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Identification of Novel Genetic Variants Associated with Insomnia and Migraine Comorbidity

  • Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Abstract and Figures

Purpose: Although insomnia and migraine are often comorbid, the genetic association between insomnia and migraine remains unclear. This study aimed to identify susceptibility loci associated with insomnia and migraine comorbidity. Patients and methods: We performed a genome-wide association study (GWAS) involving 1063 clinical outpatients at a tertiary hospital in Taiwan. Migraineurs with and without insomnia were genotyped using the Affymetrix Axiom Genome-Wide TWB 2.0. We performed association analyses for the entire cohort and stratified patients into the following subgroups: episodic migraine (EM), chronic migraine (CM), migraine with aura (MA), and migraine without aura (MoA). Potential correlations between SNPs and clinical indices in migraine patients with insomnia were examined using multivariate regression analysis. Results: The SNP rs1178326 in the gene HDAC9 was significantly associated with insomnia. In the EM, CM, MA, and MoA subgroups, we identified 30 additional susceptibility loci. Multivariate regression analysis showed that SNP rs1178326 also correlated with higher migraine frequency and the Migraine Disability Assessment (MIDAS) questionnaire score. Finally, two SNPs that had been previously reported in a major insomnia GWAS were also significant in our migraineurs, showing a concordant effect. Conclusion: In this GWAS, we identified several novel loci associated with insomnia in migraineurs in a Han Chinese population in Taiwan. These results provide insights into the possible genetic basis of insomnia and migraine comorbidity.
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Identication of Novel Genetic Variants
Associated with Insomnia and Migraine
Yu-Chin An
, Chia-Lin Tsai
, Chih-Sung Liang
, Yu-Kai Lin
, Guan-Yu Lin
, Chia-Kuang Tsai
Yi Liu
, Sy-Jou Chen
, Shih-Hung Tsai
, Kuo-Sheng Hung
, Fu-Chi Yang
Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China;
of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China;
Department of Psychiatry, Beitou
Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China;
Center for Precision Medicine and
Genomics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
Correspondence: Fu-Chi Yang, Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of
China, Tel +886-2-87923311 # 88078, Fax +886-2-87927174, Email
Purpose: Although insomnia and migraine are often comorbid, the genetic association between insomnia and migraine remains
unclear. This study aimed to identify susceptibility loci associated with insomnia and migraine comorbidity.
Patients and Methods: We performed a genome-wide association study (GWAS) involving 1063 clinical outpatients at a tertiary
hospital in Taiwan. Migraineurs with and without insomnia were genotyped using the Affymetrix Axiom Genome-Wide TWB 2.0. We
performed association analyses for the entire cohort and stratied patients into the following subgroups: episodic migraine (EM),
chronic migraine (CM), migraine with aura (MA), and migraine without aura (MoA). Potential correlations between SNPs and clinical
indices in migraine patients with insomnia were examined using multivariate regression analysis.
Results: The SNP rs1178326 in the gene HDAC9 was signicantly associated with insomnia. In the EM, CM, MA, and MoA
subgroups, we identied 30 additional susceptibility loci. Multivariate regression analysis showed that SNP rs1178326 also correlated
with higher migraine frequency and the Migraine Disability Assessment (MIDAS) questionnaire score. Finally, two SNPs that had
been previously reported in a major insomnia GWAS were also signicant in our migraineurs, showing a concordant effect.
Conclusion: In this GWAS, we identied several novel loci associated with insomnia in migraineurs in a Han Chinese population in
Taiwan. These results provide insights into the possible genetic basis of insomnia and migraine comorbidity.
Keywords: insomnia, migraine, GWAS, SNP, gene, comorbidity
Insomnia and migraine are both important worldwide health problems. According to the Global Burden of Disease
report, migraine is the sixth most troublesome disease worldwide and the most common neurological disease.
attacks are episodic headaches often associated with nausea, vomiting, and sound and light sensitivity that severely
impair the quality of life of migraineurs and can even lead to disability. In addition, migraine is associated with several
comorbidities, such as anxiety, depression, vascular accidents, epilepsy, restless legs syndrome, stress, and sleep
Insomnia, dened as the inability to initiate or maintain sleep, is nowadays the most common sleep disorder.
It affects one-third of the adult population and remarkably reduces life satisfaction.
In addition, it is associated with
various complications, such as heart disease, diabetes, gastrointestinal problems, and neurological disorders.
studies reported that migraineurs have worse sleep quality than non-migraineurs and high migraine frequency is
considered related to a higher prevalence of poor sleep quality.
In an epidemiologic study, primary headaches, including
migraine and tension headaches, were signicantly associated with insomnia comorbidities with an odds ratio (OR) of
Moreover, it has been reported that sleep interruptions can trigger migraine attacks. Besides epidemiologic
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Received: 11 March 2022
Accepted: 1 June 2022
Published: 7 June 2022
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evidence, migraine and insomnia might share some pathophysiological mechanisms in a bidirectional relationship.
Migraine and insomnia could be associated due to the dysregulation of nervous system pathways involved in both
pathologies, such as in cortical spreading depression, the trigeminovascular system, hypothalamic orexinergic system,
and several kinds of neurotransmitters which play a role as mediators.
Recent studies have shown evidence of genetic contributions to migraine and insomnia respectively, but questions
remain about the shared framework of genetic inuence. A recent meta-analysis study comprising 22 genome-wide
association studies (GWAS) identied that the genetic factors associated with a higher risk of migraine were enriched in
genes expressed in vascular and smooth muscle tissues, supporting a vascular involvement in the etiology of migraine.
Eising et al integrated migraine GWAS data with high-resolution spatial gene expression data and identied ve modules
involved in migraine pathophysiology.
Furthermore, several genetic studies on pediatric migraine have reported
polymorphisms associated with migraine.
Similarly, numerous studies have shown novel susceptibility genes
associated with insomnia. Hammerschlag et al identied three loci and seven genes associated with insomnia.
et al showed that single-nucleotide polymorphism (SNP)-based heritability for insomnia disorder signicantly correlated
with other psychiatric and physical disorders.
Furthermore, Jansen et al reported 202 loci identifying 956 genes
associated with insomnia that highlighted key brain areas implicated in this disease.
Although the co-occurrence of migraine and insomnia is widely known, to the best of our knowledge, limited studies
have investigated the shared genetic variants between them, especially in the Han Chinese population. Therefore, this
study aimed to identify susceptibility loci associated with insomnia and migraine in the Han Chinese population in
Taiwan. In addition, we stratied patients into the following subgroups: chronic migraine (CM) versus episodic migraine
(EM), and migraine with aura (MA) versus migraine without aura (MoA). To date, whether migraine with and without
aura have different genetic components remains controversial, as well as whether migraine chronication is associated
with specic genetic variants and with more frequent and severe insomnia symptoms. Hence, our second aim was to
investigate whether independent genetic variants are associated with insomnia in the migraine subgroups.
