Tachi et al. International Journal of Bipolar Disorders
https://doi.org/10.1186/s40345-023-00307-6

International Journal of Bipolar
Disorders(2023) 11:26

Open Access

RESEARCH

Mitochondrial genetic variants associatedwith bipolar disorder and Schizophrenia in a
Japanese population
Ryobu Tachi1, Kazutaka Ohi2,3*, Daisuke Nishizawa4, Midori Soda5, Daisuke Fujikane2, Junko Hasegawa4,
Ayumi Kuramitsu2, Kentaro Takai2, Yukimasa Muto2, Shunsuke Sugiyama2, Kiyoyuki Kitaichi5, Ryota Hashimoto6,
Kazutaka Ikeda4 and Toshiki Shioiri2
Abstract
Background Bipolar disorder (BD) and schizophrenia (SZ) are complex psychotic disorders (PSY), with both
environmental and genetic factors including possible maternal inheritance playing a role. Some studies haveinvestigated whether genetic variants in the mitochondrial chromosome are associated with BD and SZ. However,
the genetic variants identified as being associated are not identical among studies, and the participants were limited
to individuals of European ancestry. Here, we investigate associations of genome-wide genetic variants in the
mitochondrial chromosome with BD, SZ, and PSY in a Japanese population.
Methods After performing quality control for individuals and genetic variants, we investigated whether
mitochondrial genetic variants [minor allele frequency (MAF) > 0.01, n = 45 variants) are associated with BD, SZ, and
PSY in 420 Japanese individuals consisting of patients with BD (n = 51), patients with SZ (n = 172), and healthy controls(HCs, n = 197).
Results Of mitochondrial genetic variants, three (rs200478835, rs200044200 and rs28359178 on or near NADH
dehydrogenase) and one (rs200478835) were significantly associated with BD and PSY, respectively, even after
correcting for multiple comparisons (PGC=0.045–4.9 × 10− 3). In particular, individuals with the minor G-allele of
rs200044200, a missense variant, were only observed among patients with BD (MAF = 0.059) but not HCs (MAF = 0)
(odds ratio=∞). Three patients commonly had neuropsychiatric family histories.
Conclusions We suggest that mitochondrial genetic variants in NADH dehydrogenase-related genes may contributeto the pathogenesis of BD and PSY in the Japanese population through dysfunction of energy production.
Keywords Bipolar disorder, Schizophrenia, Mitochondria, Genetic variant, Family history*Correspondence:
Kazutaka Ohi
k_ohi@gifu-u.ac.jp
1
School of Medicine, Gifu University, Gifu, Japan2
Department of Psychiatry, Gifu University Graduate School of Medicine,Gifu, Japan3
Department of General Internal Medicine, Kanazawa Medical University,
Ishikawa, Japan

4

Addictive Substance Project, Tokyo Metropolitan Institute of Medical
Science, Tokyo, Japan
5
Laboratory of Pharmaceutics, Department of Biomedical Pharmaceutics,
Gifu Pharmaceutical University, Gifu, Japan
6
Department of Pathology of Mental Diseases, National Institute of
Mental Health, National Center of Neurology and Psychiatry, Kodaira,Tokyo, Japan© The Author(s) 2023. 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 appropriate credit to the original author(s) andthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in thisarticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not includedin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Tachi et al. International Journal of Bipolar Disorders(2023) 11:26

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Introduction
Bipolar disorder (BD) and schizophrenia (SZ) are severe
and chronic psychotic disorders (PSY) with a lifetime
prevalence of approximately 1% (Grande et al. 2016; Sahaet al. 2005). BD and SZ have high heritability of approximately 80% (McGuffin et al. 2003; Sullivan et al. 2003). To
date, the largest-scale genome-wide association studies(GWASs) have reported 64 and 287 genetic loci associated with BD and SZ, respectively (Mullins et al. 2021;
Trubetskoy et al. 2022). Moreover, these PSY extensively
share genetic factors with BD and SZ (Ohi et al. 2022b;
Ruderfer et al. 2018; Smeland et al. 2020), though eachdisorder has disorder-specific genetic factors (Ruderfer et
al. 2018). Most GWASs have focused on autosomal and/or sex chromosomes, and the genetic etiology for BD andSZ remains to be fully resolved.
Higher rates of PSY are observed in offspring of maternal probands compared to offspring of paternal probands with BD (McMahon et al. 1995) and SZ (Verge etal. 2011; Wolyniec et al. 1992). Therefore, several studies
have investigated genetic associations with PSY comprising BD and SZ of variants in the chromosome of mitochondria, the energy-producing structures within cells,
but not in autosomal and sex chromosomes (Gonçalves
et al. 2018; Hagen et al. 2018; Kato et al. 2000; MosqueraMiguel et al. 2012; Munakata et al. 2004; Ryu et al. 2018;
Sequeira et al. 2012; Xu et al. 2017; Zhang et al. 2014).
However, the mitochondrial genetic variants examinedin these studies were selected based on a candidate geneapproach, and the examined mitochondrial genetic variants were inconsistent among studies (Gonçalves et al.
2018; Hagen et al. 2018; Kato et al. 2000; Munakata et al.
2004; Ryu et al. 2018; Sequeira et al. 2012). Furthermore,
results were also inconsistent among studies because of
relatively small sample sizes.
To date, a limited number of studies have investigated genetic associations with BD and SZ of genomewide genetic variants in the mitochondrial chromosome(n = 220–465 variants) (Gonçalves et al. 2018; Hagen et al.
2018; Hudson et al. 2014; Sequeira et al. 2012) (summarized in Supplementary Table 1). These studies have identified several mitochondrial genetic variants associatedwith BD (rs28357375 and rs28357968 in 965 patientswith BD and 3,938 controls (Sequeira et al. 2012) andSZ (rs527236209, rs869096886 and rs1599988 in 4,778
patients with SZ and l5,819 controls (Gonçalves et al.
2018), rs2854131, rs2853503, rs2853504, rs193302985
and rs2853506 in 2,019 patients with SZ and 15,302 controls (Hudson et al. 2014), rs193302985 and rs2853506
in 2,538 patients with SZ and 23,743 controls (Hagen
et al. 2018), rs3937033 and rs2857291 in 1,137 patientswith SZ and 3,938 controls (Sequeira et al. 2012). Furthermore, a study investigated associations of mitochondrial genetic variants with PSY in BD and SZ and

