Genome-wide association study identifies novel susceptibility loci for migraine in Han Chinese resided in Taiwan

Abstract

Background

Susceptibility genes for migraine, despite it being a highly prevalent and disabling neurological disorder, have not been analyzed in Asians by genome-wide association study (GWAS).

Methods

We conducted a two-stage case-control GWAS to identify susceptibility genes for migraine without aura in Han Chinese residing in Taiwan. In the discovery stage, we genotyped 1005 clinic-based Taiwanese migraine patients and 1053 population-based sex-matched controls using Axiom Genome-Wide CHB Array. In the replication stage, we genotyped 27 single-nucleotide polymorphisms with p < 10⁻⁴ in 1120 clinic-based migraine patients and 604 sex-matched normal controls by using Sequenom. Variants at LRP1, TRPM8, and PRDM, which have been replicated in Caucasians, were also genotyped.

Results

We identified a novel susceptibility locus (rs655484 in DLG2) that reached GWAS significance level for migraine risk in Han Chinese (p = 1.45 × 10⁻¹², odds ratio [OR] = 2.42), and also another locus (rs3781545in GFRA1) with suggestive significance (p = 1.27 × 10⁻⁷, OR = 1.38). In addition, we observed positive association signals with a similar trend to the associations identified in Caucasian GWASs for rs10166942 in TRPM8 (OR = 1.33, 95% confidence interval [CI] = 1.14–1.54, P_permutation = 9.99 × 10⁻⁵; risk allele: T) and rs1172113 in LRP1 (OR = 1.23, 95% CI = 1.04–1.45, P_permutation = 2.9 × 10⁻²; risk allele: T).

Conclusion

The present study is the first migraine GWAS conducted in Han-Chinese and Asians. The newly identified susceptibility genes have potential implications in migraine pathogenesis. DLG2 is involved in glutamatergic neurotransmission, and GFRA1 encodes GDNF receptors that are abundant in CGRP-containing trigeminal neurons. Furthermore, positive association signals for TRPM8 and LRP1 suggest the possibility for common genetic contributions across ethnicities.

Keywords

Migraine genome-wide association study Taiwan Han Chinese Asian

Introduction

As the most common and disabling complex neurological disorder in humans, migraine is characterized by recurrent throbbing headache that may be associated with nausea, vomiting, photophobia, or phonophobia (1,2). The global one-year prevalence of migraine is 14.6% (1). In Asians, this prevalence is 9.1% (3). Clinically, migraine can be classified into migraine with or without aura, according to the International Classification of Headache Disorders (ICHD) (4,5). Migraine with aura accounts for approximately one-third of migraine cases in Western countries, but only about one-tenth of cases in Asians (3). Migraine-associated photophobia is also less commonly noted in Asian patients with migraine (6,7). These differences suggest that the genetic contribution of migraine pathogenesis could vary across different ethnic groups.

Recently, genome-wide association studies (GWASs) in Caucasians have identified common genetic variants associated with migraine with or without aura (8 –12). Collectively, 38 genetic variants have been identified (8 –12). Three of these variants, in LRP1 (8 –10,12), TRPM8 (8 –10,12), and PRDM16 (8,10,12), have been repeatedly replicated in most of the GWASs . However, whether these genetic variants in Caucasian populations also contribute to migraine susceptibility in other ethnic groups remains unclear. For example, a protective effect of LRP1 rs11172113 on migraine was noted in an Indian population (p = 0.009, odds ratio [OR] = 0.603) (13), similarly to Caucasians (8 –10), but this effect was not found in a Chinese population (14,15). TRPM8 (rs10166942) failed to show any association with migraine in studies of Chinese populations with small sample sizes (14,15).

The purpose of this study was to report the first GWAS of migraine in Asians. We performed a two-stage case-control GWAS using clinic-based migraine patients and population-based controls as discovery and validation cohorts. We sought to identify susceptibility genes for migraine without aura in Han Chinese residing in Taiwan.

Materials and methods

Ethics

This study was approved by the Institutional Review Boards of Taipei Veterans General Hospital, National Yang-Ming University, and Academia Sinica, Taiwan. Written informed consent was obtained from each participant after full explanation of the study objectives and procedures. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. 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 for publication.

