Poltavskaya et al. BMC Medical Genetics 2020, 21(Suppl 1):171
https://doi.org/10.1186/s12881-020-01107-w

RESEARCH

Open Access

Genetic polymorphisms of PIP5K2A andcourse of schizophrenia
Evgeniya G. Poltavskaya1*† , Olga Yu. Fedorenko1,2†, Natalya M. Vyalova1, Elena G. Kornetova1,
Nikolay A. Bokhan1,3,4, Anton J. M. Loonen5,6 and Svetlana A. Ivanova1,2,4
From 11th International Young Scientists School “Systems Biology and Bioinformatics” – SBB-2019
Novosibirsk, Russia. 24-28 June 2019

Abstract
Background: Schizophrenia is a severe highly heritable mental disorder. The clinical heterogeneity of schizophrenia
is expressed in the difference in the leading symptoms and course of the disease. Identifying the genetic variants
that affect clinical heterogeneity may ultimately reveal the genetic basis of the features of schizophrenia andsuggest novel treatment targets. PIP5K2A (Phosphatidylinositol-4-Phosphate 5-Kinase Type II Alpha) has been
investigated as a potential susceptibility gene for schizophrenia.
Methods: In this work, we studied the possible association between eleven polymorphic variants of PIP5K2A andthe clinical features of schizophrenia in a population of 384 white Siberian patients with schizophrenia. Genotyping
was carried out on QuantStudio 5 Real-Time PCR System with a TaqMan Validate SNP Genotyping Assay (Applied
Biosystems, USA).
Results: PIP5K2A rs8341 (χ2 = 6.559, p = 0.038) and rs946961 (χ2 = 5.976, p = 0.049) showed significant association
with course of schizophrenia (continuous or episodic). The rs8341*CT (OR = 1.63, 95% CI: 1.04–2.54) andrs946961*CC (OR = 5.17, 95% CI: 1.20–22.21) genotypes were associated with a continuous type of course, while thers8341*TT genotype (OR = 0.53, 95% CI: 0.29–0.97) was associated with an episodic type of course of schizophrenia.
Therefore rs8341*TT genotype presumably has protective effect against the more severe continuous course of
schizophrenia compared to the episodic one.
Conclusions: Our experimental data confirm that PIP5K2A is a genetic factor influencing the type of course of
schizophrenia in Siberian population. Disturbances in the phosphatidylinositol pathways may be a possible reason
for the transition to a more severe continuous course of schizophrenia.
Keywords: Schizophrenia, PIPK2A, Genetic polymorphism, Type of course, Leading symptoms* Correspondence: egboyarko@mail.ru†
Evgeniya G. Poltavskaya and Olga Yu. Fedorenko contributed equally to thiswork.
1
Mental Health Research Institute, Tomsk National Research Medical Centerof the Russian Academy of Sciences, Aleutskaya str., 4, Tomsk, RussianFederation 634014
Full list of author information is available at the end of the article© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
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Poltavskaya et al. BMC Medical Genetics 2020, 21(Suppl 1):171