identified some genetic variants (rs2857291, rs28357968,
rs28380140, rs3088053 and rs2853497) related to PSY in
2,102 patients with PSY and 3,938 controls (Sequeira etal. 2012). However, these genetic variants are not identical among studies. Furthermore, the investigated individuals were limited to those of European ancestry. The
minor allele frequencies (MAF) of most of these genetic
variants are < 1% in the Asian population (Supplementary
Table 1).
Mitochondria are essential intracellular organelles thatharbor original haploid genomes. Mitochondria play a
crucial role in oxidative phosphorylation. In humans,
thirteen proteins related to oxidative phosphorylation
are synthesized from an approximately 16,600 bp of themitochondrial genome. On the other hand, mitochondria
are sources of free radicals. As their DNA does not havehistones or effective repair mechanisms, it is particularly
susceptible to certain stress-induced damage. Mitochondrial dysfunction can cause dysfunction of the central
nervous system, which demands high energy. Associations between mitochondrial dysfunctions and PSY havebeen investigated (Nishimura et al. 2021; Wu et al. 2019),
with hypotheses that mitochondrial dysfunctions affectsynaptic, energic and metabolic pathways, resulting in SZ
and BD (Giménez-Palomo et al. 2021; Morris et al. 2020;
Steckert et al. 2010).
Although most previous studies have targeted European populations (Gonçalves et al. 2018; Hagen etal. 2018; Hudson et al. 2014; Sequeira et al. 2012), we
hypothesized that common mitochondrial genetic variants are associated with BD and SZ in both Europeanand Asian populations but that some mitochondrial
genetic variants might be associated with BD and SZ
only in Asian populations. In this study, we investigatedpossible associations of genome-wide genetic variants(MAF > 0.01, n = 45 variants) in the mitochondrial chromosome with BD, SZ, and PSY in a Japanese population.
Furthermore, we investigated common characteristics
among the patients who carried specific mitochondrial
genetic variants.

Methods
Sample description

The subjects consisted of 51 patients with BD (23males/28 females; mean age ± SD: 54.5 ± 16.8 years), 172
patients with SZ (77 males/95 females; 45.3 ± 14.0 years),and 197 HCs (129 males/68 females; 35.6 ± 13.8 years).
The patients were recruited from both outpatient andinpatient populations at Kanazawa Medical University
Hospital and related psychiatric hospitals. These participants were recruited from the Schizophrenia NonAffected Relative Project (SNARP) (Kataoka et al. 2020;
Ohi et al. 2017, 2019, 2020a, b, 2021) and the Bipolar &Schizophrenia Network on Intermediate Phenotypes

Tachi et al. International Journal of Bipolar Disorders(2023) 11:26

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in Japan (B-SNIP-J) (Ohi et al. 2022a; Ohi et al., 2022c)
All SZ patients (n = 172) and HCs (n = 197) who participated in a previous study (Ohi et al. 2020b, 2022b) were
included in the current study. Each patient was diagnosed by at least two trained psychiatrists based on
unstructured clinical interviews, medical records, andclinical conferences. The patients were diagnosed according to the criteria in the fifth edition of Diagnostic andStatistical Manual of Mental Disorders (DSM-5). HCs
were recruited through local advertisements and fromamong hospital staff at Kanazawa Medical University
and were also evaluated using the nonpatient versionof Structured Clinical Interview for DSM-IV (SCID) to
exclude individuals who had current or past contact withpsychiatric services, who had received psychiatric medication or who had a family history of any neuropsychiatric diseases among second-degree relatives. Imipramine
equivalents of total antidepressants (IMI-eq), diazepam
equivalents (DZ-eq), chlorpromazine equivalents of total
antipsychotics (CPZ-eq), and biperiden equivalents of
total antiparkinsonian drugs (BPD-eq) were calculated
based on a previous study (Inada and Inagaki 2015). Current clinical symptoms were evaluated using the 17-item
Hamilton Rating Scale for Depression (HAMD-17), theYoung Mania Rating Scale (YMRS), and the Positive and
Negative Syndrome Scale (PANSS). The premorbid IQ
was evaluated using JART (Matsuoka et al. 2006), whichis the Japanese version of the National Adult Resulting Test (NART). The demographic variables among
the three groups are summarized in Table 1. Written
informed consent was obtained from all participants
after the procedures had been thoroughly explained. This