Study participants and data collection

This study was a two-stage case-control GWAS, including a discovery cohort and a replication cohort. The initial significant findings of the discovery cohort were validated in the replication cohort, and a combined analysis of both cohorts was employed to examine the significance of the validated SNPs. For this study, including the discovery and replication cohorts of the case-control GWAS, we enrolled patients with migraine from headache or neurologic clinics in Taiwan. We recruited 85% of subjects from a single tertiary medical center (Taipei Veterans General Hospital) (Supplementary Figure 1). The discovery and replication cohorts were recruited based on the time they entered the study. Subjects who were recruited before 2012 were included in the discovery cohort and subjects recruited after that were assigned to the replication cohort.

All participants filled out a structured questionnaire that included questions on personal information, medical history, and headache history. Participants were interviewed, with their questionnaires and medical records reviewed simultaneously, by board-certified neurologists who were experienced in headache diagnosis. Diagnosis of migraine was made according to the criteria proposed in the ICHD, 2nd edition (4).

Some categories of patients were excluded from this study. First, patients with migraine with aura were excluded for two reasons: (a) The low prevalence of aura in Taiwanese migraine patients (10%) made it difficult to achieve an adequate sample size for acceptable statistical power; (b) a meta-analysis of GWASs found that with the same sample size, the power to identify risk alleles for migraine without aura was higher than that for migraine with aura (10). Second, patients with “age at onset > 35 years old” (16) were excluded. This condition was set to enrich the genetic component, because migraine is a complex disease that is subject to environmental influences (only ∼ 50% heritability). Third, after employing questionnaires to quasi-quantify the severity of psychological disturbance, patients with a Beck Depression Inventory (BDI) score greater than 20 were excluded. This criterion was used because genetic risk score analysis showed that migraine with and without comorbid depression might be genetically different disorders (17). Fourth, patients were excluded if they had a history of head injury. Fifth, Taiwanese aborigines were excluded to ensure that all participants were of Han Chinese descent.

All clinical information was uploaded to the digitalized Clinical Study Information System for computation. Control subjects in the discovery and replication cohorts of the case-control GWAS were obtained from a representative genomic sample randomly selected from The Cell Bank and Genetic Database of Non-Aboriginal Taiwanese (18). Subjects with a history of migraine were excluded by using a validated pre-enrollment screening questionnaire. The control groups were age- and sex-matched to the patient groups in both discovery and replication cohorts. The baseline characteristics of participants in both cohorts were analyzed.

Genotyping in the discovery cohort

In the discovery stage, we genotyped 642,832 single-nucleotide polymorphisms (SNPs) using the Affymetrix Axiom Genome-Wide CHB 1 Array Plate, which has the highest coverage of genome-wide common variants for Han Chinese, at the National Center for Genomics Medicine, Academia Sinica, Taiwan . SNP genotypes were called using the Axiom GT1 algorithm. Quality control (QC) criteria for SNPs were applied to exclude SNPs if they (a) were monomorphic in both cases and controls, (b) had a total call rate of less than 95% in cases and controls combined, (c) had a minor allele frequency of less than 5% and a total call rate of less than 99% in cases and controls combined, or (d) showed significant (p < 1 × 10⁻⁸) deviation from Hardy–Weinberg equilibrium in controls . For sample filtering, we excluded arrays with generated genotypes for fewer than 95% of loci.

Heterozygosity of SNPs on the X chromosome was used to verify the sex of the samples. PLINK version 1.07 software (19) was used to identify samples with genetic relatedness, indicating that they were from the same individual (or monozygotic twins) or from first, second or third degree relatives. These determinations were made on the basis of evidence for cryptic relatedness from identity-by-descent status (pi-hat cutoff of 0.125). After QC filtering, 590,945 autosomal SNPs in 1005 cases and 1053 controls were retained for analysis.

Genotyping in the replication cohort

We selected SNPs with a trend p value < 1 × 10⁻⁴, and that were within 200 kb of a gene for replication. SNPs with a trend p value < 1 × 10⁻⁴ but not within 200 kb of a gene were not chosen for replication because 1) we aimed to explore genes with known biological functions as a first step and 2) this would reduce the offsets from corrections for multiple comparisons considering our limited case numbers. We also genotyped variants at LRP1 (8 –10,12), TRPM8 (8 –10,12), and PRDM16 (8,10,12), which have been replicated in multiple Western migraine cohorts. Genotyping was performed in a replication cohort of 1120 unrelated migraine cases and 604 control individuals using the Sequenom MassARRAY iPLEX platform (Sequenom Inc, San Diego, CA, USA) via the service provided by the National Center for Genomics Medicine, Academia Sinica, Taiwan.