Materials and Methods
The study protocol was approved by the Institutional Review Board of the Tri-Service General Hospital (TSGH)
(TSGHIRB No.: 2-108-05-038) and performed strictly following the Declaration of Helsinki. The study was performed
between October 2018 and March 2021 in a cohort of 1063 patients recruited from the neurology outpatient department
at the TSGH (Figure 1). All patients provided written informed consent prior to enrollment. Each study participant
completed a screening questionnaire and was subsequently interviewed by a board-certied neurologist and headache
specialist (FCY). The study sample was then divided into a group with CM (≥ 15 episodes per month; n = 189) or EM
(< 15 episodes per month; n = 874). In addition, 298 of the 1063 study participants had MA, and 765 had MoA.
Participant Evaluation
Migraine was diagnosed according to the criteria in the third edition of the International Classication of Headache
Disorders (ICHD-3).
Patients with secondary or other concomitant primary headache disorders were excluded. The
clinical characteristics of all participants diagnosed with migraine, including aura symptoms, migraine duration (years),
frequency (headache day/month), family history, and headache intensity, were documented.
All patients completed a standardized demographic questionnaire and the Migraine Disability Assessment question-
naire (MIDAS),
Beck Depression Inventory (BDI),
and Hospital Anxiety and Depression Scale (HADS)
tionnaires. The MIDAS is a questionnaire with ve items that assess headache-related disabilities over the previous three
months. The four-point grading system was as follows: grade I (scores ranging from 0 to 5), little or no disability; grade
II (scores ranging from 6 to 10), mild disability; grade III (scores ranging from 11 to 20), moderate disability; and grade
IV (21 or greater), severe disability. The BDI scores range from 0 to 63, and individuals with scores ≥ 18 are classied as
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depressed. The HADS has seven items related to anxiety and depression and has a maximum individual subscale score
of 21.
Primary insomnia disorder was diagnosed according to the criteria in the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5)
after an evaluation during a clinical interview. The clinical characteristics of all participants
diagnosed with primary insomnia, including insomnia duration and insomnia severity, were documented. Medical and
psychiatric disorders were evaluated via structured diagnostic interviews, physical examinations, blood tests (blood cell
count, thyroid, renal, and hepatic function), and urine drug testing. Patients with secondary insomnia (eg, history of heart
disease, stroke, nephritis, psychiatric disorders, hypersomnia, parasomnia, brain tumor, hematoma, drug- or alcohol-
related, etc.) were excluded from the study.
All participants completed two brief self-rated questionnaires to assess their perception of insomnia severity using the
Pittsburgh Sleep Quality Index (PSQI)
and the Insomnia Severity Index (ISI).
The PSQI estimates sleep quality over
the previous month, including 19 self-rated items combined into seven components. It has a score range of 0–21, and
a nal score ≥ 6 indicates sleep disturbance. The ISI score is a seven-item self-rated questionnaire that evaluates the
severity and impact of insomnia symptoms in the past month. Each ISI item is rated on a scale of 0–4. The total ISI score
is divided into four categories: 0–7, no clinically signicant insomnia; 8–14, subthreshold insomnia; 15–21, moderate
insomnia; 22–28, severe insomnia.
Genotyping and Quality Control
Peripheral blood samples from patients with migraine were isolated in 5-mL EDTA vacutainers (BD, Plymouth, UK).
Genomic DNA was extracted using the QIAamp DSP DNA Mini Kit on the QIAsymphony platform (Qiagen, Hilden,
Germany). DNA quality was measured using a NanoDrop One spectrophotometer (Thermo Fisher Scientic, Waltham,
MA, USA). The DNA samples were applied to the Affymetrix Axiom Genome-Wide TWB 2.0 arrays, which contain
approximately 752,921 probes for a total of 686,463 SNPs. Among these SNPs, approximately 446,000 SNPs are
associated with the characteristics of background genotypes in Taiwanese; approximately 105,000 SNPs are clinically
relevant, whereas the rest are associated with disease features, drug response, and metabolism. The signal CEL les
generated from the Axiom TWB 2.0 SNP array were transformed to genotyping data (tped and tfam les) using
a Genotyping Console (Affymetrix).
Figure 1 Flowchart of a two-step workow of the phenotype association analysis.
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Statistical Analysis
All patients with migraine were grouped into different subsets using our standard demographic questionnaire. In order to
evaluate the genetic association between migraine risk and insomnia risk, we performed a genotype-association analysis
using PLINK based on the migraine with insomnia and migraine without insomnia groups. The P-value and odds ratio
(OR) of the phenotype association study were calculated to assess the variant relationship using the chi-square allelic test
with one degree of freedom. To investigate how gender may affect the relationship between migraine and insomnia, we
also analyzed the association between gender factors in all migraine cohorts. Additionally, migraineurs were stratied
into four groups: EM, CM, MA, and MoA, and patients in each group were further divided into subgroups according to
the presence or absence of insomnia. In addition, to validate the effect direction of the variants, we selected 255 variants
from a major insomnia GWAS
present in our SNP microarray. Among these, we genotyped 25 variants in all patients to
check the trend (Supplementary Table 1). Finally, the signicant P-values lower than 10
were retrieved. Intergenic
variants were excluded in the subsequent analyses. In addition, variants with a Minor Allele Frequency MAF (TWB)
< 0.25 and OR = 0, which represent common variants among the Taiwanese, were excluded. The remaining variants were
annotated with NCBI based on the RefSeq database using ANNOVAR.
Table 1 shows the demographic metadata of all the participants, as well as those of the migraine subgroups with or
without insomnia. There were no signicant differences in the proportion of EM/CM, body mass index, and years of
education among the groups of migraineurs with insomnia and migraineurs without insomnia. Nevertheless, all other
parameters analyzed differed signicantly between the two subgroups analyzed (P < 0.05).
Association of Insomnia in All Migraine Cohorts
We then conducted GWAS on migraineurs stratied depending on the presence or absence of the comorbidity
insomnia. The analysis yielded one signicant intronic variant with a P-value < 1E-06, rs1178326 (P = 5.43E-07)
(Table 2). The variant allele frequency in the insomnia group was 0.50%, whereas it was 3.94% in the non-insomnia
group (OR = 0.12, Figure 2).
Table 1 Demographic and Clinical Data
All Migraine All Migraine P-value
Migraine without Insomnia Migraine with Insomnia
Migraine cohort 1063 164 899
With aura/without aura 298/765 35/129 263/636 0.0189
EM/CM 874/189 143/21 731/168 0.0757
Migraine frequency (months) 7.05±7.14 5.68±6.44 7.30±7.24 4.44E-03
Migraine duration (years) 26.54±17.76 23.42±17.39 27.12±16.08 0.013
Sex (male/female) 247/816 49/112 198/704 0.0245
Age (years) 46.61±14.12 42.67±14.38 47.33±7.23 2.00E-04
Body mass index 23.63±4.17 23.65±4.08 23.63±4.19 0.94
Education (years) 13.86±3.09 14.23±3.10 13.79±3.08 0.097
MIDAS score 19.26±16.85 14.38±13.24 20.12±17.27 4.82E-06
PSQI score 9.75±4.00 3.73±1.30 10.84±3.29 7.06E-208
ISI score 9.88±6.21 3.37±3.01 11.04±5.91 2.75E-81
BDI score 11.87±8.98 7.04±6.14 12.75±9.14 1.08E-20
HADS-anxiety score 7.59±4.15 5.15±3.43 8.04±4.11 1.19E-18
HADS-depression score 6.19±4.11 3.86±3.13 6.61±4.13 2.73E-19
Note: P-values were calculated using Fisher’s exact test and the t-test.