study was performed in accordance with the Declarationof Helsinki from the World Medical Association and wasapproved by the Research Ethical Committees of Gifu
University and Kanazawa Medical University.
Genotyping and quality control

A detailed description of the genotyping and quality control (QC) applied in the study has been reported previously (Ohi et al. 2020a, b, 2021). Briefly, venous blood
was collected from the participants, and genomic DNA
was extracted from whole-blood samples. Genotyping
was performed using Infinium OmniExpressExome-8
v1.4 or v1.6 BeadChips (Illumina, San Diego, CA, USA).
After QC for removing subjects with high missing genotype rates (> 95%) and sex chromosome anomalies andgenetic variants deviating from Hardy-Weinberg equilibrium (HWE) (p < 1.0 × 10− 5) or having a low MAF < 0.01
(Ohi et al. 2020b, 2022b), only genetic variants in the
mitochondrial chromosome were extracted from thewhole-genome genotyping data using PLINK v1.90 beta.
As the sample sizes for each diagnostic group were different, the different sample size, especially smaller sample
size, would affect the SNP QC including lower MAF (e.g.,0.001–0.05) and excess SNPs might be excluded for combined diagnostic comparison group (PSY vs. HCs). Thus,
we also performed SNP QC procedure for each diagnostic comparison group (BD vs. HCs, and SZ vs. HCs). For
mitochondrial genetic variants (n = 80), those that deviated from HWE (p < 1.0 × 10− 5), had a low MAF < 0.01, or
had a poor genotype call rate (< 0.95) were excluded fromeach diagnostic comparison group (BD vs. HCs, and SZ

Table 1 Demographic characteristics of patients with BD, patients with SZ, and HCs.
Variables
Age (years)
Sex (male/female)
Education (years)
Estimated premorbid IQ
IMI-eq (mg/day)DZ-eq (mg/day)
CPZ-eq (mg/day)
BPD-eq (mg/day)
Age at onset (years)
DOI (years)
HAMD-17YMRSPANSS positive symptoms
PANSS negative symptoms

HCs(n = 197)
35.6 ± 13.8
129/6816.2 ± 2.4
108.9 ± 7.4-

BD(n = 51)54.5 ± 16.8
23/28
13.5 ± 3.0
100.8 ± 11.3
45.9 ± 99.2
6.1 ± 10.4
152.9 ± 213.3
0.1 ± 0.6
37.0 ± 16.2
17.5 ± 14.1
8.5 ± 5.9
1.7 ± 4.5-

SZ
(n = 172)45.3 ± 14.0
77/95
12.5 ± 2.2
98.2 ± 11.0
4.9 ± 27.0
6.2 ± 11.3
523.3 ± 511.4
0.8 ± 2.3
27.0 ± 11.0
18.1 ± 12.7
16.5 ± 6.2
19.4 ± 7.0

P values (F or χ2)
6.79 × 10− 18(43.5)
1.25 × 10− 4(18.0)
7.60 × 10− 41(116.2)
7.29 × 10− 22(55.3)
2.06 × 10− 6(23.8)
0.96 (< 0.1)
9.80 × 10− 7(27.7)
0.045 (4.1)
9.19 × 10− 7(25.5)
0.76 (0.1)-

post hoc
HCs < SZ < BD
HCs > BD > SZ
HCs > BD,SZ-

HCs, healthy controls; BD, bipolar disorder; SZ, schizophrenia; IQ, intelligence quotient; IMI-eq, imipramine equivalents of total antidepressants; DZ-eq, diazepam
equivalents; CPZ-eq, total antipsychotic dosage in chlorpromazine equivalents; BPD-eq, biperiden equivalents of total antiparkinsonian drugs; DOI, durationof illness; HAMD-17, 17-item Hamilton Rating Scale for Depression; YMRS, Young Mania Rating Scale; PANSS, Positive and Negative Syndrome Scale. Complete
demographic information was not obtained for all subjects (number of participants for which the estimated premorbid IQ was available: HCs, n = 177; BD, n = 46; SZ,
n = 168; number of participants for which the HAMD-17 was available: BD, n = 47). Means ± SDs are shown. P values < 0.05 are shown in boldface, and post hoc analysis
was performed

Tachi et al. International Journal of Bipolar Disorders(2023) 11:26

Page 4 of 10

vs. HCs) as well as a combined diagnostic comparisongroup (PSY vs. HCs).