Genotype imputation analysis

We conducted a genotype imputation analysis in the discovery cohort using the 1000 Genomes Phase 3 reference data (20) and IMPUTE2 as implemented (21 –23). Well-imputed SNPs (info score > 0.4) were retained followed by systematic QC, as described above (24).

Statistical analysis

Association analyses were carried out by comparing allele/genotype/haplotype frequencies between migraine cases and controls using six single-point methods: Genotype, allele-type, and Cochran–Armitage trend tests along with tests considering additive, dominant, and recessive models. The distribution of expected p values under the null hypothesis and genomic inflation value (λ) were calculated. We created the Manhattan and quantile-quantile (Q-Q) plots using the R package (25). Genetic analyses were conducted using PLINK (version 1.07) (19).

Detection of possible population stratification was carried out by using principal component analysis (PCA) as implemented in EIGENSTRAT to infer continuous axes of genetic variation (Supplementary Figure 2) . We adjusted for potential genetic heterogeneity by incorporating the first two or first 10 PCs in the logistic regression tests of association with migraine without aura. Joint analysis was conducted by combining data from the discovery and validation samples of the case-control GWAS.

Results

Study participants

We conducted a two-stage GWAS to identify genetic variants for migraine among Han Chinese residents of Taiwan (Supplementary Figure 1). During the enrollment period, 69 patients in total with age at onset > 35, 275 patients with beck depression inventory (BDI) >20, and 80 patients with both age at onset > 35 and BDI > 20 were excluded from the study during enrollment . In the discovery cohort of the case-control GWAS, we recruited 1005 clinic-based migraine patients and 1053 sex-matched, population-based controls. In the replication cohort, we examined 1120 independent clinic-based migraine patients and 604 sex-matched population-based controls. Demographic characteristics of participants are shown in Table 1.

Table 1.

Baseline characteristics of participants.

Characteristic	N	Mean age ± SD (y)	M/F, n (%)	p
Discovery GWAS
Control	1053	45.8 ± 14.8	217 (20.6)/836 (79.4)	0.647
Case	1005	38.8 ± 12.5	198 (19.7)/807 (80.3)
Replication
Control	604	53.2 ± 18.0	111 (18.4)/493 (81.6)	0.527
Case	1120	37.2 ± 10.8	220 (19.6)/900 (80.4)
Combined
Control	1657	48.5 ± 16.4	328 (19.8)/1329 (80.2)	0.920
Case	2125	38.0 ± 11.7	418 (19.7)/1707 (80.3)

Association analysis of GWAS

In the first stage, we genotyped 1005 cases and 1053 controls using the Affymetrix Axiom Genome-Wide CHB 1 Array Plate (Figure 1). After applying stringent QC criteria, we obtained 590,945 (91.93%) SNPs with an average call rate of 99.66% ± 0.43%. The value of the genomic inflation factor was 1.037, suggesting that there was little evidence for population stratification in our study sample (Figure 2). PCA showed no outliers (Supplementary Figure 2).

Figure 1.

Manhattan plot for migraine association. Manhattan plot of the discovery genome-wide association analysis of 1005 cases and 1053 controls. The x axis is chromosomal position and the y axis is the significance (–log₁₀ p) of association derived by Cochran–Armitage trend tests.

Figure 2.

Quantile-quantile plot of results from the Cochran-Mantel-Haenszel analysis. Red line represents the distribution of p values under the null hypothesis, given a study inflation factor (λ) of 1.037.

In total, 52 SNPs showed significant (p < 10⁻⁴) associations with migraine in the discovery stage, and 27 SNPs within or near (within 200 kb) a gene were genotyped in an independent cohort for replication. We identified a novel locus, rs655484 in disks large homolog 2 (DLG2), which was significantly associated with migraine in both discovery and validation cohorts. Another locus, rs3781545 in GDNF family receptor alpha-1 (GFRA1), although it only has suggestive GWAS significance in combined analysis, also passed our a priori criteria of significance for discovery and validation. (Table 2, Figure 3).

Table 2.

Association results for migraine without aura in Han Chinese resided in Taiwan.

