0
P!o##e!tedR 000
a
000
b

#s20E244& @@ @; ;; @ ; ;
F2E,2', 33G
1@9 (nR200) 34 A3 13 &1 39 &&
*, (nR2A0) A& 33 11 '9 29 4E
P!o##e!tedR 000
a
000
b

#sE34194 ;; ;+ ++ ; + +
F2E,2', 33G
1@9 (nR200) E0 2E 4 '3 1E 31
*, (nR2A0) A4 3E 9 E3 2E 4&
P!o##e!tedR 001
a
002
b

#s11AEA94A @@ @; ;; @ ; ;
F2A,2&, 30G
1@9 (nR22A) 24 A& 20 A2 4' E&
*, (nR22A) A'3 3&4 A3 E& 24 42
Pno$inalR 000
a
000
b

#s1049AA0 ++ +. .. + . .
unpublished
1@9 (nR22A) 30 A3 1E A& 44 E0
*, (nR22A) 34 4' 1' A' 42 &&
Pno$inalR 0&4
a
042
b
#s10AE3&9 .. .+ ++ . + +
F32G
1@9 (nR330) 2E AA 1' AA 4A E3
*, (nR32&) 1' A3 29 4A AA '2
P!o##e!tedR 000
a
002
b

#s9A&AE2 ++ +. .. + . .
F32G
1@9 (nR330) 34 A3 13 &0 40 &&
*, (nR32&) 3& 4& 1' A9 41 &4
P!o##e!tedR 1'1
a
1&3
b

#s1'0101' .. .+ ++ . + +
F32G
1@9 (nR330) 2& AA 19 A4 4& E4
*, (nR32&) 21 AE 22 49 A1 E9
P!o##e!tedR 03E
a
03A
b

a
@o$pa#ison o) $ino# allele )#eCuen!y between 1@9 and *,
b
@o$pa#ison o) $ino# allele !a##ia"e between 1@9 and *,
Table 4. Genot'(e# allele# and minor allele carria%e fre)uencies of t$e selected &NPs in (atients *it$ PT&D and ,I.
S*P )D Genotypes A!!e!es 4arria1e Ref(
#s13&&11& @@ @; ;; @ ; ;
F2&,31G
P;1- (nR'E) 39 41 20 &0 40 &1
*, (nREA) &0 32 ' E& 24 40
P!o##e!tedR 001
a
002
b

#s3'92909 @@ @; ;; @ ; ;
F2&,31G
P;1- (nR'E) 1' A2 30 44 A& '2
*, (nREA) 20 AA 2A 4E A3 '0
P!o##e!tedR 1E
a
24
b

#s11AEA94A @@ @; ;; @ ; ;
F2&,31G
P;1- (nR'0) E9 1E 4 'EA 12A 21
*, (nREA) E1 2' 1 'A 1A 29
P!o##e!tedR 14
a
0EA
b

#s9A&AE2 ++ +. .. + . .
upublished
P;1- (nR132) 14 4& 40 3E &3 '&
*, (nR131) 3A 4E 1' A9 41 &A
Pno$inalR 000
a
000
b

a
@o$pa#ison o) $ino# allele )#eCuen!y between P;1- and *,;
b
@o$pa#ison o) $ino# allele !a##ia"e between P;1- and *,
Table 5. Genot'(e# allele# and minor allele carria%e fre)uencies of t$e selected &NPs in (atients *it$ I& and ,I.
S*P )D Genotypes A!!e!es 4arria1e Ref(
#s&2'11E .. .+ ++ . + +
F23G
,1 (nR12E) 1E 4E 3& 41 A9 '3
*, (nR12') 3EA 40 22A AE 43 &2A
P!o##e!tedR 000
a
000
b

#s13&&11& @@ @; ;; @ ; ; unpublished
,nte#national Nou#nal o) +eneti!s and +eno$i!s 2014; 2(2): 19-29 23

S*P )D Genotypes A!!e!es 4arria1e Ref(
,1 (nR1E2) 41 3& 23 A9 41 A9
*, (nR22A) A3 3' 9 E2 2' 4E
P!o##e!tedR 000
a
003
b

#s3'92909 @@ @; ;; @ ; ;
unpublished
,1 (nR1E2) 23 A0 2E 4& A4 EE
*, (nR22A) 20 A2 2' 4E A3 '0
P!o##e!tedR 14
a
10
b

#s11AEA94A @@ @; ;; @ ; ;
unpublished
,1 (nR94) 4' 42 10 &9 31 A2
*, (nR110) EA 2A 0 '' 12 2A
Pno$inalR 000
a
000
b