(PSY vs. HC, BD vs. HC, or SZ vs. HC) were variants
with lower MAF (e.g., 0.001–0.05) in patients or in HCs.
LD relationships between mitochondrial genetic variants
in each diagnostic group are provided in Supplementary
Fig. 1. Overall, linkage disequilibrium (LD) patterns weresimilar among the three groups.
We first investigated genetic associations between
mitochondrial genetic variants and PSY consisting of BD and SZ. Of 42 genetic variants, the allelicfrequencies of six genetic variants (rs199713564,
rs200999343, rs200478835, rs28359178, rs200786872,
andrs201250154)
differed
betweenpatients
with PSY and HCs (Table 2; Fig. 1, χ2 = 4.5–7.8,
Puncorr=0.033–5.17 × 10− 3). After correcting for multiple
comparisons, only the association with rs200478835 wassignificant (PGC=0.045), with other associations being notsignificant (PGC>0.05). The MAF of the genetic variant(rs200478835) was higher in patients with PSY than inHCs.
We next investigated genetic associations of mitochondrial genetic variants with BD and SZ separately. Of 42 genetic variants, the allelic frequencies
of five (rs111033179, rs200165736, rs200478835,
rs200044200, and rs28359178) differed between
patients with BD and HCs (Table 2; Fig. 1, χ2 = 4.0–11.7,
Puncorr=0.047–6.15 × 10− 4). Even after correcting for multiple comparisons, three genetic variants (rs200478835,
rs200044200 and rs28359178) were significantly
associated with BD (PGC=0.034–4.9 × 10− 3), with nosignificant associations with the other two genetic variants (PGC>0.05). The MAFs of those genetic variants(rs200478835, rs200044200 and rs28359178) were higher
in patients with BD than in HCs. Of the 38 genetic variants, the allelic frequencies of three (rs199713564,
rs200478835, and rs201250154) differed between
patients with SZ and HCs (Table 2; Fig. 1, χ2 = 4.4–6.4,
Puncorr=0.035–0.011). However, there were no significant
genetic variants associated with SZ after correcting for
multiple comparisons (PGC>0.05).

Statistical analyses

Statistical analyses for demographic variables were performed using IBM SPSS Statistics 28.0 software (IBMJapan, Tokyo, Japan). Differences in continuous variables, such as age and years of education, among diagnostic groups were analyzed using analysis of variance(ANOVA). Differences in categorical variables, such assex, were analyzed using Pearson’s χ2 test. Genetic analyses were performed in PLINK. Differences in allele frequency between PSY and HCs, BD and HCs, and SZ and
HCs were analyzed using the χ2 test. To test for the existence of genetic structure in the data, we have performeda principal component analysis (PCA), and the first
10 principal components (PCs) were calculated using
PLINK [see Supplementary Figure S1 in our previous
study (Ohi et al. 2020b)]. We have confirmed that there
was no population stratification using PCs from the SNP
array in our Japanese participants, and the PCs extracted
from our participants were completely located on those
extracted from the JPT (Japanese in Tokyo, Japan) population (Ohi et al. 2020b). Thus, we did not use the PCs tocontrol for possible population stratification in this study.
The marginal significance level for all statistical tests was
set at Puncorr<0.05. To control for type I error due to multiple testing, we calculated the PGC value corrected bygenomic control (GC). GC is a method used to control
for multiple comparisons in genetic association study
testing multiple genetic variants (Devlin et al. 2001).
The GC method utilizes the distribution of test statistics
across all genetic variants to estimate the genomic inflation factor (λ), which reflects the extent of inflation in thetest statistics due to population structure or other confounding factors. To implement GC, the test statistics
from the individual SNP association tests are divided by
the estimated λ. This adjustment effectively counteracts
the inflation caused by population structure or othersources of systematic bias. By applying GC, more accurate P values that appropriately account for multiple
comparisons can be obtained. The significance level inthis study was set at PGC<0.05.

Results
Associations between mitochondrial genetic variants andschizophrenia, bipolar disorder, and psychotic disorders

In total, 42, 42, and 38 genetic variants in the mitochondrial chromosome remained after each QC in the PSY vs.
HC, BD vs. HC, and SZ vs. HC cohorts, respectively. The
mitochondrial allelic frequencies of all 45 genetic variants
among patients with BD, patients with SZ, and HCs are
summarized in Table 2. As shown in Table 2, all genetic
variants that survived only in one of the comparisons

Case reports of BD patients who carry the minor G-allele of
rs200044200

Individuals with the minor G-allele of NADH dehydrogenase 5 (ND5) rs200044200 were found only among
patients with BD (MAF = 0.059) and not in HCs (MAF = 0)
[odds ratio (OR)=∞]. The detailed medical information of
the three patients with BD is shown in Table 3.
The three patients commonly had neuropsychiatric family histories, though the neuropsychiatricdiagnoses differed: patient 1, SZ (aunt); patient 2, unspecified psychiatric disorder (brother); and patient 3, autism
spectrum disorder/attention-deficit hyperactivity disorder (son) and dementia (father). There were no otherRs number
rs28625645
rs3901846
rs3888511
rs111033179
rs2000974
rs111033358
rs28358573
rs200251800
rs28358580
rs200221487
rs199713564
rs3928306
rs200999343
rs2853516
rs41460449
rs201212638
rs200319905
rs3021088
rs200165736
rs28358884
rs201336180
rs2000975
rs199646902
rs201397417
rs2853826
rs200478835
rs200487531
rs200873900
rs28359169
rs2853501
rs200044200
rs28359178
rs200657506
rs28357671
rs201551481
rs200786872
rs2853506
rs201250154