Background
Schizophrenia is a severe and persistent mental disorderinvolving chronic or recurrent psychosis with a population prevalence of nearly 1% [1]. Clinical symptoms ofschizophrenia vary among individuals. The results of the
major studies on the course of the illness over 20 to 40
years of follow-up are consistent in reporting a chronic,
generally persistent course of illness for 50 to 70% of thepatients who receive an initial diagnosis of schizophrenia[2–7]. The continuous course of schizophrenia is characterized by a worse prognosis than episodic. In Ciompi’s
classic study [8] about half of patients with schizophrenia had an undulating course, with partial or full remissions followed by recurrences, in an unpredictable
pattern. About one-third had relatively chronic, unremitting course with poor outcome. In that study a minorityof patients had a steady pattern of recovery with goodoutcome. Studies on discharge indicated that about 20%
of patients don’t require re-admission, many years after
discharge. Among these studies, the Danish one [9] isparticularly interesting because the sample size and thelong follow-up. Following the first discharge, 20% of thesurviving patients had not been readmitted after 10 years
of follow-up [10].
It is long known that schizophrenia has a large genetic
component, with heritability between 64 and 81% [11,12]. It is characterized by a substantial genetic heterogeneity with contributions from common, rare, and denovo variants of a large number of genes, in addition toenvironmental factors. GWAS results indicate thatschizophrenia is a polygenic disorder, for which thousands of common genetic variants with modest individual effects act in aggregate to increase disease liability[13–15].
Recent research has considerably advanced our understanding in terms of identifying over 100 risk loci associated with schizophrenia. However, many questions
remain unanswered, including several which affect theirindividual clinical significance [16].
It is necessary to investigate the genetic architecture ofschizophrenia taking into account not only the presenceor absence of a diagnosis of schizophrenia but also theduration, type of the clinical course of disease, leading
symptoms (positive or negative) with the main goal ofidentifying reliable predictive markers as well as new
therapeutic targets that might improve the life management of patients with schizophrenia.
PIP5K2A (Phosphatidylinositol-5-Phosphate 4-Kinase,
Type II, Alpha) has been investigated as a potential susceptibility gene for schizophrenia [17–21] and antipsychotic induced tardive dyskinesia [22]. The main
product of PIP5K2A, PI(4,5) P2, is involved in transmembrane transduction of neurotransmitter signals by
regulating functions of numerous neuronal ion channels

Page 2 of 9

and transporters [23–25]. PIP5K2A upregulates the
KCNQ potassium channels [23], the glutamate transporters EAAT3 [24], and glutamate GluA1 receptor [25]via phosphatidylinositol-4,5-bisphosphate (PIP2) synthesis. KCNQ channels suppress basal activity of dopaminergic neurons and dopaminergic firing. EAAT3transporters take up excessive glutamate from the extracellular space. GluA1 receptors are some of the mostimportant excitatory receptors in the central nervous
system. It has been shown that schizophrenia linked mutation (N251S)-PIP5K2A results in reduced function of
KCNQ channels, EAAT3 transporters, GluA1 receptors
and thereby might explain the loss of dopaminergic, glutamatergic control in patients with schizophrenia carriers of this mutation [23–25]. In this work, we studied
the possible association between eleven polymorphic
variants of PIP5K2A and the clinical characteristics ofschizophrenia in a population of Caucasian Siberian patients with schizophrenia in order to establish the possible role of PIP5K2A in the clinical heterogeneity ofschizophrenia.

Methods
In this study we examined the contribution of PIP5K2A
polymorphisms to the development of the clinical features of schizophrenia, such as the leading symptoms(negative or positive) and the type of course of schizophrenia. Based upon reviewing the literature we selected
a set of eleven polymorphisms in PIP5K2A and here we
present new data on the association between them andclinical phenotypes in antipsychotic-treated patients withschizophrenia from West Siberia, Russian Federation.
Patients

The work was carried out in accordance with The Codeof Ethics of the World Medical Association (Declarationof Helsinki 1975, revised in Fortaleza, Brazil, 2013) for
experiments involving humans. In this study 384 patients from three psychiatric hospitals in Tomsk, Kemerovo, and Chita oblasts in Siberia were retrieved. The
inclusion criteria were a clinical diagnosis of schizophrenia according to ICD-10 (F20), patients aged 18–75
years, Caucasian physical appearance and a signed informed consent form to participate in the study after approval from the study (protocol N63/7.2014) from the
Local Bioethics Committee of the Mental Health Research Institute. Exclusion criteria for all patients were
non-Caucasian physical appearance (e.g., Mongoloid,
Buryats or Khakassians), organic mental disorders (e.g.,
epilepsy, Parkinson’s disease). Clinical examination anddiagnostic assessment were carried out using the Positive
and Negative Syndrome Scale (PANSS). The total PANS
S score in the group of patients with schizophrenia was
102 [92; 109] (Me [Q1; Q3]). The course of

Poltavskaya et al. BMC Medical Genetics 2020, 21(Suppl 1):171

Page 3 of 9

Table 1 Demographics and clinical characteristics of patients with schizophrenia
All (n = 384)

Male (n = 237)

Female (n = 147)

p-value*Age (mean ± SD)

42 (30–53)

39 (28–51)

47 (33–56)

0.000216

Age of beginning of disease23 (19–31)