a
@o$pa#ison o) $ino# allele )#eCuen!y between ,1 and *,
b
@o$pa#ison o) $ino# allele !a##ia"e between ,1 and *,
;he dist#ibution o) "enotypes )o# all sele!ted 10Ps in all
study "#oups !o$plied with *-P eCuilib#iu$
1i"ni)i!ant asso!iations (eithe# positi4e o# ne"ati4e) we#e
)ound between: (1) 1@9 and BDNF #s&2&A, CPLX2
#s13&&11&, CPLX2 #s3'92909, NGF #s&330, NGF
#s4'3943A, NGFR #sE34194, NGFR #s114&&1AA, NGFR
#s20E244&, NX! #s11AEA94A, BX #s10AE3&9 10Ps; (2)
P;1- and CPLX2 #s13&&11&, BCL2 #s9A&AE2 10Ps; (3) ,1
and NTNG1 #s&2'11E, CPLX2 #s13&&11&, NX!
#s11AEA94A 10Ps
/ased on !ha#a!te# o) asso!iation (positi4e o# ne"ati4e),
$ino# alleles o) the BDNF "ene #s&2&A 10P, CPLX2
#s13&&11& 10P, NGF "ene #s&330 and #s4'3943A 10Ps,
NGFR "ene #s20E244& 10P, and NX! "ene #s11AEA94A
10P, !an be !onside#ed #is8 )a!to#s o) 1@9, whe#eas the
p#esen!e o) $ino# alleles o) the CPLX2 "ene #s3'92909,
and NGFR "ene #sE34194 and #s114&&1AA 10Ps, and BX
"ene #s10AE3&9 10P de!#eases the #is8 )o# de4elop$ent o)
this diso#de#
,n !ase o) P;1-, the CPLX2 "ene #s13&&11& 10P and
BCL2 "ene #s9A&AE2 10P we#e identi)ied as #is8 )a!to#s )o#
this diseased !ondition
=inally, data obtained in !ase o) ,1 de$onst#ated that
$ino# alleles o) the NTNG1 "ene #s&2'11E 10P, CPLX2
"ene #s13&&11& 10P and the NX! "ene #s11AEA94A 10P
in!#ease #is8 )o# de4elop$ent o) st#o8e
/#ain-de#i4ed neu#ot#ophi! )a!to# p#o$otes se4e#al
)un!tions o) neu#ons, $odulates neu#ot#ans$ission,
!ont#ibutes to neu#onal "#owth, su#4i4al, and di))e#entiation,
and #e"ulates synapti! t#ans$ission and !o"niti4e p#o!esses
F3&G ;he $issense #s&2&A 10P o) the BDNF "ene a))e!ts
a!ti4ity-dependent se!#etion o) this neu#ot#ophi! )a!to#,
$e$o#y, and hippo!a$pus )un!tions F3EG .sso!iation o)
the BDNF "ene #s&2&A 10P with hu$an !o#ti!al
$o#pholo"y and bilate#al #edu!tions o) hippo!a$pus "#ay
$atte# 4olu$es in the #s&2&AS. $ino# allele !a##ie#s
!o$pa#ed with the standa#d #s&2&A+ allele ho$o7y"otes
was de$onst#ated F3'G, and a !#u!ial #ole o) this 10P in
neu#oplasti!ity alte#ations in 1@9 was #e4ealed F39G ,n
addition, a #elationship o) the #s&2&A "enotypes with a"e o)
onset and the psy!hoti! sy$pto$s o) 1@9 was obse#4ed
F40G Mo#eo4e#, the BDNF "ene #s&2&AS. $ino# allele was
)ound to asso!iate with in!#eased a""#essi4e beha4io# in
1@9-a))e!ted sub%e!ts F41G *owe4e#, the #esults )#o$ the
$eta-analyses o) asso!iation o) the BDNF "ene #s&2&A 10P
with 1@9 a#e !ont#o4e#sial, whi!h $ay #e)le!t the ethni!
di))e#en!es between studied "#oups F42,43G .!!o#din" to
ou# data, in .#$enian population the #s&2&AS. $ino# allele
)#eCuen!y was si"ni)i!antly hi"he# in patients with 1@9
than in *,, and the !a##ie#s o) this allele we#e
o4e##ep#esented in patients !o$pa#ed with *,
F20-22,24,2'-30G Tu# #esults a#e in !on!o#dan!e with the
#e!ent $eta-analysis data F42G Pe also de$onst#ated that
1@9 is !ha#a!te#i7ed by de!#eased blood le4els o)
b#ain-de#i4ed neu#ot#ophi! )a!to# and that this pa#a$ete# is
lowe# in the BDNF "ene #s&2&AS. $ino# allele !a##ie#s
!o$pa#ed to standa#d #s&2&A+ allele ho$o7y"otes F30G
0eu#op#otein net#in +1 is an i$po#tant p#o$ote# o)
neu#ite out"#owth, #e"ulato# o) synapse )o#$ation and
)un!tional a!ti4ity F44G @han"es in e?p#ession le4els o) the
NTNG1 "ene we#e )ound in a nu$be# o) diseases
!ha#a!te#i7ed by alte#ed synapti! plasti!ity in!ludin" 1@9,
bipola# diso#de#, te$po#al lobe epilepsy, and 2ett synd#o$e
F4A-49G 0e4e#theless, only )ew studies ha4e e4aluated
possible asso!iation between the NTNG1 "ene
poly$o#phis$s and diseased !onditions .$on" those a#e
"eno$e wide asso!iation study shown no asso!iation
between !o$$on 10Ps o) the NTNG1 "ene and ano#e?ia
ne#4osa in >u#opeans FA0G, study o) 9hu et al FA1G
de$onst#ated positi4e asso!iation o) the NTNG1 "ene
#s4132&04 10P and the haplotype o) #s4132&04, #s221'404,
and #s13E333& 10Ps o) this "ene with 1@9 ,n addition,