489
499
961
1005
1048
1382
1442
1709
2416
2772
2831
3010
3206
3316
3394
3398
3497
5460
6253
8414
8684
8701
9053
10,345
10,398
10,41010,609
11,696
11,96913,105
13,135
13,708
13,942
14,17814,927
14,97915,21815,236

BP

A1/A2
A/G
A/G
G/A
G/A
A/G
C/A
A/G
A/G
G/A
A/G
A/G
A/G
A/G
A/G
G/A
G/A
A/G
A/G
G/A
A/G
A/G
A/G
A/G
G/A
A/G
G/A
G/A
A/G
A/G
G/A
A/G
A/G
G/A
G/A
G/A
G/A
G/A
G/A

MAF (A1)
PSYs
BD
0.32
0.33
0.022
0.039
0.050
0.020
0.039
0.018
0.081
0.059
0.022
0.020
0.009
0
0.020
0.090
0.020
0.014
0.020
0.39
0.37
0.11
0.12
0.014
0.020
0.023
0.039
0.018
0.046
0.040
0.045
0.059
0.022
0.039
0.39
0.37
0.009
0.020
0.34
0.37
0.009
0
0.036
0.059
0.29
0.30
0.099
0.12
0.040
0.039
0.013
0
0.013
0.014
0.020
0.059
0.036
0.078
0.013
0.039
0.004
0
0.018
0.020
0.11
0.12
0.014
0
0.013
0.020
SZ
0.31
0.017
0.058
0.023
0.087
0.023
0.012
0.11
0.012
0.40
0.10
0.012
0.018
0.047
0.041
0.017
0.40
0.33
0.012
0.029
0.29
0.093
0.041
0.017
0.012
0.023
0.006
0.006
0.017
0.10
0.018
0.012

HCs
0.37
0.051
0.051
0.005
0.005
0.10
0.025
0.025
0.010
0.066
0.051
0.32
0.051
0.010
0.021
0
0.041
0.071
0.005
0.32
0.010
0.40
0.015
0.061
0.32
0.030
0.051
0.025
0.005
0.036
0
0.005
0.015
0.020
0.015
0.051
0.016
0.051

PSYs
OR
0.79
0.43
0.97
3.56
0.78
0.88
0.35
1.39
0.26
1.36
2.26
1.34
1.10
1.13
0.62
4.50
1.36
0.88
0.76
0.59
0.57
0.90
3.48
0.79
0.52
2.67
0.37
7.29
0.88
0.22
1.18
2.26
0.87
0.25
Puncorr (χ2)
0.26 (1.3)
0.12 (2.4)
0.95 (< 0.1)
0.23 (1.5)
0.46 (0.6)
0.84 (< 0.1)
0.19 (1.7)
0.37 (0.8)
0.029 (4.8)
0.14 (2.2)
0.033 (4.5)
0.75 (0.1)
0.88 (< 0.1)
0.058 (3.6)
0.80 (0.1)
0.25 (1.3)
0.13 (2.2)
0.13 (2.3)
0.90 (< 0.1)
0.18 (1.8)
0.56 (0.3)
0.23 (1.4)
0.61 (0.3)
5.17 × 10− 3(7.8)
0.61 (0.3)
0.37 (0.8)
0.38 (0.8)
0.14 (2.2)
0.030 (4.7)
0.88 (< 0.1)
0.14 (2.2)
0.83 (< 0.1)
0.033 (4.5)
0.87 (< 0.1)
0.027 (4.9)
PGC
0.42
0.26
0.97
0.39
0.59
0.89
0.35
0.52
0.12
0.29
0.13
0.82
0.92
0.17
0.86
0.41
0.28
0.28
0.93
0.34
0.68
0.39
0.71
0.045
0.71
0.52
0.53
0.29
0.12
0.91
0.28
0.88
0.13
0.90
0.11