23 (19–30)

24 (20–33)

0.116

Duration of disease, years

14.0 (7.0–25.0)

13.0 (6.0–22.0)

15.5 (8.0–30.0)

0.004*calculated with the Mann-Whitney U test

schizophrenia (continuous or episodic) was determined
by ICD-10 – in the classification of ICD-10, the fifthcharacter is used for this. Demographic and clinicalcharacteristics of patients with schizophrenia are presented in Table 1.
To study the associations between PIP5K2A polymorphisms and leading symptoms (negative or positive) the
total group of 384 patients with schizophrenia was divided into 2 subgroups according to the PANSS survey
data: a subgroup of 122 patients with leading negative
symptoms and a subgroup of 181 patients with leading
positive symptoms. The rest of the patients were not included in the comparison due to the mixed symptoms
and the lack of prevalence of positive or negative symptoms according to the PANSS. To study the role of
PIP5K2A polymorphisms in the development of thecourse of schizophrenia the total group of 384 patientswith schizophrenia was divided into 2 subgroups: a subgroup of 269 patients with continuous course of schizophrenia and a subgroup of 115 patients with episodic
course of the disease.
Blood samples were taken 8 h after overnight fasting intubes containing EDTA and stored in several aliquots at-20 °C until DNA isolation.

DNA analysis

DNA was isolated from the leukocytes in whole peripheral blood from patients with schizophrenia using thestandard phenol-chloroform method. During SNPs selection we were guided by two criteria: a) relevance of
selected SNPs to associations with schizophrenia andother mental disorders according to the literature data;b) the minor allele frequency (MAF) of selected SNPs
should have been 0.05 (5%) or greater. Information on
the selected SNPs for PIP5K2A is presented in Additional file 1. Genotyping of PIP5K2A polymorphisms(rs10828317, rs8341, rs746203, rs10430590, rs946961,
rs1132816, rs1417374, rs943190, rs943194, rs1171506,
rs11013052) was carried out on QuantStudio 5 RealTime PCR System with a TaqMan Validate SNP Genotyping Assay (Applied Biosystems, USA). Experimental
studies were carried at the core facilities centre of research equipment and experimental biological material“Medical genomics” of Tomsk National Research Medical Center.

Statistical analysis

Statistical analysis was performed using SPSS software forWindows, release 21. The genotypes were checked for
Hardy–Weinberg equilibrium using chi-square test. Chisquare test and the Fisher’s exact test, where necessary,
were used for between-group comparisons of genotypes
or allele frequencies. Pairwise linkage disequilibrium (LD)was computed in Haploview program, version 4.2 [26].
The parameters for LD computation include the correlation coefficient (r2), haplotype estimation using accelerated EM algorithm similar to the partition/ligation
method described in Qin et al., 2002 [27].

Results
Association of PIP5K2A polymorphisms with leading(positive vs. negative) symptoms of schizophrenia

The frequency and haplotype analysis found no difference between genotypes and alleles of PIP5K2A polymorphisms in patients with schizophrenia with negative
leading symptoms and those with positive leading symptoms (Additional file 2).
Association of PIP5K2A polymorphisms with type ofcourse (continuous vs. episodic) of schizophrenia

From the list of eleven SNPs studied for PIP5K2A
rs8341 (χ2 = 6.559, p = 0.038) and rs946961 (χ2 = 5.976,
p = 0.049) showed significant association with course of
schizophrenia (continuous or episodic). The rs8341*CT(OR = 1.63, 95% CI: 1.04–2.54) and rs946961*CC (OR =5.17, 95% CI: 1.20–22.21) genotypes were associatedwith a continuous type of course, while the rs8341*TT
genotype (OR = 0.53, 95% CI: 0.29–0.97) was associatedwith an episodic type of course of schizophrenia(Table 2). Therefore rs8341*TT genotype presumably
has protective effect against the more severe continuous
course of schizophrenia compared to the episodic one.
We also did PIP5K2A haplotype analysis for these variants in pairs, and a significant difference was observed
for several haplotypes (Table 3). After the detected haplotypes were adjusted for multiple comparisons (10,000
permutations), there was no significant difference in the
distribution for them.