analy7es o) 21 10Ps o) the NTNG1 "ene in 124 Napanese
s!hi7oph#eni! pedi"#ees #e4ealed asso!iation o) 1@9 with
spe!i)i! haplotypes en!o$passin" alte#nati4ely spli!ed
e?ons, 10Ps, and haplotypes !luste#ed in the AI-#e"ion o) the
NTNG1 "ene F4AG =u#the#, Thtsu8i et al in4esti"ated A&
ta" 10Ps o) the NTGN1 "ene and )ound asso!iation between
1@9 and the #s&2'11E 10P lo!ated in int#on 9 in the sa$e
haplotype blo!8 F4'G *owe4e#, ou# own data p#esented in
this #e4iew de$onst#ated no asso!iation between the
#s&2'11E 10P and 1@9 in .#$enian population F20,22,24G
;his dis!#epan!y between ou# #esults and those #epo#ted by
Thtsu8i et al $ost p#obably #e)le!ts population/ethni!
di))e#en!es between the study "#oups Tu# study )o# the )i#st
ti$e de$onst#ated the p#esen!e o) positi4e asso!iation
between the #s&2'11E 10P o) the NTNG1 "ene and ,1 F23G
.sso!iation between any )un!tional 10P o) the NTNG1 "ene
24 .nna /oya%yan et al.: +eneti! <a#iations .sso!iated with /#ain -iso#de#s: =o!us on 1ynapti! Plasti!ity and
.poptosis 2e"ulato#y +enes in 1!hi7oph#enia, Postt#au$ati! 1t#ess -iso#de# and ,s!he$i! 1t#o8e
and ,1 has not been assessed be)o#e in any population
@o$ple?in-2 is a $e$be# o) !o$ple?in )a$ily o)
p#esynapti! #e"ulato#y p#oteins e?p#essed $ainly by
e?!itato#y neu#ons FA2G ,t has been shown that
down#e"ulation o) !o$ple?in-2 $i"ht lead to !han"es in
neu#ot#ans$itte# #elease and de)i!it in synapti! t#ans$ission
!ausin" si"ni)i!ant !o"niti4e and beha4io#al abno#$alities
and is i$pli!ated in patho"enesis and p#o"#ession o) $any
diseased !onditions !ha#a!te#i7ed by alte#ed !o"niti4e
)un!tion and beha4io# FA3,A4G ,n pa#ti!ula#, de!#eased
e?p#ession le4els o) this p#otein in the p#e)#ontal !o#te?,
!e#ebellu$, and hippo!a$pus o) patients with 1@9 we#e
obse#4ed FAAG, and ou# own studies #e4ealed de!#eased
p#odu!tion o) !o$ple?in-2 p#otein in the blood o) 1@9 F30G
and P;1- F14,1A,1'G a))e!ted sub%e!ts ;he #esults obtained
in ou# study with the CPLX2 "ene indi!ated that the
#s13&&11&S; $ino# allele o) this "ene was o4e##ep#esented
in 1@9, P;1-, and ,1 patients when !o$pa#ed to *,
su""estin" a positi4e asso!iation o) this poly$o#phis$ with
these diseased !onditions F2&,30G Phile no asso!iation
between the CPLX2 #s3'92909 10P and P;1- F2&,31G o# ,1
Funpublished dataG was )ound, #s3'92909S; $ino# allele o)
this 10P was $o#e )#eCuent in !ont#ols than in 1@9 patients
F2&,30G indi!atin" p#ote!ti4e #ole o) this allele a"ainst 1@9
,t should be noted that these a#e the )i#st studies e?plo#in"
asso!iation o) the CPLX2 "ene #s13&&11& and #s3'92909
10Ps in P;1- and ,1 in any population 2e"a#din" 1@9,
ea#lie# it was shown that !u##ent !o"niti4e pe#)o#$an!e in
1@9 patients is $odi)ied by a nu$be# o) CPLX2 4a#iants
$odulatin" postt#ans!#iptional "ene e?p#ession, and that a
haplotype !o4e#in" si? 10Ps, in!ludin" #s13&&11& and
#s3'92909, showed hi"h asso!iation with this disease FA&G
0e#4e "#owth )a!to# and its #e!epto# a#e othe# essential
$ediato#s o) synapti! and $o#pholo"i!al plasti!ity, neu#onal
"#owth, su#4i4al, and di))e#entiation, espe!ially in the
de4elopin" b#ain FAE,A'G ;he $atu#e )o#$ o) ne#4e "#owth
)a!to# de#i4es )#o$ a p#e!u#so#, whi!h was #e!ently
dis!o4e#ed to e?e#t !#u!ial b#ain )un!tions #esponsible )o#
$ood and !o"niti4e a!ti4ities FA9G ,t was #epo#ted that in
"ene#ali7ed an?iety diso#de# the blood le4els o) ne#4e
"#owth )a!to# in!#ease a)te# su!!ess)ul !o"niti4e beha4io#al
the#apy F&0G Mo#eo4e#, de!#eased blood le4els o) this
p#otein in patients with 1@9 we#e obse#4ed F&1,&2G .lso, it
has been shown that !h#oni! !annabis abuse #aises 0+=
se#u$ !on!ent#ations in d#u"-nai4e patients with 1@9
!o$pa#ed to *, F&3G ;he #esults o) ou# study de$onst#ate a
positi4e asso!iation between 1@9 and the #s&330 10P o) the
NGF "ene as well as the #s114&&1AA and #s20E244& 10Ps o)
