Identifying genetic variants for age of migraine onset in a Han Chinese population in Taiwan

DOI: https://doi.org/10.1186/s10194- 021- 01301- y

Abstract-Summary Considering the involvement of genetics in migraine pathogenesis in diverse ethnic populations, genome-wide association studies (GWAS) are being conducted to identify migraine-susceptibility genes.

2.1 Genetics

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In this study, we aimed to identify the susceptibility loci of migraine considering

the AoM in an Asian population.

We conducted a GWAS in 715 patients with migraine of Han Chinese ethnicity, residing in Taiwan, to identify the susceptibility genes associated with AoM. Based on our standard demographic questionnaire, the population was grouped into differ- ent subsets.

We discovered eight novel susceptibility loci correlated with AoM that reached

the GWAS significance level in the Han Chinese population.

Background The proportion of migraine patients with aura varies between Western and Asian countries.

The results of this study indicate that the polygenic load is associated with a

lower age-at-onset and severity of migraine [137].

There are several genetic studies on pediatric migraine. Szilagyi and others reported that STin2, a polymorphism of the serotonin trans- porter gene, correlates with pediatric migraine with aura in Hungary, and that it presents with severe abdominal pain and vomiting during the attack [138].

Limited studies have examined the correlation of genetic susceptibility markers

and age-at-onset of migraine in an Asian population.

The aim of this study was to identify the susceptibility loci of migraine consider-

ing the age of migraine onset (AoM) in an Asian population.

We hypothesized that some genetic factors may be associated with the AoM. This

cohort study involved two-stage clinic-recruitment of migraine participants.

Methods All participants completed a uniform questionnaire, encompassing demographic characteristics, AoM, Migraine Disability Assessment (MIDAS) [139, 140], family history of migraine, body mass index, and years of education.

Of these SNPs, approximately 446,000 SNPs were associated with the Taiwanese genotypic background, 105,000 SNPs were clinically significant, and others are associated with disease, drug response, and metabolism, as determined by Thermo Fisher Scientific over the years.

SNP associations were examined using PLINK based on the groups for AoM. For the first stratification, in the phenotype association study, we examined the variant relationship between groups with the AoM onset before and after 12 years using the 1df chi-square allelic test, and another quantitative trait association study was applied to determine two different distributions in all migraine cohorts using regres- sion statistics and the Wald test.

In the second stratification, all original groups were separated based on the pres- ence and absence of aura and were tested using the quantitative trait associa- tion study.

Results Patients with migraine were significantly different in terms of age, age of onset, and the MIDAS score (p < 0.05).

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2 Mechanisms

The AoM median with genotype TC (approximately AoM = 44 years) was higher than that with the wild genotype CC (AoM = 20 years, β value of regression coef- ficient = 20.41).

Patients with genotype TC were likely to have higher age-at-onset migraine than

patients with the wild type.

Patients with alternative genotypes likely had later onset migraine than those

with the wild type (β = 28.37, β = 20.63, β = 22.74, β = 21.72, respectively). Discussion This is the first genome-wide association study to report eight SNPs associated with AoM in an Asian population with migraine.

Rs181024055  in NRAP is associated with late AoM in the migraine without

aura group.

NOL3 mutation may also cause delayed AoM by a loss or decrease-of-function in neuronal excitability, although the exact pathogenesis associating NOL3 and migraine needs further investigation.

As the AoM genes reported in this study are mostly known to be involved in psychiatric disorders, further in-depth investigation regarding the association between psychiatric disorders and AoM-related genes could provide a better under- standing of how these factors might influence the migraine/mood relationship.

20 years, various studies have reported candidate genes involved in the patho- genesis of migraine or other disease, but the replication and concordance in another ethnic populations are often unsatisfactory [141, 142].

Conclusions Several novel susceptibility genes associated with AoM, most of which were prob- ably insinuated in migraine, were identified in this study.

This study will enhance the diagnosis and treatment of patients with migraine;

however, a larger sample is necessary to obtain the definitive proof.

Acknowledgement A machine generated summary based on the work of Tsai, Chia-Kuang; Liang, Chih-Sung; Lin, Guan-Yu; Tsai, Chia-Lin; Lee, Jiunn-Tay; Sung, Yueh-Feng; Lin, Yu-Kai; Hung, Kuo-Sheng; Chen, Wei-Liang; Yang, Fu-Chi. 2021 in The Journal of Headache and Pain.

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