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Abstract

Background

The genetic substrate for headache in the general population has not been identified in Asians. We investigated susceptible genetic variants for self-reported headache in a large community-based Asian population.

Methods

We conducted a genome-wide association study in participants recruited from a community-based cohort to identify the genetic variants associated with headache in Taiwanese. All participants received a structured questionnaire for self-reported headache. A total of 2084 patients with “self-reported headache” and 11,822 age- and sex-matched controls were enrolled. Gene enrichment analysis using the Genotype-Tissue Expression version 6 database was performed to explore the potential function of the identified variants.

Results

We identified two novel loci, rs10493859 in TGFBR3 and rs13312779 in FGF23, that are functionally relevant to vascular function and migraine to be significantly associated with self-reported headache after adjusting age, sex and top 10 principal components (p = 8.53 × 10⁻¹¹ and p = 1.07 × 10⁻⁸, respectively). Gene enrichment analysis for genes with GWAS suggestive significance (p < 10⁻⁶) demonstrated that the expression of these genes was significantly enriched in the artery (p = 8.18 × 10⁻⁴) and adipose tissue (p = 8.95 × 10⁻⁴).

Conclusion

Our results suggest that vascular dysfunction might play important roles in the pathogenesis of self-reported headache in Asian populations.

Keywords

Headache genome-wide association tissue expression

Introduction

Headache is among the most common neurological disorders worldwide. Headache can be subdivided into two main categories: Primary and secondary. The prevalence of primary headaches is considerably higher than that of secondary headaches (1); in other words, headaches encountered in the general population are mostly primary headaches. Three billion people are estimated to have headache, including 14.4% with migraine and 26.1% with tension-type headache. While the prevalence varies among different ethnicities, the disability attributable to migraine is the highest among neurological disorders reported worldwide (2). Asians have a lower migraine prevalence than Western populations, and the mechanism underlying the ethnic diversity of migraine has not been elucidated (3).

The genetic substrate of some primary headaches, such as migraine, has been explored in large-scale studies. Genome-wide association studies (GWASs) in Caucasians have identified more than 40 common genetic variants associated with migraine (4 –7). In contrast, GWASs for headache disorders from Asian populations are scarce. To date, only two GWASs in Asian migraine patients, both conducted in Taiwan, have been published (8,9). The results from these studies inferred that while there is a shared genetic basis across ethnicities, some genetic variants contributing to the complex pathogenesis of migraine might be specific to selected populations (8). In addition, we also identified that the genetic constituents of migraine in the clinic-based cohort were distinct from those in the community-based cohort (9).

Meanwhile, studies have suggested that primary headaches, such as migraine or tension-type headache, are heritable traits with heritability of over 40–60% (10,11). Notably, one GWAS for broadly-defined headache from the UK Biobank identified 28 genetic variants associated with headache, and half of the variants have been previously identified to be risk alleles for migraine (12). Hence, although detailed headache subtypes were not available, the results of this study suggest that even a simple broadly-defined headache phenotype has substantial genetic contribution. However, whether this finding could be generalized to other ethnicities has not been elucidated to date.

To identify the genetic variants associated with self-reported headache in Taiwanese individuals, we used a GWAS for participants recruited from the Taiwan Biobank (http://www.twbiobank.org.tw) in this community-based cohort (13). By identifying susceptibility genes for self-reported headache in Taiwanese individuals, we may help to elucidate the neurobiology of headache and the ethnic factors that may contribute to self-reported headache.

Material and methods

Ethical approval and patient consent

This study was approved by the Institutional Review Boards of Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, and Academia Sinica, Taiwan. The study was conducted according to the principles expressed in the Declaration of Helsinki. All participants have provided written informed consent before participating in the Taiwan Biobank study. All collected information was de-identified before statistical data analysis. The corresponding authors had full access to all of the data in the study and had final responsibility for the decision to submit the manuscript for publication.