Discussion
Several independent linkage studies using different family samples have suggested that the chromosome regionPoltavskaya et al. BMC Medical Genetics 2020, 21(Suppl 1):171

Page 4 of 9

Table 2 Frequency distribution of genotypes and alleles of PIP5K2A polymorphisms in patients with schizophrenia with different
types of course of the disease
SNP

rs10828317

rs8341

rs746203

rs10430590

rs946961

rs1132816

rs1417374

rs943190

Genotype
AlleleFrequency
Group ofpatients with a continuous
course of schizophrenia(n = 269)

Group ofpatients with an episodic
course of schizophrenia(n = 115)

CC

0.187

0.175

CT

0.403

0.412

TT

0.410

0.412

C

0.388

0.382

Chi-squarep-value

0.072

0.965

OR

Cl 95%

1.08

0.61–1.91

0.96

0.62–1.50

0.99

0.64–1.55

0.030

0.870

1.03

0.75–1.41

0.97

0.71–1.34

6.559

0.038

0.85

0.54–1.32

T

0.612

0.618

CC

0.387

0.426

CT

0.502

0.383

1.63

1.04–2.54

TT

0.112

0.191

0.53

0.29–0.97

C

0.638

0.617

T

0.362

0.383

CC

0.133

0.195

CT

0.494

0.381

TT

0.373

0.425

C

0.380

0.385

0.280

4.756

0.600

0.093

0.010

0.900

1.754

0.416

1.09

0.79–1.50

0.92

0.67–1.26

0.63

0.35–1.14

1.59

1.01–2.50

0.80

0.51–1.26

0.98

0.71–1.35

1.02

0.74–1.41

0.76

0.46–1.25

T

0.620

0.615

AA

0.467

0.437

AT

0.434

0.402

1.14

0.68–1.89

TT

0.099

0.061

1.70

0.62–4.60

A

0.684

0.738

T

0.316

0.262

CC

0.108

0.023

CG

0.478

0.529

GG

0.414

0.448

C

0.347

0.287

1.690

5.976

0.190

0.049

2.100

0.150

1.959

0.376

0.77

0.52–1.14

1.30

0.87–1.94

5.17

1.20–22.21

0.82

0.50–1.33

0.87

0.53–1.42

1.32

0.91–1.92

0.76

0.52–1.10

0.75

0.45–1.26

G

0.653

0.713

AA

0.621

0.685

AG

0.294

0.270

1.13

0.66–1.94

GG

0.085

0.045

1.97

0.66–5.89

A

0.768

0.820

G

0.232

0.180

AA

0.129

0.151

AG

0.469

0.349

GG

0.402

0.500

A

0.363

0.326

2.080

3.735

0.150

0.154

0.780

0.380

5.326

0.070

0.73

0.47–1.12

1.38

0.89–2.13

0.83

0.41–1.67

1.65

0.99–2.75

0.67

0.41–1.10

1.18

0.82–1.71

0.85

0.59–1.22

0.57

0.30–1.08

G

0.637

0.674

CC

0.131

0.209

CT

0.502

0.372

1.70

1.03–2.81

TT

0.367

0.419

0.80

0.49–1.32

C

0.382

0.395

T

0.618

0.605

0.090

0.760

0.95

0.66–1.35

1.06

0.74–1.51

Poltavskaya et al. BMC Medical Genetics 2020, 21(Suppl 1):171

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Table 2 Frequency distribution of genotypes and alleles of PIP5K2A polymorphisms in patients with schizophrenia with different
types of course of the disease (Continued)
SNP

rs943194

rs1171506

rs11013052

Genotype
AlleleFrequency
Group ofpatients with a continuous
course of schizophrenia(n = 269)

Group ofpatients with an episodic
course of schizophrenia(n = 115)