Abbreviations: EM, episodic migraine; CM, chronic migraine; MIDAS, Migraine Disability Assessment Scale; PSQI, Pittsburgh Sleep Quality Index; ISI, Insomnia Severity
Index; BDI, Beck Depression Inventory; HADS, Hospital Anxiety and Depression Scale.
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When analyzing gender-associated factors, we found that in both gender groups there was only one variant associated
between gender and migraine: rs145888117 (P = 7.00E-07) for the male group and rs28535526 (P = 5.12E-07) for the
female group (Supplementary Table 2). The OR trend is similar to our nding (rs1178326) in all migraine cohorts;
however, the variants are not in the same position.
Association in the Subgroups in EM/CM
Additionally, we performed an association analysis to identify the potential genetic differences between migraineurs
suffering from EM and CM with and without insomnia. Two genome-wide signicant (P < 10
) SNPs were identied in
the EM group (Figures 2 and 3), and 14 variants we identied in the CM group (Table 3,Figure 3). Most of these variants
were intronic and presented a MAF < 5%. The frequency of the signicant variants in the EM and CM groups was lower
in the insomnia group than that in the non-insomnia group. The OR of all these variants was lower than one.
Table 2 Association Between All Migraine Patients Grouped by the Presence or Absence of Insomnia
SNP Position
MAF TWB Gene Type Variant
Variant Allele Frequency OR P-value
rs1178326 chr7:18195234 0.01 0.012 HDAC9 Intronic T>C 0.50% 3.94% 0.12 [0.05, 0.32] 5.43E-07
Notes: All migraine patients were grouped based on insomnia and compared using PLINK. The signicant variants were listed by empirical P-value < 1E-6, with the allele
frequency, odds ratio (OR), and 95% condence interval.
Abbreviations: MAF, Minor allele frequency in the East Asian group in dbSNP; TWB, Minor allele frequency in the Taiwan Biobank.
Figure 2 The distribution of variant allele frequency of the variant in (A) all migraine cohort, (Band C) EM, and (D) MoA groups. Boxplots of distributions between groups
and genotypes. The x-axis shows the genotype of the variants, and the y-axis indicates the phenotype. The abundance of each condition in the genotypes is marked above
each bar. In the entire migraine cohort (A), we found three different distributions of the variant rs1178326 (HDAC9). The genotype TT was associated with the insomnia
group, whereas the genotype CTwas associated with the non-insomnia group. The genotype CC is not shown in this study. In addition, for other groups in EM and MoA, we
found a similar trend of distribution of variant rs17082263 (SCFD2) and rs143607843 (IQCG) in the EM group, and rs4876117 (DLGAP2) in the MoA group.
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Association in the Subgroups in MA/MoA
Moreover, we performed association analyses between the migraineurs with and without aura and with and without
insomnia. In the MA group, 13 variants were genome-wide signicant, whereas only one variant was signicant in the
MoA group (Table 3,Figures 2 and 3). The patterns found in the MA/MoA group were similar to those in the EM/CM
group, with odds ratios lower than one. Additionally, these variants related to migraineurs tended to occur more
frequently in the non-insomnia group as compared to those in the insomnia group.
Multivariate Association Study
We then performed a multivariate regression analysis on migraine frequency, MIDAS, ISI, BDI, HADS-anxiety, and
HADS-depression scores. In all migraine cohorts, SNP rs1178326 showed a signicant association between migraine
frequency and MIDAS (P = 0.006, 0.004; OR = 0.73, 1.16; 95% condence interval = 0.59–0.91, 1.05–1.28,
Replication Study
Finally, we aimed to validate the results of a previous major GWAS on insomnia. For this purpose, we selected 25 loci
present in a TWB2 SNP array (Supplementary Table 1) and analyzed them in all migraineurs. Among the SNPs tested,
rs10947428 and rs728017 were signicantly different between insomnia and non-insomnia migraineurs (Table 4). The
odds ratios associated with both markers were lower than one (0.04 and 0.19, respectively), indicating that the variant
allele seemingly appeared more frequently in the non-insomnia group rather than that in the insomnia group.
Figure 3 Variant frequency and odds ratio (OR) in the subgroups episodic migraine (EM), chronic migraine (CM), migraine with aura (MA), and migraine without aura
(MoA). The x-axis shows the genome-wide signicant variants found in the association analysis of EM vs CM (A) and MA vs MoA (B), also reported in Table 2. The y-axis
shows the variant allele frequency in the insomnia group. The diameter of the circles represents the OR of each variant.