Study participants and data collection

The Taiwan Biobank (TWB) is a general population-based public health research resource established by the National Center for Genomics Medicine, Academia Sinica, Taiwan, which recruited cancer-free adults aged between 30 and 70 years. Participants were required to complete a structured questionnaire that included questions on personal information and medical history. The questionnaire also inquired about headache history, specifically regarding a) personal and family history of headache, b) headache-associated symptoms, and c) the severity and frequency of headache attacks in the past 3 months. The questions were:

Do you have a history of migraine?

Do your family members have a history of migraine? If yes, please specify who he/she is.

Have you had a headache or migraine in the past three months?

3-1. When you had a headache, did the headache affect your work, study or daily life?

3-2. When you had a headache, was the intensity of the headache mild, moderate or severe?

3-3. When you had a headache, did you feel nausea?

3-4. When you had a headache, did you find the light make you uncomfortable?

Participants who had a “yes” response to either question 1 or 3 were considered as the self-reported headache group, and those with “no” responses to both questions were considered as the control group. As the response rate to the questions inquiring about specific headache features (i.e. questions 3-1, 3-2, 3-3 and 3-4) was low, we did not pursue detailed phenotyping from these questions in this study. Later, all participants were interviewed, and their questionnaires and medical records were reviewed simultaneously.

At the time of analysis, data from 23,996 participants were available from the TWB. After excluding participants with kinship relations within three generations, 21,858 participants were eligible for analysis. Individuals over 55 years old were also excluded to avoid the inadvertent recruitment of subjects with secondary headaches. Participants with a history of depression, bipolar disorder, schizophrenia, epilepsy or any major neuropsychiatric disorders were also excluded. Finally, 2084 patients with “self-reported headache” and 11,822 age- and sex-matched controls who had no personal or family history of headache were enrolled (Figure 1).

Figure 1.

Flow chart depicting the selection methods. Self-reported headache and control group selection flow chart. All subjects are between 30–55 years old. Individuals with kinship relation, depression, bipolar disorder, schizophrenia or epilepsy were excluded.

Single nucleotide polymorphism (SNP) genotyping and imputation

All study subjects received whole-genome SNP genotyping at the National Center for Genomics Medicine, Academia Sinica. A total of 653,291 SNPs were genotyped using the Affymetrix Axiom Genome-Wide TWB1 Array Plate (TWB1 Array; Affymetrix, Inc., Santa Clara, CA, USA), which was designed based on the CHB Array (8) and further included SNPs previously reported to have clinical significance in Taiwanese individuals (14). The genomic inflation factor (λ = 1.0247) was subsequently calculated, and principal component analysis (PCA) was conducted to identify the top 10 principal components (PCs) via PLINK. Logistic regression was used to evaluate association of SNPs with self-reported headache by adjusting age, sex, and the top 10 PCs of ancestry. PC1 and PC2 were plotted to assess systematic differences in the genetic composition between cases and controls (Figure 2).

Figure 2.

Principal component analysis (PCA) to assess systematic differences in the genetic composition. The PCA was conducted to identify the top 10 principal components (PCs). The x axis is PC1 and the y axis is PC2. The red dots represent the 11,822 controls and the blue dots represent the 2084 cases. The genomic inflation factor (λ = 1.0247) was calculated via PLINK.

We also utilized imputation data released by TWB for our GWAS. Well-imputed SNPs (information score >0.8) out of the 9,820,005 variants on chr1-chr22 were retained followed by systematic quality control (QC). The QC criteria were applied to exclude SNPs if they (a) were monomorphic in cases or controls, (b) had a total call rate <95% in cases and controls combined, (c) had a minor allele frequency of <5% and a total call rate of that allele <99% in cases and controls combined, (d) exhibited significant (p < 0.05) deviation from Hardy–Weinberg equilibrium in cases or controls, or (e) exhibited a significant difference in the genotype call rates between cases and controls (p < 0.05). For sample filtering, we excluded arrays with generated genotypes for fewer than 95% of loci. Finally, 7,842,171 imputation loci were yielded. We examined whether previously identified SNPs from GWASs for self-reported headache or migraine could be replicated in these patients. To confirm the statistical power of our study, post-hoc power analysis was done with the online Genetic Association Study power calculator (https://csg.sph.umich.edu/abecasis/gas_power_calculator/index.html) (15).