GG

0.118

0.123

GT

0.489

0.444

TT

0.392

0.432

G

0.363

0.346

Chi-squarep-value

0.506

0.776

0.160

0.690

2.938

0.230

OR

Cl 95%

0.95

0.44–2.06

1.20

0.72–1.99

0.85

0.51–1.42

1.08

0.74–1.57

0.93

0.64–1.35

2.80

0.82–9.55

T

0.637

0.654

AA

0.097

0.037

AG

0.413

0.432

0.92

0.56–1.54

GG

0.490

0.531

0.85

0.51–1.40

A

0.304

0.253

G

0.696

0.747

AA

0.083

0.048

AC

0.365

0.333

CC

0.552

0.619

A

0.266

0.214

C

0.734

0.786

1.510

0.220

1.762

0.414

1.770

0.180

1.29

0.86–1.93

0.78

0.52–1.16

1.82

0.61–5.46

1.15

0.68–1.94

0.76

0.46–1.25

1.33

0.87–2.02

0.75

0.50–1.14

Bold text indicates p-value< 0.05

Table 3 Association of PIP5K2A haplotypes with course of schizophrenia
SNPs

Haplotype

Frequency

Group 1, Group 2 frequencies

Chi square

Pasym

PPerm

rs736203/rs943190

TT

0.571

0.565, 0.585

0.269

0.60430.9971CC

0.342

0.332, 0.366

0.836

0.3606

0.9437TC

0.046

0.053, 0.031

1.715

0.19040.7448rs10430590/rs1132816

rs943190/rs1132816

rs11013052/rs1132816

rs1132816/rs943194

CT

0.040

0.050, 0.018

4.463

0.03460.2097AA

0.570

0.557, 0.608

1.397

0.23720.5328TA

0.211

0.211, 0.212

0.001

0.9750

1.0

AG

0.127

0.128, 0.126

0.005

0.94510.9998TG

0.091

0.104, 0.054

3.990

0.04580.1130TA

0.497

0.501, 0.487

0.108

0.74300.9812CA

0.285

0.268, 0.334

2.827

0.09270.2276TG

0.117

0.117, 0.119

0.008

0.93090.9998CG

0.101

0.115, 0.061

4.276

0.0386

0.0946CA

0.643

0.632, 0.675

1.075

0.29980.6804AA

0.139

0.137, 0.145

0.079

0.77910.9898AG

0.114

0.129, 0.073

4.119

0.04240.1423CG

0.104

0.103, 0.107

0.029

0.86520.9973AG

0.606

0.595, 0.637

1.004

0.31630.9144AC

0.175

0.173, 0.183

0.099

0.75350.9998GC

0.175

0.175, 0.103

5.158

0.02310.1419GG

0.063

0.058, 0.077

0.786

0.37540.9502

Pasym - asymptotic P value, PPerm - empirical P value for 10,000 permutations. Group 1 – group of patients with continuous course of schizophrenia (n = 269),
Group 2 – group of patients with episodic course of schizophrenia (n = 115). Bold text indicates p-value< 0.05

Poltavskaya et al. BMC Medical Genetics 2020, 21(Suppl 1):171

where PIP5K2A locates is schizophrenia susceptible[28–42]. Many neurotransmitter receptors which havebeen attributed to schizophrenia are connected to thephosphatidylinositol (PI) pathway, and genes involvedin the PI pathway are potential candidates for schizophrenia susceptibility. PIP5K2A is an important enzyme in the PI pathway, and is therefore significant
for schizophrenia study [19]. PIP5K2A has beenshown to be associated with schizophrenia [17–21].
However, the effect of PIP5K2A polymorphisms on
the clinical manifestations of the disease has been little investigated. In this study, the course of schizophrenia was studied and attempted to identify
associations of genetic polymorphisms of the PIP5K2A
with the type of course of schizophrenia and the leading symptoms.
PIP5K2A is located on chromosome 10 (Fig. 1). The
length of the region comprising the studied polymorphisms is 303 kb.
Only two of the investigated SNPs in this study are located in the exons; they are 10,828,317 in exon 7 andrs1132816 in exon 1. The rest of the studied SNPs arelocated in intergenic/non-coding regions. However,these polymorphisms are also important. Several association studies have investigated the relationship between
genetic variants at PIP5K2A and schizophrenia. Sewekow
et al. (2003) investigated the linkage region on chromosome 10p12 by analyzing 55 densely spaced genetic variants in 71 schizophrenia families of German origin andfound two SNPs rs10828317 and rs1417374 to be significantly associated with schizophrenia [43]. A familybased transmission disequilibrium test involving subjects
from the German and Israeli populations found that
SNPs rs1417374, rs10828317, rs11013052, rs943190,
rs10430590, rs746203 and rs8341 in PIP5K2A are significantly associated with schizophrenia [17].
In our work from the list of eleven SNPs studied for
PIP5K2A none contributed to the development of leading symptoms (positive or negative) of schizophrenia.
We obtained data on the association of two SNPs rs8341
and rs946961 with the type of course of schizophrenia(continuous or episodic). The rs8341*CT andrs946961*CC genotypes were associated with a continuous type of course, while the rs8341*TT genotype wasassociated with an episodic type of course of schizophrenia. Therefore rs8341*TT genotype presumably has