the NGFR "ene F2E,2',33G .lso, a ne"ati4e asso!iation
between this diso#de# and #s4'3943A 10P o) the NGF "ene
as well as the #sE34194 10P o) the NGFR "ene was )ound
F2E,2',33G . non-synony$ous #s&330 10P o) the NGF
"ene is thou"ht to a))e!t int#a!ellula# p#o!essin" and
se!#etion o) the 0+= p#otein F&4G >a#lie# it was shown that
the #s&330 10P is asso!iated with e?e!uti4e dys)un!tion in
patients with .l7hei$e#Ds disease, an?iety #elated t#aits and
a))e!ti4e diso#de#s F&AG *owe4e#, study o) asso!iation
between 1@9 and the #s&330 10P o) the NGF "ene has been
pe#)o#$ed )o# the )i#st ti$e by us F2E,2',33G ;he sa$e
applies to the #s4'3943A 10P o) the NGF "ene F2E,33G
.nothe# poly$o#phis$ o) the NGF "ene, the #s12E&003&
10P was shown to asso!iate with sus!eptibility to 1@9 in
:o#ean population, and si"ni)i!ant di))e#en!es in the .+
and @. haplotype )#eCuen!ies in the lin8a"e diseCuilib#iu$
blo!8 within the #s12E&003& and #s4'3943A 10Ps between
1@9 patients and *, we#e )ound indi!atin" the
#s12E&003&S@ $ino# allele as a #is8 )a!to# )o# 1@9 in
:o#eans F&&G( 2e"a#din" the NGFR "ene 10Ps, ou# study
)o# the )i#st ti$e de$onst#ated asso!iation o) the #s20E244&,
#s114&&1AA and #sE34194 10Ps o) this "ene with 1@9
F2E,2',33G 0otably, the #s114&&1AA synony$ous 10P o)
the NGFR "ene was not studied be)o#e in any diseased
!ondition ,t has to be also $entioned that no data #elati4e to
)un!tional state o) ne#4e "#owth )a!to# and its #e!epto# in
1@9 eithe# at p#otein o# "eneti! le4els we#e #epo#ted be)o#e
;he #s20E244& 10P o) the NGFR "ene and the haplotype
!ontainin" the #sE34194 10P in the 3I-J;2 #e"ion o) the
NGFR "ene we#e #e!ently )ound to be asso!iated with an
in!#eased #is8 o) .l7hei$e#Ds disease in @hinese F&EG
.nne?in-.A p#otein is able in the p#esen!e o) @a
K2
to bind
to ne"ati4ely !ha#"ed phospholipids, whi!h )#o$ the ea#ly
sta"es o) apoptosis al#eady t#ans)e#s )#o$ the inne# to the
oute# $e$b#ane o) a !ell unde#"oin" apoptosis F&'-&9G
.nne?in-.A is an i$po#tant $odulato# o) the p#o!ess o)
pha"o!ytosis o) apoptoti! !ells and in)la$$ato#y #ea!tions
di#e!ted to #e$o4al o) dyin" !ells ,n!#eased le4els o) this
p#otein indu!e de4elop$ent o) in)la$$ato#y #ea!tions
FE0-E2G, whi!h a#e !ha#a!te#isti! )eatu#es o) 1@9 F22G,
P;1- F14G, and ,1 FE3G ;he in!#eased se#u$ le4els o) this
p#otein we#e )ound by us in ,1 F19G and 1@9 F2AG and by
othe# #esea#!h "#oup in 1@9 FE4G, and we also dete!ted the
de!#eased le4els o) this p#otein in P;1- F1A,1'G ;he
#s11AEA94A 10P (-1@/;) in the :o7a8 !onsensus seCuen!e
o) the #e"ulato#y pa#t o) the NX! "ene plays a 8ey #ole in
the initiation o) t#ans!#iption FEAG, and the #s11AE94AS;
$ino# allele o) this "ene !o##elates with the hi"he# le4el o)
synthesis o) this p#otein in the blood FEAG .ll $entioned
abo4e initiated ou# inte#est to study this 10P in 1@9, P;1-
and ,1 ,n !ase o) ,1, the #s11AE94A 10P #ep#esents a spe!ial
inte#est, sin!e ea#lie# it was shown that the #s11AEA94 10P
o) the NX! "ene positi4ely asso!iates with !a#dio4as!ula#
diso#de#s FEAG and that #s11AEA94S; $ino# allele o) this 10P
in!#eases the #is8 )o# de4elop$ent o) 4enous th#o$boses
FE&G Phile ou# #esults on "enotypin" o) the #s11AE94A 10P
o) the NX! "ene su""est no asso!iation between this 10P
and P;1- F2&,31G, we #e4ealed positi4e asso!iation between
the #s11AE94A 10P and 1@9 F2A,2&,30G as well as the
#s11AE94A 10P and ,1 Funpublished dataG ;hese #esults
enable to !onside# the ; $ino# allele o) the #s11AE94A 10P
as a #is8 )a!to# )o# both 1@9 and ,1 ,t has to be $entioned
that in the ea#lie# published study the asso!iation between
1@9 and )un!tional 10P o) anothe# #ep#esentati4e o) the
anne?in )a$ily, the NX- "ene, was shown FEEG .lso, in
ou# study p#esented he#e we )ound no asso!iation between
,nte#national Nou#nal o) +eneti!s and +eno$i!s 2014; 2(2): 19-29 2A