Gene enrichment analysis

To further explicate the GWAS results and determine how these genetic variants may contribute to the neurobiology of self-reported headache, we conducted tissue expression analysis from GTEx (https://www.gtexportal.org/home/) integrated in Functional Mapping and Annotation of GWAS (FUMA) (16,17). Enrichment analysis on gene sets with a suggestive level of GWAS significance (p < 1 × 10⁻⁶) was performed.

Statistical analysis

Genetic analyses were conducted using PLINK (version 1.9) (18). Six single-point methods; that is, genotype, allele-type, and Cochran–Armitage trend tests along with tests considering additive, dominant, and recessive models by comparing allele/genotype/haplotype frequencies, were applied for the association analyses. Manhattan and quantile-quantile (Q-Q) plots were graphed using the R package.

Results

Baseline characteristics of the subjects

After excluding those with kinship relations and ID mismatches, we recruited 2084 self-reported headache patients and 11,822 sex-matched, population-based controls (Figure 1). The demographic characteristics of the participants are shown in Table 1. A total of 13,906 subjects were recruited, and 15% of them have self-reported headache.

Table 1.

Baseline characteristics of study subjects.

Characteristics	n	Mean age, mean ± SD	M/F (%)
Self-reported headache	2,084	41.74 ± 6.98	677 (32.49)/1,407 (67.51)
Controls	11,822	42.24 ± 7.13	6,257 (52.93)/5,565 (47.07)

GWAS result

We identified three SNPs (rs10493859, rs720333, and rs713744) that reached GWAS significance of p < 1 × 10⁻⁸ in real genotyping data. Using the whole genome imputation data, two SNPs identical to the real genotyping data (rs720333 and rs713744) and another four novel SNPs (rs10849051, rs7308018, rs10744645, and rs13312779) attained GWAS significance. Among these seven SNPs, two were within or near a gene (within 200 kb), while the other five were intergenic variants (Figure 3, Table 2). The two novel loci that were within or near a gene, rs10493859 in transforming growth factor beta receptor 3 (TGFBR3) and rs13312779 in fibroblast growth factor 23 (FGF23), were significantly associated with self-reported headache in a community-based cohort in Taiwan. The ORs and 95% CIs of TGFBR3 and FGF23 were 0.513 (0.422–0.623) and 1.215 (1.137–1.298), and p-value (adjusted with age, sex, and the top 10 PCs of ancestry) were 8.53 × 10⁻¹¹ and 1.07 × 10⁻⁸, respectively. PCA (Figure 2) and Q-Q plot (Figure 4) suggested that there was little evidence of population stratification in our study sample. Post-hoc power analysis was done by using the information of rs10493859, which was the SNP with the most significant p-value in our study (risk allele frequency = 0.02). By using an additive disease model (case: n = 2084; control: n = 11,822; case-control ratio = 0.176; significance level p = 1 × 10⁻⁸, prevalence = 0.15; genotype relative risk = 2), the calculated statistical power of our study was 0.92.

Figure 3.

Manhattan plot of GWAS on self-reported headache using the Taiwan Biobank community-based cohort. The x axis is chromosomal position and the y axis is the significance (–log10 p) of association derived by Cochran– Armitage trend tests. The red represents the whole genome imputation data and the blue represents real genotyping data.

Table 2.

Association results for self-reported headache in Taiwanese.

Locus rank	SNP	Chr	Gene	Position	Riskallele	MAF(case, control)	OR	95% CI	p(allelic)	p(trend)^c
1	rs10493859	1	TGFBR3	92273644	A	(0.0272, 0.0518)	0.513	0.422–0.623	3.54 × 10^−13a	8.53 × 10⁻¹¹
2	rs10849051	12	Intergenic	4498407	C	(0.4998, 0.4498)	1.22	1.143–1.303	2.84 × 10^−9b	3.74 × 10⁻⁹
3	rs7308018	12	Intergenic	4497672	A	(0.4998, 0.4499)	1.22	1.142–1.303	2.84 × 10^−9b	3.85 × 10⁻⁹
4	rs720333	12	Intergenic	4493938	G	(0.5007, 0.4519)	1.215	1.138–1.297	5.99 × 10^−9a	8.12 × 10⁻⁹
5	rs7131744	12	Intergenic	4496280	G	(0.536, 0.4867)	1.218	1.14–1.301	4.46 × 10^−9a	3.59 × 10⁻⁹
6	rs10744645	12	Intergenic	4495795	T	(0.4995, 0.4506)	1.216	1.138–1.298	5.72 × 10^−9b	7.91 × 10⁻⁹
7	rs13312779	12	FGF23	4483976	G	(0.4968, 0.4482)	1.215	1.137–1.298	8.98 × 10^−9b	1.07 × 10⁻⁸