						Risk allele frequency					Joint analysis of stage 1 + 2
SNP	Chr	Gene	Position	Risk allele	Stage	Migraine	Control	OR	95% CI	p (trend)	OR	95% CI	p (trend)	p (PC2)	p (PC10)
rs10803531	2	GPR39	133227542	C	1	0.972	0.949	1.878	1.352–2.610	1.356 × 10⁻⁴
					2	0.964	0.951	1.358	0.966–1.909	7.708 × 10⁻²	1.580	1.256–1.989	8.306 × 10⁻⁵	1.719 × 10⁻⁴	1.291 × 10⁻⁴
rs7565931	2	UPP2	158888869	C	1	0.237	0.185	1.366	1.174–1.588	5.000 × 10⁻⁵
					2	0.223	0.196	1.179	0.991–1.404	6.346 × 10⁻²	1.276	1.140–1.429	2.246 × 10⁻⁵	8.164 × 10⁻⁵	7.188 × 10⁻⁵
rs3781545	10	GFRA1	117949460	G	1	0.842	0.784	1.472	1.255–1.727	1.809 × 10⁻⁶
					2	0.829	0.795	1.266	1.048–1.530	1.436 × 10⁻²	1.378	1.223–1.553	1.265 × 10⁻⁷	9.270 × 10⁻⁷	5.546 × 10⁻⁷
rs655484	11	DLG2	84183435	C	1	0.974	0.941	2.338	1.678–3.255	2.466 × 10⁻⁷
					2	0.979	0.953	2.337	1.565–3.490	2.133 × 10⁻⁵	2.423	1.883–3.118	1.448 × 10⁻¹²	5.082 × 10⁻⁸	4.383 × 10⁻⁸

Abbreviations: SNP, single nucleotide polymorphism; Chr, chromosome; OR, odds ratio for risk allele; CI, confidence interval; PC, principal component. Stage 1 (GWAS) included 1005 cases and 1053 controls. Stage 2 (replication stage) included 1120 cases and 604 controls. P (trend), the p values of the trend test. P (PC2) and p (PC10) are p values adjusted by the first two or first 10 PCs, respectively. Risk allele, allele with higher frequency in cases compared to controls. All genomic information is from human genome build hg19.

Figure 3.

Regional plots of association signals. Regional plots for two newly identified loci associated with migraine in the discovery cohort. Each regional plot shows the chromosomal position (GRCh37/hg19) of SNPs in the specific region against –log₁₀ p values from association results of genotyped and imputed SNPs in stage 1 GWAS samples and stage 2 replication samples.

In the discovery dataset, rs655484 in DLG2 was the most significant SNP (OR = 2.34, p = 2.47 × 10⁻⁷). The association between rs655484 and migraine was further confirmed in the validation dataset, with a similar genetic impact (OR = 2.34, p = 2.1 × 10⁻⁵). Joint analysis of both cohorts showed a strong association between rs655484 in DLG2 and migraine (p = 1.45 × 10⁻¹²). The results remained significant after adjustment for PCs from a population stratification analysis (Table 2).

The second most significant SNP in the discovery cohort was rs3781545 in GFRA1 (OR = 1.47, p = 1.81 × 10⁻⁶). In the discovery stage, there were two genotyped SNPs and 14 imputed SNPs in GFRA1 with p < 10⁻⁴, supporting a strong association between GFRA1 and migraine susceptibility (Figure 3). The significant association was confirmed in the validation cohort. Joint analysis of both cohorts showed that rs3781545 in GFRA1 increased migraine risk by 1.38-fold (p = 1.27 × 10⁻⁷).

Also significantly associated with migraine in the discovery cohort were two other SNPs, rs10803531 in G protein-coupled receptor 39 (GPR39; p = 1.34 × 10⁻⁴) and rs7565931 in uridine phosphorylase 2 (UPP2; p = 5.00 × 10⁻⁵). Although the associations became less significant (with marginal p values) in the validation cohort, joint analysis of both cohorts showed significant associations between these two SNPs and migraine susceptibility. SNP rs10803531 in GPR39 was associated with a 1.58-fold risk of migraine (p = 8.31 × 10⁻⁵), and rs7565931 in UPP2 was associated with a 1.28-fold risk (p = 2.25 × 10⁻⁵). The results were similar after we adjusted for PCs from a population stratification analysis (Table 2).

Replications of genetic variants identified in Caucasian GWASs

We examined whether SNPs that have been repetitively found to be associated with migraine risk in Caucasians (i.e., TRPM8, LRP1, and PRDM16) were also associated with migraine in our cohort of Han Chinese migraine patients. We observed positive association signals with a similar trend to the associations identified in Caucasian GWASs for rs10166942 in TRPM8 (OR = 1.33, 95% CI = 1.14–1.54, P_permutation = 9.99 × 10⁻⁵; risk allele: T) and rs1172113 in LRP1 (OR = 1.23, 95% CI = 1.04–1.45, P_permutation = 2.9 × 10⁻²; risk allele: T). Results from an imputation analysis of data from the 1000 Genomes Phase 3 project revealed similar trends.