the NX11 "ene )un!tional #s1049AA0 10P and 1@9
FunpublishedG, whe#eas #esults o) ou# p#e4ious
in4esti"ations indi!ated in!#eased e?p#ession le4els o) this
"ene in 1@9 F1&G
. )a$ily o) /!l-2 p#oteins !onstitutes one o) the $ost
biolo"i!ally #ele4ant !lasses o) apoptosis #e"ulato#s a!tin" at
the e))e!te# sta"e o) apoptosis, with so$e $e$be#s
)un!tionin" as supp#esso#s o) apoptosis and othe#s as
p#o$ote#s o) apoptosis ;he ulti$ate 4ulne#ability o) !ells to
di4e#se apoptoti! sti$uli is dete#$ined by the #elati4e #atio
o) 4a#ious p#o-apoptoti! and anti-apoptoti! $e$be#s o) the
/!l-2 )a$ily FE',E9G /!l-2 p#ope# and /a? a#e $e$be#s o)
the /!l-2 )a$ily p#oteins F'0G /!l-2 p#ope# is an inte"#al,
$e$b#ane-asso!iated p#otein with anti-apoptoti! and
antio?idati4e e))e!ts F'0,'1G /!l-2 is a $a%o# anti-apoptoti!
p#otein that inhibits apoptoti! and ne!#oti! !ell death
indu!ed by a di4e#se set o) ad4e#se !onditions F'2G /!l-2
also plays !#iti!al #oles in neu#onal $o#pho"enesis and
synapti! plasti!ity F'3,'4G, and #edu!ed /!l-2 )un!tion is
hypothesi7ed to !ont#ibute to the i$pai#$ent o) !ellula#
plasti!ity and #esilien!e in patients with $ood diso#de#s F'2G
/.B is p#o-apoptoti! $e$be# o) the )a$ily o) /!l-2-#elated
p#oteins, whi!h has an e?tensi4e a$ino a!id ho$olo"y with
/!l-2 F'A, '&G Phethe# the !ell will li4e o# die $ay depend
on the le4el o) eithe# p#otein; while /!l-2 p#e4ents death,
/.B is a death p#o$ote# FE'-'0G Post$o#te$ studies
de$onst#ated the in!#eased e?p#ession le4el o) /.B
en!odin" "ene F'EG as well as hi"h /.B//!l-2 p#oteins #atio
in the te$po#al !o#te? o) patients with 1@9 F''G *owe4e#, it
is yet un!lea# whethe# these patholo"i! alte#ations a#e
"eneti!ally dete#$ined o# !aused by othe# )a!to#s ;he
potential asso!iation between 1@9 and )un!tional 10Ps o)
"enes en!odin" /!l-2 )a$ily p#oteins, BX #s10AE3&9 and
BCL2 #s9A&AE2, #s1'0101', was assessed )o# the )i#st ti$e
by us F32G, and no study has yet e?plo#ed these 10Ps in 1@9
in any othe# population ;he sa$e applies to ou# study on
e4aluation o) asso!iation between the BCL2 "ene #s9A&AE2
10P and P;1- Funpublished dataG. ;he BX "ene
#s10AE3&9 10P was )ound by us ne"ati4ely asso!iated with
1@9: the p#esen!e o) BX #s10AE3&9S+ $ino# allele,
espe!ially in ho$o7y"ous )o#$, was asso!iated with
de!#eased #is8 o) de4elopin" 1@9 F32G ,t has to be
$entioned that no data on asso!iation o) this 10P with any
diseased !ondition has been #epo#ted be)o#e Tpposite to the
BX "ene #s10AE3&9 10P, the BCL2 "ene #s1'0101' and
#s9A&AE2 10Ps ha4e been intensi4ely studied in di))e#ent
!onditions ;he #s1'0101' 10P was $ostly )ound to be
asso!iated with on!olo"i!al diso#de#s F'9-92G as well as with
poo#e# !lini!al out!o$es and $o#tality in patients with
t#au$ati! b#ain in%u#y F93G ;he #s9A&AE2 10P was shown to
asso!iate with the #is8 )o# de4elopin" bipola# diso#de# and
was no$inated as $odulato# o) the e?p#ession o) /!l-2
p#otein and !ellula# 4ulne#ability to apoptosis F94G
P#e!lini!al studies show that this 10P e?e#ts )un!tional
e))e!ts on /!l-2 e?p#ession, as the . ho$o7y"ous "enotype
is asso!iated with si"ni)i!antly lowe# /!l-2 $20.
e?p#ession, A0O lowe# /!l-2 p#otein le4els, and "#eate#
!ellula# sensiti4ity to st#ess-indu!ed apoptosis F94G ;his
10P was #epo#ted to a))e!t "#ay $atte# 4olu$e in a#eas
8nown to play 8ey #oles in the neu#obiolo"y o) #ewa#d
p#o!esses and e$otion #e"ulation and in the
pathophysiolo"y o) $ood diso#de#s F9AG .lso, it was
de$onst#ated that the #s9A&AE2 10P $ay $odulate
!o"niti4e )un!tion and #e"ional "#ay $atte# 4olu$e in
non-de$ented elde#ly $en, and a))e!t lan"ua"e
pe#)o#$an!e th#ou"h its e))e!t on the #i"ht $iddle te$po#al