SNP: single nucleotide polymorphism; Chr: chromosome; OR: odds ratio; CI: confidence interval; MAF: minor allele frequency; P (trend): the p-values of the trend test; Risk allele: allele with higher frequency in cases compared to controls.

^aReal genotyping data.

^bImputation data.

^cAdjusted with age, sex, and the top 10 principal components of ancestry.

Figure 4.

Quantile-quantile plot of results from genotyped data. Q-Q plot showed little evidence for population stratification.

In addition to the seven SNPs that reached GWAS significance, SNPs with suggestive significance were also investigated. Six additional genes were identified: cut like homeobox 1 (CUX1), protein kinase, camp-dependent, regulatory, type II, beta (PRKAR2B), chondroitin sulfate synthase 3 (CHSY3), Hedgehog acyltransferase (HHAT), nuclear factor I/B (NFIB), and serine/threonine protein kinase 38-like protein (STK38L) (Supplementary Table 1,2 (8,12)).

Gene enrichment analysis by FUMA

To determine whether these loci are enriched for expression in different tissue types, we performed tissue expression analysis by GTEx (version 6) integrated in the FUMA. We evaluated the expression of the two genes that reached GWAS significance and six genes with GWAS suggestive significance in the 53 specific tissue types in the GTEx version 6 database. The expression levels of the genes associated with self-reported headache were significantly enriched in the arterial tissue (i.e. aorta) (p = 8.18 × 10⁻⁴). Enrichment analysis also indicated that the expression levels of the genes were upregulated in adipose tissue (p = 8.95 × 10⁻⁴) (Figure 5).

Figure 5.

Gene enrichment analysis of 53 specific tissues by GTEx ver. 6 in FUMA. The expression levels of the genes associated with self-reported headache were significantly enriched in the arterial tissue and upregulated in adipose tissue.

Discussion

To the best of our knowledge, this study is the first GWAS of self-reported headache in Taiwanese and Asians. We found two susceptibility genes, TGFBR3 and FGF23, that are functionally relevant to the pathogenesis of self-reported headache. While TGFBR3 might implicate vascular dysfunction by altering the transforming growth factor-β (TGFβ) signaling pathway (19), FGF23 has been implicated in migraine pathogenesis by affecting vascular function (6). Corroborating this finding, gene enrichment analysis demonstrated that the genes associated with self-reported headache in our population were highly enriched in vascular tissue, which was consistent with the finding of the largest migraine GWAS meta-analysis (6).

TGFBR3 is a novel gene that we determined to be associated with self-reported headache. The TGF-β signaling pathway can modulate tissue development and repair processes, such as cell differentiation, cell cycle progression, cellular migration, adhesion, and extracellular matrix production (20). The TGFβ receptor (TGFBR) and cell surface-binding proteins involved in the signaling pathway are essential for normal brain vascular development (21). TGFBR2 is known to be associated with vascular disease (22). Interestingly, a previous clinic-based migraine GWAS identified TGFBR2 as one of the novel susceptibility genes (7). We surmised that TGFBR3 might contribute to a self-reported headache phenotype with similar mechanisms. For example, TGFBR3 often binds to other TGFBR superfamily members and functions as a coreceptor to initiate signaling (20). Second, TGFBR3 is a potential negative regulator of TGFβ signaling to protect vessels from damage and dysfunction (23). As vascular dysfunction has been reportedly important in the pathogenesis of migraine in multiple studies (6,24 –27), we suspect that TFGBR3 might be one of the mediators that contribute to impaired vascular function in patients with self-reported headache.