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Table 3 Association Between Insomnia Subgroups: EM, CM, MA, and MoA
Groups SNP Position
MAF TWB Gene Type Variant
Variant Allele Frequency OR P-value
EM rs17082263 chr4:53005816 0.03 0.015 SCFD2 Intronic C>T 0.43% 4.46% 0.093 [0.03,0.27] 1.00E-07
rs143607943 chr3:197898149 0.01 0.0076 IQCG Intronic C>T 0.09% 2.68% 0.032 [0.00,0.26] 6.37E-07
CM rs17009732 chr4:125465671 0.00 0.022 FAT4 Intronic A>G 0.39% 16.67% 0.02 [0,0.17] 4.59E-09
rs3785860 chr17:61286196 0.00 0.037 BCAS3 Intronic T>G 1.19% 20.00% 0.05 [0.01,0.20] 3.01E-08
rs117254988 chr17:81271302 0.07 0.039 SLC38A10 Intronic G>A 3.15% 26.67% 0.09 [0.03,0.26] 1.27E-07
rs143572955 chr6:22054437 0.03 0.04 CASC15 ncRNA_intronic A>G 0.79% 16.67% 0.04 [0.007,0.22] 1.28E-07
rs113567972 chr5:152265953 0.05 0.027 LINC01933 ncRNA_intronic G>A 0.39% 13.33% 0.03 [0.0028,0.24] 3.46E-07
rs150577542 chr7:103724411 0.05 0.027 RELN Intronic ->AT 0.39% 13.33% 0.03 [0.003,0.24] 3.46E-07
rs76585997 chr7:129721275 0.02 0.027 NRF1 Intronic G>A 0.39% 13.33% 0.03 [0.003,0.24] 3.46E-07
rs150819573 chr15:59507459 0.00 0.022 FAM81A Intronic G>A 0.39% 13.33% 0.03 [0.003,0.24] 3.46E-07
rs117776222 chr1:234086299 0.01 0.009 SLC35F3 Intronic G>A 0.40% 13.33% 0.03 [0.003,0.24] 3.86E-07
rs76358129 chr5:152246648 0.05 0.03 LINC01933 ncRNA_intronic T>C 0.40% 13.33% 0.03 [0.003,0.24] 3.86E-07
rs113929593 chr5:152265017 0.05 0.027 LINC01933 ncRNA_intronic A>G 0.40% 13.33% 0.03 [0.003,0.24] 3.86E-07
rs74526104 chr11:117575288 0.12 0.066 DSCAML1 Intronic A>G 4.72% 30.00% 0.12 [0.044,0.31] 5.64E-07
rs141086120 chrX:65489841 0.04 0.04 ZC3H12B Intronic C>T 1.30% 19.23% 0.06 [0.012,0.25] 5.99E-07
rs3094584 chr6:31416071 0.185 0.077 MICA Downstream G>A 2.76% 23.33% 0.09 [0.03,0.29] 8.50E-07
MA rs3763971 chr11:34150834 0.07 0.024 ABTB2 Downstream G>C 0.79% 14.00% 0.049 [0.01,0.20] 5.12E-09
rs78345995 chr8:118640335 0.00 0.0096 SAMD12-AS1 ncRNA intronic G>C 0.52% 12.00% 0.039 [0.01,0.20] 1.51E-08
rs74383774 chr11:11875451 0.06 0.087 USP47 Intronic C>T 5.24% 28.00% 0.14 [0.07,0.31] 1.90E-08
rs12026894 chr1:245268001 0.07 0.075 KIF26B Intronic G>A 6.28% 30.00% 0.16 [0.08,0.33] 3.74E-08
rs28382698 chrX:55009628 0.00 0.021 ALAS2 Intronic A>G 0.89% 14.63% 0.052 [0.01,0.22] 4.54E-08
rs76268860 chr10:69260819 0.05 0.047 HKDC1 Intronic A>G 2.09% 18.00% 0.097 [0.04,0.27] 5.34E-08
rs3120649 chr1:152311335 0.027 0.014 FLG Exonic G>A 0.52% 10.00% 0.05 [0.009,0.25] 6.02E-07
rs78315102 chr4:169932700 0.00 0.011 LINC02275 ncRNA_intronic G>A 0.52% 10.00% 0.05 [0.009,0.25] 6.02E-07
rs77108059 chr10:14584991 0.02 0.022 FAM107B Intronic T>A 0.52% 10.00% 0.05 [0.009,0.25] 6.02E-07
rs190376766 chr14:61899133 0.03 0.025 SYT16 Intronic T>C 0.52% 10.00% 0.05 [0.009,0.25] 6.02E-07
rs141176236 chr5:103529675 0.00 0.039 LINC02115 ncRNA_intronic G>A 2.62% 18.00% 0.12 [0.05,0.32] 6.10E-07
rs9365252 chr6:161113583 0.06 0.027 MAP3K4 Intronic C>T 1.57% 14.58% 0.09 [0.03,0.29] 6.95E-07
rs12045578 chr1:245247818 0.08 0.076 KIF26B Intronic G>T 4.97% 24.00% 0.17 [0.07,0.37] 9.50E-07
MoA rs4876117 chr8:1654231 0.053 0.059 DLGAP2 Intronic G>A 5.14% 14.7% 0.31 [0.20,0.50] 6.03E-07
Notes: A phenotype association study was performed on all migraine cohorts of the insomnia group and then grouped based on four conditions: EM, CM, aura, and without aura. Signicant variants with P-value < 1E-6 are listed with the
allele frequency, odds ratio (OR), and 95% condence interval.
Abbreviations: EM, episodic migraine; CM, chronic migraine; MA, migraine with aura; MoA, migraine without aura; MAF, minor allele frequency of East Asian group in dbSNP; TWB, minor allele frequency in Taiwan Biobank.
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Table 4 Replication of Findings in a Previous Major Insomnia GWAS
SNP Position
MAF TWB Gene Type Variant
Variant Allele Frequency OR P-value Source
rs10947428 chr6:33679281 0.035 0.032 ITPR3 Intronic T>C 0.86% 16.67% 0.04 [0.0036,0.52] 5.71E-04 Jasen, P.R. et al. Nat
Genet (2019)rs728017 chr6:123971449 0.073 0.10 NKAIN2 Intronic A>G 6.03% 25.00% 0.19 [0.042,0.88] 0.020
Note: The proles of variants reported in a previous large GWAS were found in all migraine cohorts of the insomnia group.
Abbreviations: MAF, minor allele frequency of the East Asian group in dbSNP; TWB, minor allele frequency in the Taiwan Biobank.
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Here, we analyzed 1063 migraineurs stratied into patients with and without insomnia and found that the rs1178326
variant in the HDAC9 gene was signicantly associated with insomnia. Additionally, we stratied the migraineurs
depending on the frequency of the symptoms (EM vs CM) and the presence of an aura (MA vs MoA), further comparing
differences between patients with and without insomnia in each subgroup. Two, 14, 13, and 1 SNP in the EM, CM, MA,
and MoA groups, respectively, were signicantly associated with insomnia. Multivariate regression analysis indicated
that the SNP rs1178326 was also signicantly associated with migraine frequency and MIDAS scores. Moreover, we
replicated the association and the direction of the effects of two SNPs (rs10947428 in ITPR3 and rs728017 in NKAIN2)
that were signicant in a previous insomnia GWAS.
In the demographic and clinical data (Table 1), the MIDAS, ISI, PSQI, HADS, and BDI questionnaire responses
differed signicantly between the two groups. Our results are consistent with previous studies, which have indicated that
the co-existed comorbidity of anxiety and depression signicantly correlates with a higher prevalence of poor sleep
quality in migraineurs.
HDAC9 encodes histone deacetylase 9 (HDAC9), a member of the class II HDAC family that plays key roles in
numerous tissues by regulating histone phosphorylation, thereby shaping the transcriptional landscape. The human
HDAC9 gene is located on chromosome 7p21 and is highly expressed in the heart, muscles, and brain. HDAC9 has
been implicated in numerous pathophysiological processes, including neurological disorders, cardiac growth,
T-regulatory cell function, muscle differentiation, and cancers.
Several reports investigated the association between
HDAC9 and the risk of ischemic stroke or coronary artery disease in the Han Chinese population.
HDAC9 gene
deciency may attenuate atherosclerosis and increase risk by altering ischemic brain responses and neuronal survival.
Recently, HDAC9 was reported as a potential causal link between insomnia and coronary artery disease.
a Mendelian randomization analysis showed that short sleep duration and frequent insomnia symptoms are associated
with a subtype of ischemic stroke.