"y#us F9&G ,n addition, it was shown that the #s9A&AE2 10P
asso!iates with in!#eased ante#io# !in"ulate !o#ti!al
"luta$ate F9EG and dis#upted int#a!ellula# !al!iu$
ho$eostasis in bipola# , diso#de# F9'G and that abno#$al
BCL2 "ene e?p#ession in the .. "enotype o) the #s9A&AE2
10P !ont#ibutes to dys)un!tional @a
2K
ho$eostasis F99G
Tu# study #e4ealed no asso!iation between 1@9 and the
BCL2 "ene #s9A&AE2 and #s1'0101' 10Ps F32G and
indi!ated positi4e asso!iation between the BCL2 "ene
#s9A&AE2 10P and P;1- Funpublished dataG
,n su$$a#y, with #e"a#d to the "enes en!odin" the
synapti! plasti!ity #e"ulato#y p#oteins, we )ound positi4e
asso!iations between 1@9 and the BDNF "ene #s&2&A 10P,
the NGF "ene #s&330 and #s4'3943A 10Ps, as well as the
NGFR "ene #s20E244& 10P, whe#eas ne"ati4e asso!iation
with this diso#de# was )ound )o# the CPLX2 "ene
#s3'92909 10P as well as the NGFR "ene #sE34194 and
#s114&&1AA 10Ps =o# the CPLX2 "ene #s13&&11& 10P
positi4e asso!iation with all th#ee diseases was )ound, and
the sa$e asso!iation was dete!ted between ,1 and the
NTNG1 "ene #s&2'11E 10P
,n !ase o) the "enes en!odin" the apoptosis #e"ulato#y
p#oteins, we )ound positi4e asso!iations o) the NX! "ene
#s11AEA94A 10P with both 1@9 and ,1 as well as o) the
BCL2 "ene #s9A&AE2 10P with P;1- .lso, we
de$onst#ated that p#oapoptoti! BX "ene #s10AE3&9 10P is
ne"ati4ely asso!iated with 1@9
1in!e ou# studies #e)e# to one distin!t population
(.#$enians), the obtained #esults, pa#ti!ula#ly those #epo#ted
by us )o# the )i#st ti$e, should be #epli!ated in othe# populations
0ot all "enes assessed in 1@9 ha4e been e4aluated by us in
P;1- and ,1 ;his should be done in the )utu#e studies and
$o#e )un!tional 10Ps o) the sele!ted "enes should be
in4esti"ated in ea!h diso#de# to ha4e a !o$plete 4iew on the
#ole o) "eneti! p#edisposition and "ene-en4i#on$ent
inte#a!tions in patho$e!hanis$s o) 1@9, P;1-, and ,1
5( 4on$!usions
Tn the basis o) the obtained #esults we !on!lude that
"eneti!ally dete#$ined alte#ations in synapti! plasti!ity and
apoptosis a#e in4ol4ed in patho$e!hanis$s o) 1@9, P;1-,
and ,1 ;he $ino# ; allele o) the CPLX2 "ene #s13&&11&
poly$o#phis$ #ep#esents #is8 )a!to# )o# all studied diseased
!onditions indi!atin" i$po#tant )un!tional si"ni)i!an!e o)
this "eneti! 4a#iation in $aintenan!e o) synapti! plasti!ity
.nothe# i$po#tant !on!lusion o) these studies is that $ino#
alleles o) so$e poly$o#phi! 4a#iants o) "enes, en!odin"
2& .nna /oya%yan et al.: +eneti! <a#iations .sso!iated with /#ain -iso#de#s: =o!us on 1ynapti! Plasti!ity and
.poptosis 2e"ulato#y +enes in 1!hi7oph#enia, Postt#au$ati! 1t#ess -iso#de# and ,s!he$i! 1t#o8e
synapti! plasti!ity and apoptosis #e"ulato#y p#oteins, $ay
play a p#ote!ti4e #ole #elati4e to 1@9 de!#easin" the #is8 )o#
de4elop$ent o) this diso#de# ,n su$$a#y, ou# studies
e$phasi7e the i$po#tant !ont#ibution o) !han"es in
synapti! plasti!ity and apoptosis #e"ulation to
patho$e!hanis$s o) 1@9, P;1-, and ,1 as well as
si"ni)i!ant input o) "eneti! )a!to#s to these !han"es
A$kno&!e"1ement
;he autho#s e?p#ess than8s to ad$inist#ation and
physi!ians o) Medi!al Psy!hiat#i! @ente#, 1t#ess @ente# o)
U.#tMedU Medi!al @ente#, and >#ebouni Medi!al @ente# o)
the Minist#y o) *ealth o) the 2epubli! o) .#$enia, P#o)
Ma#tin Pet#e8 and -# =#antise8 M#a7e8 (Pala!8y
Jni4e#sity o) Tlo$ou!, @7e!h 2epubli!) ;he studies
#e4iewed in this pape# we#e suppo#ted by the 0ational
.!ade$y o) 1!ien!es and the 1tate @o$$ittee o) 1!ien!e
o) the 2epubli! o) .#$enia, .01>= (J1.) and the
,nte#national <ise"#ad =und (>J)
4ompetin1 interests
;he autho#s de!la#e no !on)li!t o) inte#ests