Fig. 1 Localization of the PIP5K2A gene on chromosome 10

Page 6 of 9protective effect against the more severe continuous
course of schizophrenia compared to the episodic one.
Figure 2 represents the Linkage disequilibrium (LD)plot showing the positions of eleven PIP5K2A polymorphisms in patients with schizophrenia. LD measures
were made with the program Haploview version 4.2.
A linkage disequilibrium pattern was performed for 11
SNPs. The highest value of D’ (0,976) and r2 (0.9) was
for rs8341 and rs946961 polymorphisms. A haplotype
analysis was performed for these SNPs, but we did not reveal any significant associations with the studied clinicalcharacteristics of schizophrenia. In the pairwise analysis of
haplotypes, data were obtained on the association of fivedifferent haplotypes with the course of schizophrenia.
However, after conducting permutation tests, the p level
did not reach the significance level. Nevertheless, the dataobtained leave open the question about the significance ofthe polymorphisms included in these haplotypes in the development of the clinical picture of the disease. It is interesting that a synonymous mutation rs1132816 (triplet
TST, encoded by serine, is replaced by TCC) is amongfour of these five haplotypes. Currently, it is believed thatsynonymous mutations do not affect the function of theprotein, since they do not change the amino acid that is
encoded by the modified part of the gene. But there is apossibility that such a mutation matters at the stages oftranscription or translation of a protein, in any way changing the rate of percentages or the frequency of errors.
Nevertheless, it is clear from the data obtained that the
rs1132816 polymorphism does not have sufficient power
for an independent effect on the course of schizophrenia.
Thus, we received confirmation of participation only
rs8341 and rs946961 in the development of the schizophrenia clinical phenotypes. PIP5K2A controls the function of neuronal KCNQ potassium channels via
phosphatidylinositol-4,5-bisphosphate (PIP2) synthesis[23], which suppress basal activity of dopaminergic neurons and dopaminergic firing. Therefore PIP5K2A modulation of KCNQ potassium channels might influence well
dopaminergic neurotransmission in schizophrenia [44].
This regulation could be disrupted in mutant forms of
PIP5K2A, which may contribute to the schizophrenia
phenotype. Moreover, PIP5K2A is a signaling element in
the glutamatergic system regulation, specifically it upregulates glutamate transporter EAAT3 [24], which takes up
glutamate from the extracellular space, and glutamate

Poltavskaya et al. BMC Medical Genetics 2020, 21(Suppl 1):171

Page 7 of 9

Fig. 2 Linkage disequilibrium (LD) pattern for the 11 PIP5K2A variants identified in Russian population of patients with schizophrenia. The plot
was generated using Haploview 4.2. Pairwise r2 values are shown in diamonds that represent the pairwise LD between the 2 SNPs at the top left
and right of the corresponding diamond. Colour Scheme: White, shades of pink for D’ < 1; bright red for D’ = 1

GluA1 receptor [25]. It was shown that functionally impaired kinase like PIP5K2A(N251S) may disturb local
PIP2 compositions leading to down regulation of EAAT3[24], and GluA1 [25] and thus be partially effective
through deranged glutamate metabolism in the brain of
schizophrenic patients carrying this mutation. We assume
that this could at least in theory be true for the studied
SNPs. Disturbances of the PI path may be a possible reason for the transition to a more severe continuous courseof schizophrenia. However, clarification of its possible rolein the etiology of schizophrenia will require further
studies.