Sleep deprivation may increase HDAC expression in the hippocampus, adversely
affecting structural and functional synaptic plasticity and memory formation, leading to spatial memory decline, which
could be reversed by HDAC inhibition.
Therefore, we hypothesized that HDAC9 is functionally involved in migraine
and insomnia through the dysregulation of the cardiovascular system. Further research is necessary to elucidate the
specic mechanism of the insomnia-related HDAC9 variant in migraineurs.
In the EM group, we found two insomnia-related SNPs (rs17082263 in SCFD2 and rs143607943 in IQCG). SCFD2
encodes Sec1 family domain-containing protein 2, a protein involved in protein transport and vesicle docking during
exocytosis. Despite previous studies that implicated SCFD2 as a susceptibility gene for insomnia,
later studies failed to
fully replicate these results.
IQCG encodes the IQ motif-containing G protein, which interacts with several proteins and
contributes to regulating calcium and calmodulin-dependent protein kinase IV activity, neuronal polarized growth and
plasticity, fertilization, mitosis, and cytoskeletal organization.
The SNP in rs9880989 in IQCG was identied among the
top ten susceptibility loci associated with migraine in bipolar disorder.
Although IQCG may also be involved in
insomnia and migraine, further studies are warranted to unravel underlying mechanisms.
In the CM group, 14 SNPs were associated with insomnia. SLC38A10 encodes a member of the solute carrier
(SLC) family. Hundreds of SLC genes have been identied in the brain, contributing to the transport of sugars, amino
acids, vitamins, neurotransmitters, and inorganic/metal ions. SLC38A10 acts as a glutamate transporter and can affect
neuronal viability by protecting against glutamate toxicity and oxidative stress.
Mounting evidence suggests that
glutamate excitotoxicity contributes to migraine and insomnia.
As glutamate transporters could be novel
therapeutic targets, it is necessary to further explore the role of SLC38A10 in these disorders. RELN encodes reelin,
an extracellular matrix glycoprotein controlling cell-cell interactions, critical for cell positioning and neuronal
migration during brain development. Reelin is reportedly involved in several neuropsychiatric disorders, including
schizophrenia, bipolar disorder, major depression, autism, and Alzheimer’s disease.
Reduced RELN expression may
contribute to epilepsy pathogenesis and is considered a shared causal pathway between migraine and epilepsy.
NRF1 encodes nuclear respiratory factor 1, which is involved in the transcription of oxidative phosphorylation
components. NRF1 activates the expression of several metabolic genes and is upregulated during sleep deprivation.
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Zhu et al demonstrated that NRF1 positively regulates numerous circadian genes.
Furthermore, Li et al identied
that NRF1 affects sleep initiation and may regulate the human GABA receptor subtype A β1 subunit gene in neurons,
which is associated with epilepsy, autism, bipolar disorder, and schizophrenia.
Finally, we found three SNPs in
LINC01933, encoding a long non-coding RNA. A recent study reported altered expression of LINC01933 in the brain,
which was associated with sleeping-related loci 5 in the Neanderthal population.
Further studies are necessary to
investigate the potential involvement of these genes in insomnia and the CM group.
In the MA group, we found 13 SNPs associated with insomnia. Two SNPs were in KIF26B, which encodes the
Kinesin Family Member 26 B. Kinesins are transporters of membranous organelles in mammalian neurons.
of sleep duration, KIF26B was reportedly associated with a short sleep duration of fewer than 6 hours.
In addition,
Hautakangas et al performed a genome-wide meta-analysis of migraine and found a lead SNP in KIF26B, although not
signicant in the MA subgroup.
MAP3K4 encodes mitogen-activated protein kinase (MAPK) kinase 4. MAPK pathways are involved in regulating
calcitonin gene-related peptide (CGRP) release, a migraine-related neuropeptide secreted by the trigeminal ganglion.
Suppressing MAPK/NF-кB signaling could attenuate migraine in a nitroglycerin-induced rat model.
Zhang et al found that substance P may activate MAPK pathways in satellite glial cells of the trigeminal ganglion,
contributing to inammatory orofacial pain associated with peripheral sensitization.
Moreover, substance P seemingly
initiates and perpetuates cortical spreading depression, an electrophysiological phenomenon associated with MA.
Additionally, substance P may inuence the increase of REM latency and time awake, leading to a central arousing
Overall, these studies support a potential link between MA and insomnia. Besides KIF26B and MAP3K4, other
signicant loci did not present a clear link between migraine and insomnia, highlighting the need for further research.
In the MoA group, we identied rs4876117 in DLGAP2 associated with insomnia. DLGAP2 encodes Discs Large
Homolog Associated Protein 2. It was initially identied as a candidate gene for mental retardation and post-traumatic
stress disorder affecting the hippocampus and was recently associated with schizophrenia and Alzheimer’s disease.
DLGAPs are expressed in the postsynapse, interact with several proteins, and are involved in the function of NMDA,
AMPA, and glutamate receptors.
In addition, Catusi et al studied patients with 8p23.2-pter microdeletions, suggesting
that DLGAP2 deregulation may inuence other families of post-synaptic scaffolding proteins. DLGAP2 is considered
a strong candidate for neurodevelopmental/behavioral phenotypes.
Moreover, DLGAP2 was an affected gene in an
established murine model of CM triggered by nitroglycerin. Disruption of glutamatergic and dopaminergic synapses and
rhythmic processes in the trigeminal ganglia and the nucleus accumbens may be a mechanism associated with migraine
but require further validation.
When investigating the association between gender effects on migraineurs with insomnia, we found one variant in
each gender, rs145888117 in CDC14B for the male group and rs28535526 in TAFA5 for the female group. CDC14B
encodes Cell Division Cycle 14B, a member of the dual-specicity protein tyrosine phosphatase family, involved in the
exit of cell mitosis and regulation of DNA damage repair.
Furthermore, CDC14B was shown to exhibit oncogenic
characteristics in mammals via Ras-MAPK cascade.
The association of CDC14B in male migraineurs with insomnia
may need more validation via MAPK pathways. TAFA5 encodes TAFA Chemokine Like Family Member 5, a member of
the TAFA family, and was found highly expressed in the embryonic and postnatal mouse brain, especially in the
hippocampus. Genetic deletion of TAFA5 may contribute to an increase in depressive-like behaviors and signicantly
reduce glutamate release and neuronal activity in the hippocampus.
Whether migraine, insomnia, and depression share
similar pathogenesis via TAFA5, especially in females, is warranted for further validation.
Multivariate regression analysis showed that SNP rs1178326 in HDAC9 was also signicantly associated with higher
migraine frequency and MIDAS scores, a clue that this locus plays an important role in migraine with insomnia. Further
larger studies are warranted to investigate HDAC9 in the association of migraine and insomnia with their frequency and
To validate our results, we selected 255 variants from a major insomnia GWAS
to the same SNP microarray. Out of
255, 25 SNPs in the TWB2 SNP arrays, SNPs rs10947428 in ITPR3 and rs728017 in NKAIN2 were signicantly detected
in the migraine cohort of the insomnia group. Furthermore, although the allele frequencies in Taiwan Biobank and UK
Biobank differed, our results are consistent with the previous study.