Table 2 Differences in mitochondrial allelic frequencies among patients with BD, patients with SZ, and HCs
BD
OR
0.85
0.76
0.38
8.00
0.55
0.77
0
1.95
0.28
0.38
1.23
2.49
1.95
1.92
0.98
0.82
8.00
1.26
1.95
0.89
0
0.96
0.92
4.24
0.76
0
0.54
16.68
2.64
0
1.29
2.49
0
0.37
Puncorr (χ2)
0.62 (0.2)
0.73 (0.1)
0.35 (0.9)
0.047 (4.0)
0.35 (0.9)
0.81 (0.1)
0.25 (1.3)
0.58 (0.3)
0.20 (1.6)
0.34 (0.9)
0.52 (0.4)
0.083 (3.0)
0.58 (0.3)
0.45 (0.6)
0.98 (< 0.1)
0.76 (0.1)
0.047 (4.0)
0.48 (0.5)
0.58 (0.3)
0.71 (0.1)
0.38 (0.8)
0.96 (< 0.1)
0.81 (0.1)
9.70 × 10− 3(6.7)
0.73 (0.1)
0.25 (1.3)
0.56 (0.3)
6.15 × 10− 4(11.7)
8.94 × 10− 4(11.0)
0.28 (1.2)
0.30 (1.1)
0.82 (< 0.1)
0.083 (3.0)
0.37 (0.8)
0.33 (0.9)
PGC
0.69
0.78
0.44
0.10
0.44
0.84
0.35
0.65
0.29
0.44
0.60
0.15
0.65
0.54
0.99
0.80
0.10
0.56
0.65
0.76
0.47
0.96
0.84
0.034
0.78
0.35
0.63
4.9 × 10− 3
6.4 × 10− 3
0.37
0.40
0.86
0.15
0.47
0.43

SZ
OR
0.78
0.33
1.15
4.64
0.85
0.91
0.45
1.76
0.22
1.39
2.19
1.15
0.86
1.17
0.56
3.48
1.39
0.73
0.77
0.46
0.89
3.27
0.79
0.68
0.32
4.67
0.38
0.28
1.15
2.19
1.13
0.22
Puncorr (χ2)
0.25 (1.3)
0.083 (3.0)
0.75 (0.1)
0.13 (2.3)
0.64 (0.2)
0.90 (< 0.1)
0.33 (0.9)
0.13 (2.3)
0.035 (4.4)
0.13 (2.3)
0.051 (3.8)
0.89 (< 0.1)
0.84 (< 0.1)
0.75 (0.1)
0.21 (1.5)
0.25 (1.3)
0.13 (2.3)
0.14 (2.1)
0.78 (0.1)
0.15 (2.1)
0.61 (0.3)
0.011 (6.4)
0.65 (0.2)
0.60 (0.3)
0.14 (2.2)
0.13 (2.3)
0.38 (0.8)
0.23 (1.4)
0.87 (< 0.1)
0.051 (3.8)
0.88 (< 0.1)
0.034 (4.5)
PGC
0.47
0.27
0.84
0.34
0.77
0.93
0.54
0.33
0.18
0.33
0.21
0.93
0.90
0.84
0.43
0.47
0.33
0.35
0.86
0.35
0.74
0.11
0.77
0.74
0.34
0.34
0.58
0.44
0.91
0.21
0.92
0.18

Tachi et al. International Journal of Bipolar Disorders(2023) 11:26
Page 5 of 10

Tachi et al. International Journal of Bipolar Disorders

PGC
0.74
0.88
0.85
0.85
0.90
0.44

Discussion
This is the first study to investigate associations ofgenome-wide genetic variants in the mitochondrial
chromosome with BD, SZ and PSY in a Japanese population. Of mitochondrial genetic variants, five, three, andsix were associated with BD, SZ and PSY, respectively.
Of these variants, three (rs200478835, rs200044200 and
rs28359178) and one (rs200478835) were significantly
associated with BD and PSY, respectively, even after correcting for multiple comparisons. The minor alleles ofrs200478835, rs200044200 and rs28359178 were commonly associated with risks of BD and PSY. Interestingly,
the minor G-allele of rs200044200 was observed only inthree patients with BD but not in HCs. The common feature of the three patients with BD was a neuropsychiatricfamily history. Our findings suggest that mitochondrial
genetic variants may be associated with BD and PSY in
both European and Japanese populations.
We found rs200478835, rs200044200 and rs28359178
to be associated with BD and rs200478835 with PSY
in a Japanese population. In contrast, previous studies
have not investigated associations of these genetic variants with BD or PSY in European populations (Gonçalves et al. 2018; Hagen et al. 2018; Hudson et al. 2014;
Sequeira et al. 2012). MAFs of rs200478835, rs200044200
and rs28359178 in European populations are 0.0049,
0.0041, and 0.11, respectively (https://www.ncbi.nlm.
nih.gov/snp/). Due to low MAFs, these studies might
not have investigated associations in European populations. rs200478835 of the arginine-tRNA (TRNR) gene(protein noncoding) is located approximately 500 bp
downstream of the NADH dehydrogenase 3 (ND3) gene(protein coding) and approximately 2 kb upstream of the
NADH dehydrogenase 4 (ND4) gene (protein coding).
rs200044200 and rs28359178 are both missense variants,
A (Ala) > T (Thr) and A (Ala) > T (Thr), respectively, of
the ND5 gene.
NADH dehydrogenase is a membrane-associatedprotein localizing to mitochondrial membranes and isalso known as complex I. NADH dehydrogenase is the
enzyme that catalyzes the first reaction of the electrontransfer system, which is vital for energy production.
Previous studies have suggested that NADH dehydrogenase expression and activity in cells are decreased inpatients with BD and SZ (Andreazza et al. 2010; Das etal. 2022; Holper et al. 2019). Furthermore, mutations in
the ND4 and ND5 genes of the mitochondrial genome
are associated with BD and SZ (Bamne et al. 2008; Fryeet al. 2017; Torrell et al. 2013). These findings suggest thatmitochondrial genetic variants in genes related to NADH