The second susceptible gene that we identified is FGF23. FGF23 is a physiological regulator of serum phosphate. This protein helps to maintain normal phosphate levels by inhibiting renal tubular phosphate transport. It also controls vitamin D metabolism by negatively regulating osteoblast differentiation and bone matrix mineralization (28). Therefore, FGF23 is essential for normal phosphate and vitamin D metabolism. Disturbance of phosphate homeostasis is a risk factor for cardiovascular diseases. A previous study showed that FGF23-related hyperphosphataemia causes endothelial and vascular dysfunction by disrupting the nitric oxide pathway (29,30). Meanwhile, elevated FGF23 is positively related to small vessel disease and magnetic resonance imaging-defined brain infarction (31). This evidence suggests that FGF23 is associated with subclinical cerebrovascular damage. In our study, we proposed that FGF 23 is associated with a self-reported headache phenotype, which might be mediated by cerebrovascular dysfunction. In keeping with our data, a previous GWAS found that the genomic locus rs1024905 is significantly related to migraine without aura, which is between FGF6 (25 kb downstream) and FGF23 (29 kb upstream) (6).

Our gene enrichment analysis by combining FUMA showed that self-reported headache is significantly related to arterial tissue. This result corresponds with a previous migraine GWAS study, suggesting that the loci related to migraine were enriched for genes expressed actively in arterial tissue (6). Recent studies have found overlaps of genetic risk loci for migraine, ischemic stroke, and coronary heart disease (32,33). Commonality among these disorders indicates that shared biological processes may contribute to vessel dysfunction (24,26,34). Furthermore, increased aortic stiffness and central systolic blood pressure are found among migraineurs without overt vascular risk factors (26,27). Our finding is compatible with this theory, supporting the role of vascular dysfunction in migraine pathogenesis. We also found that our identified loci were significantly enriched in adipose tissue. It is known that migraine is comorbid with obesity, and adipokines from adipose tissue are believed to be associated with migraine (35,36). Altered blood levels of adipokines are noted in patients with migraine (37) and even in non-obese chronic migraineurs (38). Based on the findings, it is possible that adipose tissue also plays an important role in the pathogenesis of self-reported headache. Combined with this supportive evidence, we proposed that both vascular and adipokine dysfunction are associated with a self-reported headache phenotype in Taiwanese patients.

There are several implications in our study. First, this study is the first community-based GWAS of self-reported headache in Taiwanese individuals. Asians are known to have different headache phenotypes demographically compared with Caucasians (39). Instead of narrowing to a specific subtype of headache, we expanded our scale to evaluate self-reported headaches that are encountered most often in the general population. While the identified risk loci did not replicate the findings of the UK Biobank study (12), they may indicate that self-reported headaches may have different genetic constituents among different ethnicities. In fact, our previous clinic-based migraine GWAS indicated that the genetic constituents could be different for migraine across ethnicities (8). Second, our results indicate that vascular mechanisms may be important in self-reported headaches, which include not only migraine but also other primary headaches, such as tension-type headache. Vasogenic mechanisms are considered to have a shared polygenic basis between migraine, stroke, and cardiovascular disease (32,33). While vascular dysfunction has been clearly demonstrated in migraine, the role of the cerebrovascular system in other primary headaches still needs to be elucidated.