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Our study had several strengths. First, we had a carefully chosen population in which migraine and insomnia were
diagnosed by qualied neurologists according to a strictly audited protocol. Second, we evaluated individuals using
validated questionnaires, sleep quality, migraine frequency, and comorbidities like anxiety and depression. Multivariate
regression analysis and stratied analysis of migraine subgroups enabled the investigation of the genetic association of
insomnia in migraineurs. Third, Affymetrix’s Axiom Genome-Wide TWB 2.0 array covers a highly representative
sample of the gene pool in Taiwan. Our results also showed different allele frequencies in other populations in previous
major studies. Nonetheless, this study also had limitations. The statistical power was limited due to the relatively modest
sample size. Further studies with larger sample sizes and a more diverse population are warranted to enhance external
validity and extend these results in the future.
In conclusion, our study revealed that the SNP rs1178326 located in the HDAC9 gene was signicantly associated with
insomnia in a cohort of migraineurs from the Han Chinese population in Taiwan. Furthermore, several novel suscept-
ibility loci associated with insomnia were identied in subgroups EM, CM, MA, and MoA. These results provide insights
into the possible genetic basis of insomnia and migraine. Further larger studies are warranted to investigate these genes in
shared pathogenesis to obtain denitive evidence.
Data Sharing Statement
All data are available from the corresponding author upon request.
The authors thank the participants and investigators from Taiwan Precision Medicine Initiative, the Center for Precision
Medicine and Genomics of Tri-Service General Hospital, National Defense Medical Center, and Genetics Generation
Advancement Corporation for their assistance with genetic testing and statistical analysis.
Author Contributions
All authors made a signicant contribution to the work reported, whether that is in the conception, study design,
execution, acquisition of data, analysis, and interpretation, or in all these areas; took part in drafting, revising, or
critically reviewing the article; gave nal approval of the version to be published; have agreed on the journal to which the
article has been submitted; and agree to be accountable for all aspects of the work.
This work was supported partly by grants from the Ministry of Science and Technology of Taiwan (grant numbers MOST
108-2314-B-016-023- and MOST 110-2314-B-016 −036 -MY2), Tri-Service General Hospital, Taiwan (grant numbers
TSGH-D-109101, TSGH-D-110048, TSGH-C111-091), and Academia Sinica (grant numbers AS-40-05-GMM, AS-GC
The authors declare that they have no competing interests in this work.
1. Global Burden of Disease Study C. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic
diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet.2015;386
(9995):743–800. doi:10.1016/S0140-6736(15)60692-4
2. Lin YK, Lin GY, Lee JT, et al. Associations between sleep quality and migraine frequency: a cross-sectional case-control study. Medicine.2016;95
(17):e3554. doi:10.1097/MD.0000000000003554
3. An YC, Liang CS, Lee JT, et al. Effect of Sex and adaptation on migraine frequency and perceived stress: a cross-sectional case-control study. Front
Neurol.2019;10:598. doi:10.3389/fneur.2019.00598
4. Zeitlhofer J, Schmeiser-Rieder A, Tribl G, et al. Sleep and quality of life in the Austrian population. Acta Neurol Scand.2000;102(4):249–257.
Nature and Science of Sleep 2022:14
DovePress 1085
Dovepress An et al
Powered by TCPDF ( by TCPDF (
5. Byrne EM. The relationship between insomnia and complex diseases-insights from genetic data. Genome Med.2019;11(1):57. doi:10.1186/s13073-
6. Uhlig BL, Engstrom M, Odegard SS, Hagen KK, Sand T. Headache and insomnia in population-based epidemiological studies. Cephalalgia.
2014;34(10):745–751. doi:10.1177/0333102414540058
7. Tiseo C, Vacca A, Felbush A, et al. Migraine and sleep disorders: a systematic review. J Headache Pain.2020;21(1):126. doi:10.1186/s10194-020-
8. Dodick DW, Eross EJ, Parish JM, Silber M. Clinical, anatomical, and physiologic relationship between sleep and headache. Headache.2003;43
(3):282–292. doi:10.1046/j.1526-4610.2003.03055.x
9. Holland PR, Barloese M, Fahrenkrug J. PACAP in hypothalamic regulation of sleep and circadian rhythm: importance for headache. J Headache
Pain.2018;19(1):20. doi:10.1186/s10194-018-0844-4
10. Gormley P, Anttila V, Winsvold BS, et al. Meta-analysis of 375,000 individuals identies 38 susceptibility loci for migraine. Nat Genet.2016;48
(8):856–866. doi:10.1038/ng.3598
11. Eising E, Huisman SMH, Mahfouz A, et al. Gene co-expression analysis identies brain regions and cell types involved in migraine pathophysiol-
ogy: a GWAS-based study using the Allen Human Brain Atlas. Hum Genet.2016;135(4):425–439. doi:10.1007/s00439-016-1638-x
12. Chang X, Pellegrino R, Garifallou J, et al. Common variants at 5q33.1 predispose to migraine in African-American children. J Med Genet.2018;55
(12):831–836. doi:10.1136/jmedgenet-2018-105359
13. Koute V, Michalopoulou A, Siokas V, et al. Val66Met polymorphism is associated with decreased likelihood for pediatric headache and migraine.
Neurol Res.2021;43:1–9.
14. Hammerschlag AR, Stringer S, de Leeuw CA, et al. Genome-wide association analysis of insomnia complaints identies risk genes and genetic
overlap with psychiatric and metabolic traits. Nat Genet.2017;49(11):1584–1592. doi:10.1038/ng.3888
15. Stein MB, McCarthy MJ, Chen CY, et al. Genome-wide analysis of insomnia disorder. Mol Psychiatry.2018;23(11):2238–2250. doi:10.1038/
16. Jansen PR, Watanabe K, Stringer S, et al. Genome-wide analysis of insomnia in 1,331,010 individuals identies new risk loci and functional
pathways. Nat Genet.2019;51(3):394–403. doi:10.1038/s41588-018-0333-3
17. Headache Classication Committee of the International Headache S. The international classication of headache disorders, 3rd edition (beta
version). Cephalalgia.2013;33(9):629–808. doi:10.1177/0333102413485658
18. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess
headache-related disability. Neurology.2001;56(6 Suppl 1):S20–S28. doi:10.1212/WNL.56.suppl_1.S20
19. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry.1961;4:561–571.
20. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand.1983;67(6):361–370. doi:10.1111/j.1600-0447.1983.