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200E;1E(3):1&A-E0
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0, -ean /, 0ishi$u#a 1, 1e8i :, :ato ;, ,toha#a 1,
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and "ene e?p#ession analyses o) net#in-+1 and -+2 "enes in
s!hi7oph#enia /iol Psy!hiat#y 200A;AE(4):3'2-93
F4&G /o#" ,, =#eude :, :\ba#t 1, *o))$ann :, Men7el @, (a!!one
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1a#"an -, :als!heue# <M -is#uption o) 0et#in +1 by a
balan!ed !h#o$oso$e t#anslo!ation in a "i#l with 2ett
synd#o$e >u# N *u$ +enet 200A;13('):921-E
F4EG >astwood 1(, *a##ison PN -e!#eased $20. e?p#ession o)
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and bipola# diso#de# 0eu#opsy!hopha#$a!olo"y 200';33(4):
933-4A
F4'G Thtsu8i ;, *o#iu!hi 3, :o"a M, ,shi"u#o *, ,nada ;, ,wata 0,
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.sso!iation o) poly$o#phis$s in the haplotype blo!8
spannin" the alte#nati4ely spli!ed e?ons o) the 0;0+1 "ene
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0eu#os!i (ett 200';43A(3):194-E
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FA2G *a##ison PN, >astwood 1( P#e)e#ential in4ol4e$ent o)
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2ibbe :, =#ied#i!hs *, 2adyush8in :., >l-:o#di .,
/ensele# =, *ann8e :, 1pe#lin" 1, 1!hwe#dt)e"e# -,
;hanh]use# ,, +e#!hen M=, +ho#bani M, +utwins8i 1,
*il$es @, (eppe#t 2, 2onnenbe#" ., 1owislo N, 1tawi!8i 1,
1t^dt8e M, 17us7ies @, 2ei$ :, 2i""e#t N, >!8stein =, =al8ai
P, /i!8eb^lle# *, 0a4e :., /#ose 0, >h#en#ei!h *
Modi)i!ation o) !o"niti4e pe#)o#$an!e in s!hi7oph#enia by
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FA9G 1tanis7 .M, 1tanis7 N. 0e#4e "#owth )a!to# and
neu#oi$$une inte#a!tions in in)la$$ato#y diseases .nn 0
3 .!ad 1!i 2000;91E:2&'-E2
F&0G No!8e#s-1!he#ubl M@, 9ub#ae"el -, /ae# ;, (inden M,
-an8e#-*op)e *, 1!hulte-*e#b#u""en T, 0eu P, *ellwe" 2
0e#4e "#owth )a!to# se#u$ !on!ent#ations #ise a)te#
su!!ess)ul !o"niti4e-beha4iou#al the#apy o) "ene#ali7ed
an?iety diso#de# P#o" 0eu#opsy!hopha#$a!ol /iol
Psy!hiat#y 200E;31(1):200-4
F&1G Bion" P, 9en" 3, 9hu 9, ;an -, Bu =, (u N, Pan N, Ma M
2edu!ed 0+= se#u$ le4els and abno#$al P300 e4ent-#elated
potential in )i#st episode s!hi7oph#enia 1!hi7oph# 2es
2010;119(1-3):34-9
F&2G Bion" P, 9en" 3, N Pan N, Biaohan -*, ;an -, (u N, Bu =, (i
*3, 9hu 9, Ma M ;he #ole o) 0+= and ,(-2 se#u$ le4el in
assistin" the dia"nosis in )i#st episode s!hi7oph#enia
Psy!hiat#y 2es 2011;1'9(1):E2-&
F&3G No!8e#s-1!he#ubl M@, Matthies J, -an8e#-*op)e *, (an"
J>, Mahlbe#" 2, *ellwe" 2 @h#oni! !annabis abuse #aises
ne#4e "#owth )a!to# se#u$ !on!ent#ations in d#u"-nai4e
s!hi7oph#eni! patients N Psy!hopha#$a!ol 2003;1E(4):439-
4A
F&4G 1yed 9, -udb#id"e =, :ent ( .n in4esti"ation o) the
neu#ot#ophi! )a!to# "enes +-0=, 0+=, and 0;3 in
sus!eptibility to .-*- .$ N Med +enet / 200E;144/(3):
3EA-'
F&AG -i Ma#ia >, +io#"io >, Jliana <, /on4i!ini @, =a#a4elli =,
@a$$a#ata 1, 0o4ello M@, +ali$be#ti -, 1!a#pini >,
9anetti T, +enna#elli M, ;abaton M Possible in)luen!e o) a
non-synony$ous poly$o#phis$ lo!ated in the 0+=
p#e!u#so# on sus!eptibility to late-onset .l7hei$e#Is disease
and $ild !o"niti4e i$pai#$ent N .l7hei$e#s -is 2012;29(3):
&99-E0A
F&&G Pa#8 N:, (ee 1M, :an" P1, :i$ 1:, @ho .2 0+=
poly$o#phis$s and haplotypes a#e asso!iated with
s!hi7oph#enia in :o#ean population Mol @ell ;o?i!ol
2011;E:3EA-'0
F&EG @hen" *@, 1un 3, (ai (@, @hen 13, (ee P@, @hen N*,
@hen ;=, @hen **, Pen ((, 3ip P:, @hu 3M, @hen PN,
@hen 3@ +eneti! poly$o#phis$s o) ne#4e "#owth )a!to#
#e!epto# (0+=2) and the #is8 o) .l7hei$e#Is disease N 0e"at
2esults /io$ed 2012;11:A
F&'G +e#8e <, Moss 1> .nne?ins: )#o$ st#u!tu#e to )un!tion
Physiol 2e4 2002;'2(2):331-E1
F&9G /oe#s$a **, :ietselae# /(, 1tol8 (M, /enna"h$ou!h .,
*o)st#a (, 0a#ula N, *eidendal +., 2eutelin"spe#"e# @P
Past, p#esent, and )utu#e o) anne?in .A: )#o$ p#otein
dis!o4e#y to !lini!al appli!ations N 0u!l Med
200A;4&(12):203A-A0
FE0G Muno7 (, =#ey /, Paus!h =, /au$ P, Muelle# 2, /#a!h4o"el
/, Pos!hl >, 2odel =, 4on de# Ma#8 :, *e##$ann M, +aipl J
;he #ole o) anne?in .A in the $odulation o) the i$$une
#esponse a"ainst dyin" and dead !ells @u## Med @he$
200E;14(3):2E1-E
FE1G +aipl J1, Muno7 (>, 2odel =, Paus!h =, =#ey /, /#a!h4o"el
/, 4on de# Ma#8 :, Pos!hl > Modulation o) the i$$une
syste$ by dyin" !ells and the phosphatidylse#ine-li"and
anne?in .A .utoi$$unity 200E;40(4):2A4-9
FE2G Ma#tin M, (e))le# N, /lo$ .M .nne?in .2 and .A se#4e as
new li"ands )o# @1X on apoptoti! !ells N /iol @he$ 2012;
2'E(40):33E33-44
FE3G -i 0apoli M, .#a8elyan ., /oya%yan ., +odoy ., Papa =
@hapte# 2 ;he a!ute phase in)la$$ato#y #esponse in st#o8e:
syste$i! in)la$$ation and neu#oin)la$$ation ,n: Pit7e# N.
(ed) P#o"#ess in ,n)la$$ation 2esea#!h, 0o4a 1!ien!e
Publishe#s ,n!, J1., 200A, pp9A-14A
FE4G =#an!es!oni (P, @e#es_# :M, Mas!a#enhas 2, 1te#t7 (, +a$a
@1, /el$onte-de-.b#eu P ,n!#eased anne?in-< and de!#eased
;0=-alpha se#u$ le4els in !h#oni!-$edi!ated patients with
s!hi7oph#enia 0eu#os!i (ett 2011;A02(3):143- &
FEAG +on7`le7-@one%e#o 2, @o##al N, 2old`n <, Ma#tane7 @, Ma#an
=, 2i4e#a N, ,niesta N., (o7ano M(, Ma#!o P, <i!ente < .
!o$$on poly$o#phis$ in the anne?in < :o7a8 seCuen!e
(-1@H;) in!#eases t#anslation e))i!ien!y and plas$a le4els o)
anne?in <, and de!#eases the #is8 o) $yo!a#dial in)a#!tion in
youn" patients /lood 2002;100(&):20'1-&
FE&G <an *ee#de P(, -e+#oot P+, 2eutelin"spe#"e# @PM ;he
!o$ple?ity o) the phospholipid bindin" p#otein .nne?in <
;h#o$b *ae$ost 199A;E3(2):1E2-9
FEEG (iu @M, =ann @1, @hen @3, (iu 3(, Tyan" 3N, 3an" P@,
@han" @@, Pen @@, @hen PN, *wan" ;N, *sieh M*, (iu
@@, =a#aone 1<, ;suan" M;, *wu *+ .0B.E, PPP3@/,
-0.N@9, and 9M30-1E "enes at !h#o$oso$e 10C22
asso!iated with the sub"#oup o) s!hi7oph#enia with de)i!its in
attention and e?e!uti4e )un!tion /iol Psy!hiat#y
2011;E0(1):A1-'
FE'G 2oset 2, T#tet (, +il-+o$e7 + 2ole o) /!l-2 )a$ily
$e$be#s on apoptosis: what we ha4e lea#ned )#o$ 8no!8-out
$i!e =#ont /ios!i 200E;12:4E22-30
FE9G 3oule 2N, 1t#asse# .;he /@(-2 p#otein )a$ily: opposin"
a!ti4ities that $ediate !ell death 0at 2e4 Mol @ell /iol
200';9(1):4E-A9
F'0G :o#s$eye# 1N, 1hutte# N2, <eis -N, Me##y ->, Tlt4ai 90
/!l2//a?: a #heostat that #e"ulates an anti-o?idant pathway
and !ell death 1e$in @an!e# /iol 1993;4(&):32E-32
,nte#national Nou#nal o) +eneti!s and +eno$i!s 2014; 2(2): 19-29 29