Supplementary information

Conclusions
In conclusion, we found an association of type ofcourse (continuous or episodic) of schizophrenia with
PIP5K2A rs8341 and rs946961 that confirms PIP5K2A
to be a genetic factor influencing the type of courseof schizophrenia in Siberian population. Strength of
our study is the relatively large patient population. A
relative weakness is understudying of other risk variants of PIP5K2A. Disturbances in the phosphatidylinositol pathways may be a possible reason
for the transition to a more severe continuous courseof schizophrenia. A further search for genetic markers
associated with the development of clinical phenotypes in schizophrenia is needed.

Acknowledgements
This work was carried out within the framework of Tomsk Polytechnic
University Competitiveness Enhancement Program.

Supplementary information accompanies this paper at https://doi.org/10.
1186/s12881-020-01107-w.
Additional file 1. Information on the selected SNPs for PIP5K2A.
Additional file 2. PIP5K2A SNPs in positive vs. negative schizophrenia
symptoms.
Abbreviations
BDNF: brain derived neurotrophic factor; CI: Lower and upper bound 95%
confidence intervals; CNP: 2′3’-cyclonucleotide 3′-phosphodiesterase;
HWE: Hardy-Weinberg equilibrium; ICD-10: International Statistical
Classification of Diseases and Related Health Problems 10th Revision;
LD: Linkage disequilibrium; OR: Odds ratio; PI: phosphatidylinositol;
PIP5K2A: Phosphatidylinositol-4-Phosphate 5-Kinase Type II Alpha; SNP: Single
nucleotide polymorphism

About this supplement
This article has been published as part of BMC Medical Genetics Volume 21
Supplement 1, 2020: Selected Topics in “Systems Biology and Bioinformatics”- 2019: medical genetics. The full contents of the supplement are available
online at https://bmcmedgenet.biomedcentral.com/articles/supplements/
volume-21-supplement-1.
Authors’ contributions
SI and AL instigated, designed, coordinated, and supervised the study. EP
designed and performed the statistical analysis and contributed to writing
the paper. OF wrote the study protocol, selected the SNPs, and contributed
to writing the paper. EP, NV, EK, and OF monitored the study, collectedclinical data, and isolated DNA. EP and NV genotyped the samples andrecorded all data in an Excel database. NB and EK supervised the clinicalPoltavskaya et al. BMC Medical Genetics 2020, 21(Suppl 1):171

Page 8 of 9work. EP drafted the manuscript. SI and AL supervised the writing. OF
commented on the manuscript. All authors read the paper and agree with
its content.

9.

Funding
This work was in part supported by the Russian Foundation for Basic
Research, grant # 18–315-20019. The funding bodies played no role in thedesign of this study and collection, analysis, and interpretation of data and inwriting of the manuscript. Publication costs for this article have been fundedby authors.

10.

Availability of data and materials
The data generated in current study is available in the public repository byidentifier https://doi.org/10.6084/m9.figshare.12525401.
Ethics approval and consent to participate
This work was performed in accordance with The Code of Ethics of theWorld Medical Association for experiments involving humans (Declaration of
Helsinki 1975, revised in Fortaleza, Brazil, 2013). All participants gave theirsigned informed consent to participate, and the study was approved by the
Local Bioethics Committee of the Mental Health Research Institute (protocol
N63/7.2014).

11.

12.

13.

14.

15.
Consent for publication
Not applicable.
16.
Competing interests
The authors declare that they have no competing interests.
17.
Author details
1
Mental Health Research Institute, Tomsk National Research Medical Centerof the Russian Academy of Sciences, Aleutskaya str., 4, Tomsk, RussianFederation 634014. 2National Research Tomsk Polytechnic University, Tomsk,
Russian Federation. 3National Research Tomsk State University, Tomsk,
Russian Federation. 4Siberian State Medical University Hospital, Moscowsky
Trakt, 2, Tomsk, Russian Federation. 5Groningen Research Institute ofPharmacy, PharmacoTherapy, Epidemiology & Economics, University ofGroningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands.
6
GGZ Westelijk Noord-Brabant, Hoofdlaan 8, 4661 AA Halsteren, The
Netherlands.

18.

19.

20.
Published: 22 October 2020
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