21. Regier DA, Kuhl EA, Kupfer DJ. The DSM-5: classication and criteria changes. World Psychiatry.2013;12(2):92–98. doi:10.1002/wps.20050
22. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh sleep quality index: a new instrument for psychiatric practice and
research. Psychiatry Res.1989;28(2):193–213. doi:10.1016/0165-1781(89)90047-4
23. Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med.2001;2
(4):297–307. doi:10.1016/S1389-9457(00)00065-4
24. Vgontzas A, Cui L, Merikangas KR. Are sleep difculties associated with migraine attributable to anxiety and depression? Headache.2008;48
(10):1451–1459. doi:10.1111/j.1526-4610.2008.01175.x
25. Yeung WF, Chung KF, Wong CY. Relationship between insomnia and headache in community-based middle-aged Hong Kong Chinese women.
J Headache Pain.2010;11(3):187–195. doi:10.1007/s10194-010-0199-y
26. Yuan Z, Peng L, Radhakrishnan R, Seto E. Histone deacetylase 9 (HDAC9) regulates the functions of the ATDC (TRIM29) protein. J Biol Chem.
2010;285(50):39329–39338. doi:10.1074/jbc.M110.179333
27. Zhou X, Guan T, Li S, et al. The association between HDAC9 gene polymorphisms and stroke risk in the Chinese population: a meta-analysis. Sci
Rep.2017;7:41538. doi:10.1038/srep41538
28. Han Z, Dong X, Zhang C, Wu Y, Yuan Z, Wang X. Polymorphism of HDAC9 gene is associated with increased risk of acute coronary syndrome in
Chinese Han population. Biomed Res Int.2016;2016:3746276. doi:10.1155/2016/3746276
29. Lane JM, Jones SE, Dashti HS, et al. Biological and clinical insights from genetics of insomnia symptoms. Nat Genet.2019;51(3):387–393.
30. Korostovtseva L. Ischemic stroke and sleep: the linking genetic factors. Cardiol Ther.2021;10:349–375. doi:10.1007/s40119-021-00231-9
31. Duan R, Liu X, Wang T, Wu L, Gao X, Zhang Z. Histone acetylation regulation in sleep deprivation-induced spatial memory impairment.
Neurochem Res.2016;41(9):2223–2232. doi:10.1007/s11064-016-1937-6
32. Bahler M, Rhoads A. Calmodulin signaling via the IQ motif. FEBS Lett.2002;513(1):107–113. doi:10.1016/S0014-5793(01)03239-2
33. Knott SV. Investigating Susceptibility to Bipolar Disorder, Migraine and Epilepsy Doctoral dissertation. PhD degree in School of Medicine, Cardiff
University; 2016.
34. Tripathi R, Aggarwal T, Fredriksson R. SLC38A10 transporter plays a role in cell survival under oxidative stress and glutamate toxicity. Front Mol
Biosci.2021;8:671865. doi:10.3389/fmolb.2021.671865
35. Gasparini CF, Grifths LR. The biology of the glutamatergic system and potential role in migraine. Int J Biomed Sci.2013;9(1):1–8.
36. Mormile R, Mazzei G, Vittori G, De Michele M, Squarcia U. Insomnia and shift-work sleep disorder: a crosstalk between glutamate excitotoxicity
and decreased GABAergic neurotransmission? Sleep Biol Rhythms.2012;10:340–341. doi:10.1111/j.1479-8425.2012.00574.x
37. Guidotti A, Grayson DR, Caruncho HJ. Epigenetic RELN dysfunction in schizophrenia and related neuropsychiatric disorders. Front Cell Neurosci.
2016;10:89. doi:10.3389/fncel.2016.00089
38. Eising E, A Datson N, van den Maagdenberg AM, Ferrari MD. Epigenetic mechanisms in migraine: a promising avenue? BMC Med.2013;11
(1):26. doi:10.1186/1741-7015-11-26
39. Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev.2012;92(3):1087–1187.
Nature and Science of Sleep 2022:14
An et al Dovepress
Powered by TCPDF ( by TCPDF (
40. Zhu W. Mechanisms and Functional Roles of Nuclear Respiratory Factor 1 (NRF1) Binding Sites in the Human Genome doctoral dissertation. PhD
degree in School of Public Health, University of Pittsburgh; 2011.
41. Li Z, Cogswell M, Hixson K, Brooks-Kayal AR, Russek SJ. Nuclear respiratory factor 1 (NRF-1) controls the activity dependent transcription of
the GABA-A receptor Beta 1 subunit gene in neurons. Front Mol Neurosci.2018;11:285. doi:10.3389/fnmol.2018.00285
42. Dannemann M, Milaneschi Y, Yermakovich D, et al. Neandertal introgression dissects the genetic landscape of neuropsychiatric disorders and
associated behavioral phenotypes. medRxiv.2021;4:54.
43. Aizawa H, Sekine Y, Takemura R, Zhang Z, Nangaku M, Hirokawa N. Kinesin family in murine central nervous system. J Cell Biol.1992;119
(5):1287–1296. doi:10.1083/jcb.119.5.1287
44. Lahtinen A, Puttonen S, Vanttola P, et al. A distinctive DNA methylation pattern in insufcient sleep. Sci Rep.2019;9(1):1193. doi:10.1038/s41598-
45. Hautakangas H, Winsvold BS, Ruotsalainen SE, et al. Genome-wide analysis of 102,084 migraine cases identies 123 risk loci and subtype-specic
risk alleles. medRxiv.2021;56:e34.
46. Lei L, Yuan X, Wang S, et al. Mitogen-activated protein kinase pathways are involved in the upregulation of calcitonin gene-related peptide of rat
trigeminal ganglion after organ culture. J Mol Neurosci.2012;48(1):53–65. doi:10.1007/s12031-012-9772-y
47. Lai T, Chen L, Chen X, He J, Lv P, Ge H. Rhynchophylline attenuates migraine in trigeminal nucleus caudalis in nitroglycerin-induced rat model by
inhibiting MAPK/NF-small ka, CyrillicB signaling. Mol Cell Biochem.2019;461(1–2):205–212. doi:10.1007/s11010-019-03603-x
48. Zhang Y, Song N, Liu F, et al. Activation of mitogen-activated protein kinases in satellite glial cells of the trigeminal ganglion contributes to
substance P-mediated inammatory pain. Int J Oral Sci.2019;11(3):24. doi:10.1038/s41368-019-0055-0
49. Richter F, Eitner A, Leuchtweis J, et al. The potential of substance P to initiate and perpetuate cortical spreading depression (CSD) in rat in vivo.
Sci Rep.2018;8(1):17656. doi:10.1038/s41598-018-36330-2
50. Lieb K, Ahlvers K, Dancker K, et al. Effects of the neuropeptide substance P on sleep, mood, and neuroendocrine measures in healthy young men.
Neuropsychopharmacology.2002;27(6):1041–1049. doi:10.1016/S0893-133X(02)00369-X
51. Rasmussen AH, Rasmussen HB, Silahtaroglu A. The DLGAP family: neuronal expression, function and role in brain disorders. Mol Brain.2017;10
(1):43. doi:10.1186/s13041-017-0324-9
52. Catusi I, Garzo M, Capra AP, et al. 8p23.2-pter microdeletions: seven new cases narrowing the candidate region and review of the literature. Genes.