There are several limitations in our study. First, the phenotype of self-reported headache could not be fully evaluated. This is a common limitation of large community-based studies. Whether the susceptibility genes are related to specific types of primary headaches remains to be explored. Second, previously identified SNPs significant for clinic-based migraine patients in Taiwan were not replicated in this study. This might imply that the genetic constituents for headaches in community-based cases are different from migraine in clinic-based cases, which could be supported by our previous study showing that HLA class I variants contribute only to clinic-based migraine patients but not community-based migraine patients (9). Third, our sample size is relatively smaller. While the UK Biobank used a larger sample size of over 70,000 cases, our sample size is around 2000. Nevertheless, post-hoc power analysis indicated that it was still adequately powered. Also, our subjects are younger when comparing with the UK Biobank (41.74 ± 6.98 years old vs. 54.38 ± 7.95 years old) (12). These differences may interfere with the results. Fourth, around 40% of samples have been removed and this may have significant impact on the GWAS and tissue expression results. We applied stricter inclusion criteria, such as removing samples with mental health issues and limiting the age to less than 55 years old, to decrease the interferences from secondary headaches. Hence, our cases were more homogeneous and less broadly defined than those included in the UK study (12). As previous studies suggested that headache and mental illness might have shared genetic factors (40), excluding those with mental illness could fail to identify such correlation. Further study to investigate the genetic correlation between headache and mental illness phenotype, such as using the cross-trait linkage disequilibrium score regression (LDSC) method (41), should be considered in the future. Fifth, the prevalence of self-reported headache in this TWB cohort is lower than the broadly-defined headache reported in the UK biobank study (15% vs. 33.3%) (12). Concerning the prevalence of migraine in Taiwan also being lower than the global prevalence of (9.1% vs. 14.4%) (42,43), it is possible that the differences came from ethnic diversities. Also, the prevalence of self-reported headache in this study is higher than that of migraine in Taiwan (42), indicating that patients with primary headaches other than migraine, such as tension-type headache, were likely also recruited in our self-reported headache group. Finally, although there is supportive evidence showing that the two genes we identified might be related to self-reported headaches, how they contribute to the pathogenesis remains to be confirmed.

Conclusion

We identified two susceptibility genes, TGFBR3 and FGF23, which are associated with self-reported headaches in Taiwanese individuals. These two genes are functionally relevant to self-reported headaches, probably by altering vascular function. Future studies are needed to elucidate the commonalities and diversities of headache susceptibility genes among different ethnicities and thus obtain a better understanding of the pathogenesis of headache disorders.

Clinical implications

The genetic contribution of the self-reported headache phenotype is substantial, and there may be a shared genetic basis of self-reported headache and migraine in Asians.

Two susceptibility genes for self-reported headache, TGFBR3 and FGF23, are functionally relevant to vascular function and expressed actively in arterial tissue.

Vascular dysfunction might play important roles in the pathogenesis of self-reported headaches and possibly also in migraine.

Supplemental Material

sj-pdf-1-cep-10.1177_03331024211037269 - Supplemental material for Genome-wide association study reveals susceptibility loci for self-reported headache in a large community-based Asian population

Supplemental material, sj-pdf-1-cep-10.1177_03331024211037269 for Genome-wide association study reveals susceptibility loci for self-reported headache in a large community-based Asian population by Yu-Chien Tsao, Shuu-Jiun Wang, Chia-Lin Hsu, Yen-Feng Wang, Jong-Ling Fuh, Shih-Pin Chen and Cathy Shen-Jang Fann in Cephalalgia

Footnotes

Acknowledgment

This research has been conducted using the Taiwan Biobank Resource. We thank all study participants for their generous contribution and the Taiwan Biobank for making the data available.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Brain Research Center, National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (SPC and SJW); the Ministry of Science and Technology, Taiwan [MOST-107-2314-B-010-021, 108-2314-B-010 -022 -MY3 & MOST 110-2326-B-A49A-501 -MY3 (SPC); MOST 108-2321-B-010-014-MY2, MOST 108-2321-B-010-001-, MOST 108-2314-B-010-023-MY3 & MOST 110-2321-B-010 -005 - (SJW); and MOST 108-2314-B-001-007 & MOST 109-2314-B-001 -006 -MY2 (CSF]; Ministry of Health and Welfare, Taiwan [MOHW107-TDU-B-211-123001 and MOHW 108-TDU-B-211-133001] (SJW); Taipei Veterans General Hospital, Taiwan [VGH-109-C-090 & V109E-005-1 (SJW); VGH-109-C-139 and VGH-109-D52-001-MY3-1 (SPC)]. The funders of the above facilities had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication

ORCID iDs

Shuu-Jiun Wang

Yen-Feng Wang

Shih-Pin Chen

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