The reference genome sequence is GRCh38/hg38. Puncorr values < 0.05 are shown in boldface. PGC values < 0.05 are shown in boldface and underlined

MAF, minor allele frequency; BP, biological position; OR, odds ratio; PSY, psychotic disorder; BD, bipolar disorder; SZ, schizophreniaBP
15,314
15,323
15,49715,75815,86015,941
16,390

A1/A2
A/G
A/G
A/G
G/A
G/A
G/A
A/G

MAF (A1)
PSYs
BD
0.022
0.039
0.036
0.039
0.041
0.039
0.009
0
0.036
0.039
0.018
0.020
0.040
0.059

SZ
0.035
0.041
0.012
0.035
0.017
0.035

HCs
0.010
0.046
0.046
0.015
0.041
0.020
0.015

PSYs
OR
2.24
0.78
0.88
0.59
0.88
0.88
2.72

Puncorr (χ2)
0.33 (1)0.61 (0.3)
0.79 (0.1)
0.56 (0.3)
0.8 (0.1)
0.86 (< 0.1)
0.12 (2.4)

PGC
0.48
0.71
0.85
0.67
0.86
0.90
0.27

BD
OR
3.98
0.85
0.85
0
0.96
0.97
4.04

Puncorr (χ2)
0.14 (2.2)
0.84 (< 0.1)
0.84 (< 0.1)
0.38 (0.8)
0.96 (< 0.1)
0.97 (< 0.1)
0.071 (3.3)

PGC
0.23
0.87
0.87
0.47
0.97
0.98
0.14

SZ
OR
0.76
0.89
0.76
0.85
0.86
2.34

common characteristics, such as types of BD, developmental disorders or premorbid IQ, among these patients.

Rs number
rs527236176
rs527236177
rs199951903
rs527236193
rs201023973
rs193303003
rs41378955

Table 2 (continued)

Page 6 of 10

Puncorr (χ2)
0.60 (0.3)
0.82 (0.1)
0.77 (0.1)
0.77 (0.1)
0.84 (< 0.1)
0.22 (1.5)(2023) 11:26

Tachi et al. International Journal of Bipolar Disorders(2023) 11:26

Page 7 of 10

Fig. 1 Associations of mitochondrial genetic variants with bipolar disorder, schizophrenia, and psychotic disorders. The red line indicates a P value of 0.01;
the blue line indicates a P value of 0.05. Genes (blue arrow) and RNAs (green) in the mitochondrial chromosome are indicated. HCs, healthy controls; PSY,
psychotic disorders; BD, bipolar disorder; SZ, schizophrenia

Table 3 Case series of three BD patients with the minor G-allele of rs200044200
Age (years)
Sex
Age at onset (years)
Duration of illness (years)
Family history

Types of BD
Developmental disorders
Years of education
Premorbid IQ
Present IQ
Present occupation
Former occupation
Primary symptom
Psychotic episode
Rapid cycler
Present prescription (mg/day)

BD patient 1
48
female25
23
SZ (aunt)

BD patient 2
58
male
44
14
Unspecified psychiatric disorder(brother)

I
14
92
80
Support for continuous employment type A
Children’s nurse
Mania
+
+
Aripiprazole 12 mg,
Zotepine 25 mg,
Biperiden 2 mg,
Clonazepam 2 mg,
Loflazepic acid 2 mg,
Flunitrazepam 4 mg,
Triazolam 0.25 mg,
Valproic acid 800 mg

II
12
110
n.a.
Unemployed
Bus driver
Depression
Flunitrazepam 2 mg,
Lithium 400 mg

BD patient 3
44
male
35
9
ASD/ADHD(son), Dementia (father)
II
16
104
n.a.
Unemployed
Clerical work
Depression+
Quetiapine
100 mg,Flunitrazepam 2 mg,
Zopiclone
7.5 mg,Lithium
900 mgBD, bipolar disorder; ASD, autism spectrum disorder; ADHD, attention-deficit hyperactivity disorderdehydrogenase may contribute to the pathogenesis of BD
and SZ via dysfunction of energy production.
As stated above, several previous studies have identified significant genetic associations between several
mitochondrial genetic variants (rs28357375, rs28357968,
rs527236209, rs869096886, rs1599988, rs2854131,

rs2853503,
rs2853504,
rs193302985,
rs2853506,
rs3937033, rs2857291, rs28380140, rs3088053, andrs2853497) and BD, SZ or PSY in European populations(Gonçalves et al. 2018; Hagen et al. 2018; Hudson et al.
2014; Sequeira et al. 2012). Of these genetic variants associated with BD, SZ or PSY in European populations, theTachi et al. International Journal of Bipolar Disorders(2023) 11:26