Discussion

To the best of our knowledge, this report describes the results of the first migraine GWAS to be performed in an Asian population. We identified two novel migraine susceptibility genes, DLG2 and GFRA1, both of which had plausible pathogenic implications in migraine. Of note, only the association for DLG2 was significant at GWAS significance level, whereas the associations for GFRA1, as well as the other two genes GPR39 and UPP2, were only of suggestive significance. Furthermore, by testing for loci in TRPM8 and LRP1 in the replication stage, we identified two migraine susceptibility genes with positive association signals similar to those previously found in GWASs in Western populations.

DLG2 encodes a protein of the membrane-associated guanylate kinase family and forms a postsynaptic multimeric scaffold for the clustering of receptors, ion channels, and signaling proteins. This gene might have several functions in migraine pathogenesis. First, DLG2 is related to the expression of glutamate receptor NMDAR and NMDAR-mediated postsynaptic excitotoxicity (26,27). The role of glutamate in migraine pathogenesis has been widely demonstrated (28,29). Copy number variants or mutations disrupting DLG2 affect the risk of schizophrenia (30 –32), another disease in which glutamate plays an important role . Second, DLG2 is associated with nociception, as demonstrated by marked losses of NMDAR-dependent morphine analgesic tolerance (33) and blunted NMDAR-dependent persistent pain induced by peripheral nerve injury (26) in DLG2 knock-out mice.

We found that rs3781545 in GFRA1 was associated with an increased risk of migraine. According to the Genotype-Tissue Expression (GTEx) project (34), brain expression levels of GFRA1 varied among different rs3781545 genotypes (Supplementary Figure 3). Individuals carrying different alleles of rs3781545 might have distinct GFRA1 expressions that alter pain threshold and migraine susceptibility. GFRA1 protein is widely expressed in neurons of the human spinal trigeminal nucleus (35) and trigeminal ganglion, especially neurons containing calcitonin-gene related peptide (CGRP) (36). These observations support the direct relevance of GFRA1 in the trigeminovascular pathway of migraine pathogenesis. Reduced levels of GDNF, the ligand of GFRA1, were found in the cerebrospinal fluid of chronic migraine patients (37). Another SNP (rs7015657) near GFRA2 was associated with migraine with aura in a previous genome-wide meta-analysis (10). GFRA3 is expressed in TRPM8-positive neurons. Its ligand, artemin, can induce cold pain in a TRPM8-dependent manner (38). All of these observations support the potential role of the glial cell line-derived neurotrophic factor family in migraine pathogenesis.

GPR39 is a G protein coupled metabotropic Zn²⁺ receptor, and widely expressed in the brain (39). The role of GPR39 in migraine pathogenesis has not been reported. GPR39 is associated with the zinc-related changes in the level of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), and GPR39 knockout mice show depression and anxiety-like behavior (40). In addition, the expression of GPR39 is downregulated by inhibition of serotonergic, noradrenergic, and dopaminergic transmission and potentiated by glutamatergic transmission (41). GPR39 may pave a novel pathway in the migraine pathogenesis.

UPP2 encodes uridine phosphorylase 2, which catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil. Uridine, a substrate for the synthesis of DNA, RNA, membrane constituents, and glycosylation, is a major pyrimidine nucleoside taken up by the brain. UPP2 is important in sensing and initiating cellular responses to oxidative stress (42). These findings are consistent with the proposed mechanisms in a previous meta-analysis of migraine GWASs (10).

Our study has several implications. First, our findings provide genetic evidences to support prevailing theories of migraine pathogenesis, including glutamatergic neurotransmission, altered nociception, and oxidative stress (10,28,29). The novel genes that we identified all have been implicated in regulating glutamatergic/GABAergic homeostasis. LRP1 is also important for glutamatergic neurotransmission, while DLG2, GFRA1, and TRPM8 are important for nociception. UPP2 and LRP1 could contribute to the response of oxidative stress. Second, the successful replication of TRPM8 and LRP1 identified in GWASs from Western countries validates our migraine ascertainment and suggests a shared genetic basis of migraine across ethnic groups. Third, our novel findings, despite having only small to moderate effect size, have the highest odds ratio among the SNPs that have been reported in migraine GWASs (8 –12). Thus, a clinic-based approach with experts specialized in headache diagnoses, with face-to-face interview for individual patients, is more likely to identify novel variants for patients at the severe end of the disease spectrum and to minimize the required sample size.