2021;12(5):652. doi:10.3390/genes12050652
53. Jeong H, Moye LS, Southey BR, et al. Gene network dysregulation in the trigeminal ganglia and nucleus accumbens of a model of chronic
migraine-associated hyperalgesia. Front Syst Neurosci.2018;12:63. doi:10.3389/fnsys.2018.00063
54. Lin H, Ha K, Lu G, et al. Cdc14A and Cdc14B redundantly regulate DNA double-strand break repair. Mol Cell Biol.2015;35(21):3657–3668.
55. Wei Z, Zhang P. A phosphatase turns aggressive: the oncogenicity of Cdc14B. Cell Cycle.2011;10(15):2414. doi:10.4161/cc.10.15.15887
56. Huang S, Zheng C, Xie G, et al. FAM19A5/TAFA5, a novel neurokine, plays a crucial role in depressive-like and spatial memory-related behaviors
in mice. Mol Psychiatry.2021;26(6):2363–2379. doi:10.1038/s41380-020-0720-x
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Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
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FAM19A5/TAFA5 is a member of the family with sequence similarity 19 with unknown function in emotional and cognitive regulation. Here, we reported that FAM19A5 was highly expressed in the embryonic and postnatal mouse brain, especially in the hippocampus. Behaviorally, genetic deletion of Fam19a5 resulted in increased depressive-like behaviors and impaired hippocampus-dependent spatial memory. These behavioral alterations were associated with the decreased expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and N-methyl-D-aspartic acid receptors, as well as significantly reduced glutamate release and neuronal activity in the hippocampus. Subsequently, these changes led to the decreased density of dendritic spines. In recent years, the roles of chronic stress participating in the development of depression have become increasingly clear, but the mechanism remains to be elucidated. We found that the levels of FAM19A5 in plasma and hippocampus of chronic stress-treated mice were significantly decreased whereas overexpression of human FAM19A5 selectively in the hippocampus could attenuate chronic stress-induced depressive-like behaviors. Taken together, our results revealed for the first time that FAM19A5 plays a key role in the regulation of depression and spatial cognition in the hippocampus. Furthermore, our study provided a new mechanism for chronic stress-induced depression, and also provided a potential biomarker for the diagnosis and a new strategy for the treatment of depression.
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Inflammatory orofacial pain, in which substance P (SP) plays an important role, is closely related to the cross-talk between trigeminal ganglion (TG) neurons and satellite glial cells (SGCs). SGC activation is emerging as the key mechanism underlying inflammatory pain through different signalling mechanisms, including glial fibrillary acidic protein (GFAP) activation, phosphorylation of mitogen-activated protein kinase (MAPK) signalling pathways, and cytokine upregulation. However, in the TG, the mechanism underlying SP-mediated orofacial pain generated by SGCs is largely unknown. In this study, we investigated whether SP is involved in inflammatory orofacial pain by upregulating interleukin (IL)-1β and tumour necrosis factor (TNF)-α from SGCs, and we explored whether MAPK signalling pathways mediate the pain process. In the present study, complete Freund’s adjuvant (CFA) was injected into the whisker pad of rats to induce an inflammatory model in vivo. SP was administered to SGC cultures in vitro to confirm the effect of SP. Facial expression analysis showed that pre-injection of L703,606 (an NK-1 receptor antagonist), U0126 (an inhibitor of MAPK/extracellular signal-regulated kinase [ERK] kinase [MEK] 1/2), and SB203580 (an inhibitor of P38) into the TG to induce targeted prevention of the activation of the NK-1 receptor and the phosphorylation of MAPKs significantly suppressed CFA-induced inflammatory allodynia. In addition, SP promoted SGC activation, which was proven by increased GFAP, p-MAPKs, IL-1β and TNF-α in SGCs under inflammatory conditions. Moreover, the increase in IL-1β and TNF-α was suppressed by L703, 606, U0126 and SB203580 in vivo and in vitro. These present findings suggested that SP, released from TG neurons, activated SGCs through the ERK1/2 and P38 pathways and promoted the production of IL-1β and TNF-α from SGCs, contributing to inflammatory orofacial pain associated with peripheral sensitization.
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Abstract Insomnia is a common condition whose pathophysiology is poorly understood. Large genetic studies have provided insights into the etiology of insomnia, highlighting biological pathways that are shared with other complex disorders. Increased focus on treating sleep problems in the clinic and through public health interventions may reduce the overall burden of disease in human populations.
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Migraine causes severe health and social issues worldwide. Rhynchophylline (Rhy) is one of the major active components of Uncaria rhynchophylla that is used for the treatment of headache in Traditional Chinese Medicine. In the current study, the effect of Rhy on nitroglycerin (NTG)-induced migraine was assessed and the associated mechanism was also explored to explain its function. Rats were pre-treated with Rhy of two doses (10 mg/kg and 30 mg/kg) and then subjected to NTG to induce migraine symptoms. Thereafter, the electroencephalogram (EEG) signaling, spontaneous behaviors, levels of indicators related to oxidative stress, and expression of calcitonin gene-related peptide (CGRP) were measured to assess the anti-migraine function of Rhy. Moreover, the activities of MAPK/NF-κB pathway under the administrations of Rhy were also detected. The results showed that NTG induced EEG and behavior disorders in rats, which was associated with the initiation of oxidative stress and increased expression of CGRP. Nevertheless, the pre-treatments with Rhy attenuated the damages induced by NTG by reversing the levels of all the above indicators. The results of western blotting demonstrated that the anti-migraine effect of Rhy was accompanied by the inhibition of MAPK/NF-кB pathway. The findings outlined in the current study revealed an alternative mechanism of Rhy in protecting brain tissues against migraine: the agent exerted its effect by suppressing MAPK/NF-кB pathway, which would ameliorate impairments associated with migraine.
Background: Migraine is a complex multifactorial disorder and its pathogenesis still remains unclear. Evidence suggests the involvement of the activated trigeminovascular pathway, in which BDNF seems to play an important role. Therefore, BDNF polymorphisms are promising candidate susceptibility factors. Aim: BDNF rs6265 functional polymorphism was analyzed in order to determine its possible association with pediatric headache and migraine risk. Methods: The research included 120 consecutive pediatric patients who were diagnosed with headache and 120 healthy controls. The diagnosis was in compliance with the International Classification of Headache Disorders. Blood samples were collected from all participants and genotyped for rs6265. Results: BDNF rs6265 was significantly associated with decreased headache risk, particularly in the dominant model [Odds Ratio, OR (95% confidence interval, C.I.): 0.47 (0.26–0.85), p = 0.011] and the log-additive model [OR (95% C.I.): 0.48 (0.28–0.82), p = 0.0053]. During the sensitivity analysis, the associations were also maintained among patients with migraine. Conclusions: This is the first study to reveal a significant association of this BDNF variant with headache risk. Additionally, Val66Met was also for the first time related to decreased childhood migraine risk.