Page 8 of 10

current study examined associations only for rs2853506
related to the risk of SZ in European populations with
BD, SZ or PSY in a Japanese population after applying
our QC. However, the minor G-allele of rs2853506 was
not significantly associated with SZ in the Japanese population, even though the direction of the association wasconsistent between the present (OR = 1.13) and previous(OR ≈ 1.30) studies (Hagen et al. 2018). This finding suggests that some mitochondrial genetic variants might becommonly associated with risk of BD and SZ in different
populations.
We found individuals with the minor G-allele of
rs200044200 only among three patients with BD(MAF = 0.059) but not in HCs (MAF = 0) (OR=∞). Moreover, all the BD patients with the minor G-allele of
rs200044200 (100%, 3/3) had several neuropsychiatricfamily histories, such as SZ, neurodevelopmental disorders, dementia, and unspecified psychiatric disorder.
Of our all patients with BD, 33.3% (17/51) had neuropsychiatric family histories; 29.2% of patients with BD
who did not have the minor G-allele of rs200044200 had
neuropsychiatric family histories. The minor G-allele of
rs200044200 was significantly associated with neuropsychiatric family histories in patients with BD (P = 0.033).
Compared with that of rs200044200 in European populations (MAF = 0.0041), the MAF was higher in East
Asian populations (MAF = 0.019). However, it has beenreported that rs200044200 is benign for Leigh syndrome(https://www.ncbi.nlm.nih.gov/clinvar/RCV000854899/),
which is a progressive neurodegenerative disorder caused
by abnormalities in mitochondrial energy generation(Thorburn et al. 1993), even though the SNP is a missense
variant. In contrast, it is unknown whether rs200044200
affects mitochondrial function in PSY, including BD.
While the rs200044200 mitochondrial missense variant
may be associated with an increased risk of BD in some
populations, further research is needed to fully understand its role in the development of this condition andto determine how it may interact with other genetic andenvironmental factors.

whole-blood-specific but brain-specific mitochondrial
genetic variants in genomic DNA extracted from brain
samples in patients with BD, SZ or PSYs.

Limitations

There are some limitations to the interpretations of ourfindings. The sample size of our study was small compared to previous studies, potentially resulting in falsepositive and -negative findings. Due to QC based on
MAFs in our small sample size, we might have excluded
some SNPs investigated in previous studies. Because
our participants were recruited at a single institute,sample selection bias might have occurred. Further
study with a larger sample size at multiple institutes ina Japanese population is needed. Although we investigated mitochondrial genetic variants in genomic DNA
extracted from whole-blood samples, there might be notConclusions
We investigated associations of BD, SZ and PSY withgenome-wide genetic variants in the mitochondrial chromosome in a Japanese population. Of 45 genetic variants,
three (rs200478835, rs200044200 and rs28359178) andone (rs200478835) were significantly associated with BD
and PSY, respectively. Interestingly, the minor G-allele of
rs200044200 was detected only in three patients with BD
but not in HCs. The common feature of these patientswith BD was neuropsychiatric family histories. Our findings suggest that mitochondrial genetic variants may be
associated with BD and PSY in European populations aswell as in the Japanese population.
Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s40345-023-00307-6.
Supplementary Material 1
Acknowledgements
We would like to thank all individuals who participated in this study.
Author contributions
KO supervised the entire project; collected the data; wrote the manuscript;
and was critically involved in the design, analysis and interpretation of thedata. RT, and K.O. were responsible for performing the literature review
and data analyses and drafting the manuscript. DN, MS, JH, KK, RH and KI
were involved in the genotyping. KO, DF, AK, KT, YM, SS, and TS were heavily
involved in the collection of the majority of the data and intellectuallycontributed to data interpretation. All authors contributed to and approved
the final manuscript.
Funding
This work was supported by Grants-in-Aid for Scientific Research (C)(19K08081, 21K07497, 22K07614), Young Scientists (B) (16K19784), Young
Scientists (20K16624) and KAKENHI Advanced Animal Model Support (AdAMS)(16H06276) from the Japan Society for the Promotion of Science (JSPS); AMED
under Grant Number JP21uk1024002 and JP22dk0307112; a grant from the
SENSHIN Medical Research Foundation; a grant from the Uehara Memorial
Foundation; a grant from the Takeda Science Foundation; a grant from the
YOKOYAMA Foundation for Clinical Pharmacology (YRY-1807); and a grantfrom the Smoking Research Foundation.
Data Availability
Our data are not publicly available because they contain information that
could compromise the research participants’ privacy/consent.

Declarations
Ethics approval and consent to participate
Written informed consent was obtained from all participants after theprocedures had been thoroughly explained. This study was performedin accordance with the Declaration of Helsinki from the World Medical
Association and was approved by the Research Ethical Committees of Gifu
University and Kanazawa Medical University.
Consent for publication
Not applicable.

Tachi et al. International Journal of Bipolar Disorders(2023) 11:26

Competing interests
All authors have no confict of interest to report.
Received: 7 March 2023 / Accepted: 12 July 2023

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