Our study has several limitations. First, only common variants were included from the GWAS results in this study. Further investigations would be required to look at rare variants, as they are likely to have the larger effect size, and to use predictive software tools to obtain an indication of whether they are damaging or not. Second, the Axiom Genome-Wide CHB Array we used in our discovery cohort did not contain the SNPs for TRPM8 (rs10166942) and LRP1 (rs1172113) identified in prior Caucasian GWASs, so it was not possible for us to study these two SNPs during the discovery stage at genome-wide level. Our study had a much smaller sample size compared with Caucasian GWASs, where the sample sizes were up to 69 times larger (12), therefore it had less power to identify the associations. To correct for multiple comparisons, we applied permutation testing and the results showed positive signals at these two SNPs (permutation p-values for rs10166942 and rs1172113 were 9.99 × 10⁻⁵ and 2.9 × 10⁻², respectively), with similar trends to those identified in the Caucasian GWASs. Third, despite the fact that this was the first Asian migraine GWAS, the small sample size, especially the low number of controls in the replication cohort, is a potential drawback of our study. In addition, excluding migraine patients who have an age at onset higher than 35 and those with severe depression significantly affected sample size. However, we chose to have “stricter criteria” to enrich the homogeneity and genetic components of our study population considering the available study resources. It should be noted that our findings were derived from a strictly selected population, and might not be generalizable to all migraine populations. Fourth, we focused on SNPs that are located or near a gene in the replication analysis for the logistical considerations described in the methods. Similarly, we studied only three SNPs that were repetitively replicated, rather than all reported SNPs in Caucasian GWASs. It would be important to explore the significance of all potentially relevant SNPs in the future. Finally, it should be noted that if adjusted for PC, the p-values for DLG2 varied quite substantially in the combined analysis. This might suggest a possible confounding effect that was already adjusted statistically in the analysis. Comparing to other GWASs, the OR for DLG2 appeared to be high. There is a need to address the fact that the minor allele frequency of DLG2 is very low and the 95% confidence interval (1.883–3.118) for the OR of DLG2 is wide.

In this study, we identified novel genetic variants and replicated two previously identified variants for migraine susceptibility. Functional studies are mandatory to dissect the molecular mechanisms and to identify potential therapeutic targets for this complex neurological disorder.

Clinical implications

Two novel susceptibility genes, DLG2 and GFRA1, were identified for migraine without aura at the genome-wide level in Asians.

DLG2 is a membrane-associated guanylate kinase responsible for glutamatergic neurotransmission, supporting the theory of neuronal hyperexcitability.

GFRA1 is a receptor of glial-derived neurotrophic factor expressed in CGRP-containing trigeminal neurons, suggesting its importance in modulating the trigeminovascular system.

Successful replication of TRPM8 and LRP1 suggests a shared genetic basis of migraine across ethnicities.

Footnotes

Acknowledgements

We wish to thank all individuals in this study for their generous participation. We thank the National Center for Genome Medicine of Taiwan for the technical/bioinformatics/statistics support.

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 Ministry of Education, Aim for the Top University Plan (to SWJ and LSK); Brain Research Center, National Yang-Ming University (to SWJ and LSK); Taipei Veterans General Hospital [V100E6-001, V101E7-003, V102E9-001, V103E9-006, V104E9-001, V105E9-001-MY2-1] (to SWJ); Ministry of Science and Technology of Taiwan [MOST 104-2314-B-010-015-MY2, and MOST 103-2321-B-010-017-] (to SWJ); Ministry of Science and Technology support for the Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan [MOST 103-2911-I-008-001] (to SWJ); National Center for Genome Medicine of the National Core Facility Program for Biotechnology, Ministry of Science and Technology, Taiwan; Institute of Biomedical Sciences, Academia Sinica [Grant No. IBMS-CRC103-P04, 104-2314-B-001-003-] (to CSJF); Taiwan Han Chinese Cell and Genome Bank of Academia Sinica; Translational Resource Center for Genomic Medicine of National Research Program for Biopharmaceuticals (NRPB), Taiwan; and Ministry of Health and Welfare, Taiwan [MOHW 103-TDU-B-211-113-003, MOHW 104-TDU-B-211-113-003, MOHW 105-TDU-B-211-113-003] (to SJW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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