F'1G 3an" N, (iu B, /halla :, :i$ @0, ,b#ado .M, @ai N, Pen" ;,,
Nones -P, Pan" B P#e4ention o) apoptosis by /!l-2: #elease
o) !yto!h#o$e ! )#o$ $ito!hond#ia blo!8ed 1!ien!e
199E;2EA(A303):1129-32
F'2G @hen +, Man%i *: ;he e?t#a!ellula# si"nal-#e"ulated 8inase
pathway: .n e$e#"in" p#o$isin" ta#"et )o# $ood stabili7e#s
@u## Tpin Psy!hiat#y 200&;19:313-23
F'3G @hen -=, 1!hneide# +>, Ma#tinou N@, ;one"awa 1 /!l-2
p#o$otes #e"ene#ation o) se4e#ed a?ons in $a$$alian @01
0atu#e 199E;3'A:43A-9
F'4G Nonas > /!l-?l #e"ulates synapti! plasti!ity Mol ,nte#4
200&;&:20'-22
F'AG Tltwai 90, Milli$an @(, :o#se$eye# 1N /!l2 hete#odi$e#s
in 4i4o with a !onse#4ed ho$olo" /a?, that a!!ele#ates
p#o"#a$$ed !ell death @ell 1993;E4:&09-19
F'&G 1u#hone (M, ;ennoe M;, *enssonow 1= /!l-2-asso!iated
B P#otein /eau /assin: /etas!#ipt Publishin", 2011
F'EG Na#s8o" (=, 1elin"e# >1, (iebe#$an N., +il$o#e N*
@o#ti!al /!l2 p#otein e?p#ession and apoptoti! #e"ulation in
s!hi7oph#enia /iol Psy!hiat#y 2000;4':&41-A0
F''G Na#s8o" (=, 1elin"e# >1, (iebe#$an N., +il$o#e N*
.poptoti! p#oteins in the te$po#al !o#te? in s!hi7oph#enia:
hi"h /a?//!l2 #atio without !aspase-3 a!ti4ation .$ N
Psy!hiat#y 2004;1&1:109-1A
F'9G Milani (, +upta M, .nde#sen M, -ha# 1, =#y8n]s M,
,sa8sson ., (a#sson 2, 1y4]nen .@ .lleli! i$balan!e in
"ene e?p#ession as a "uide to !is-a!tin" #e"ulato#y sin"le
nu!leotide poly$o#phis$s in !an!e# !ells 0u!lei! .!ids 2es
200E;3A(A):34
F90G :i$ -*, Bu P, Ma @, (iu B, 1i$ino4it!h :, Messne# *.,
(ipton N* +eneti! 4a#iants in the !andidate "enes o) the
apoptosis pathway and sus!eptibility to !h#oni! $yeloid
leu8e$ia /lood 2009;113(11):2A1E-2A
F91G >un 3+, *on" ,:, :i$ 1:, Pa#8 *:, :won 1, @hun" -*,
:won :* Poly$o#phis$ (#s1'0101', ;h#E;h#) o) /@(2 is
asso!iated with papilla#y thy#oid !an!e# in :o#ean population
@lin >?p Tto#hinola#yn"ol 2011;4(3):149-A4
F92G +u 1, Pu X, 9hao B, Pu P, +ao 9, ;an B, Xian N, @hen *,
Bie 3, Nin (, *an /, (u - .sso!iation o) @.1P3
poly$o#phis$ with he$atolo"i! to?i!ity in patients with
ad4an!ed non-s$all-!ell lun" !a#!ino$a t#eated with
platinu$-based !he$othe#apy @an!e# 1!i
2012;103('):14A1-9
F93G *oh 09, Pa"ne# .:, .le?ande# 1., @la#8 2/, /ee#s 12,
T8on8wo -T, 2en -, @onley 3P /@(2 "enotypes:
)un!tional and neu#obeha4io#al out!o$es a)te# se4e#e
t#au$ati! b#ain in%u#y N 0eu#ot#au$a 2010;2E('):1413-2E
F94G Man%i *: /!l-2: . 8ey #e"ulato# o) a))e!ti4e #esilien!e in
the pathophysiolo"y and t#eat$ent o) se4e#e $ood diso#de#s
/iol Psy!hiat#y 200';&3(1uppl 1):2431
F9AG 3uan P, /au$ .>, 9hou 2, Pan" 3, (a%e +, M!Mahon =N
/!l-2 poly$o#phis$s asso!iated with $ood diso#de#s and
antidep#essant-#esponsi4eness #e"ulate /!l-2 "ene
e?p#ession and !ellula# #esilien!e in hu$an ly$phoblastoid
!ell lines /iol Psy!hiat#y 200';&3(1uppl 1):&31
F9&G 1al4ado#e +, 0u"ent .@, @hen +, .8ula 0, 3uan P, @annon
-M, 9a#ate @. N#, M!Mahon =N, Man%i *:, -#e4ets P@
/!l-2 poly$o#phis$ in)luen!es "#ay $atte# 4olu$e in the
4ent#al st#iatu$ in healthy hu$ans /iol Psy!hiat#y
2009;&&('):'04-E
F9EG (iu M>, *uan" @@, *wan" NP, 3an" .@, ;u P@, 3eh *(,
*on" @N, (iou 3N, @hen N=, (in @P, ;sai 1N >))e!t o) /!l-2
#s9A&AE2 10P on #e"ional "#ay $atte# 4olu$es and !o"niti4e
)un!tion in elde#ly $ales without de$entia ."e (-o#d#)
2013;3A(2):343-A2
F9'G 1oei#o-de-1ou7a M+, 1al4ado#e +, Mo#eno 2., Ttaduy M@,
@hai$ :;, +atta7 P=, 9a#ate @. N#, Ma!hado-<iei#a 2
/!l-2 #s9A&AE2 poly$o#phis$ is asso!iated with in!#eased
ante#io# !in"ulate !o#ti!al "luta$ate in euthy$i! bipola# ,
diso#de# 0eu#opsy!hopha#$a!olo"y 2013;3'(3):4&'-EA
F99G Je$u#a ;, +#een M, @o#son ;P, Pe#o4a ;, (i PP, Pa#sh NN
/!l-2 10P #s9A&AE2 asso!iates with dis#upted int#a!ellula#
!al!iu$ ho$eostasis in bipola# , diso#de# /ipola# -iso#d
2011;13(1):41-A1