Association of GABRA1 Polymorphisms with Migraine with Aura: A Preliminary Case–Control Study in a Turkish Cohort

Öz

ABSTRACT Aim: The objective of this study is to ascertain the association between two prevalent GABRA1 polymorphisms (rs12658835, rs35166395) and migraine with aura . In addition, the investigation will encompass the clinical characteristics of the condition, including trigger patterns and family history. Material and Method: 108 persons with clinically proven migraine with aura and 107 demographically matched healthy controls were enrolled in a multicenter case-control study (Atatürk University Faculty of Medicine Neurology Department and Palandöken State Hospital Neurology Outpatient Clinic; 01 Feb–01 Jun 2013). Sociodemographics, migraine characteristics, triggers, and family history were recorded through structured in-person interviews. A sample of peripheral blood was used to extract genomic DNA. SNP genotyping was performed using a validated real-time PCR allelic discrimination kit for GABRA1 rs12658835 and rs35166395. The case/control status was hidden from the lab staff. Results: The migraine with aura cohort was predominantly female (82.4%) with a mean age of 33.8 ± 12.4 years; the control group exhibited a similar distribution of sex and age (both p > 0.05, Mann–Whitney U for age). rs12658835 exhibited an excess of mutant genotype in migraine with aura (7.4%, 8/108) in comparison to the control group (0%, 0/107), p = 0.007. The genotype distributions of rs35166395 (wild/mutant/heterozygous: 60/16/24% in migraine with aura vs. 65/13/22% in controls) did not differ (p > 0.05). In the context of migraine with aura cases, a family history of migraine was associated with an elevated probability of activity-impairing attacks (69.4% overall; OR ≈ 2.06; p = 0.02) and pain exacerbation during physical activity (p = 0.02). No substantial gender-based disparities were observed in other clinical characteristics. Conclusion: In this Turkish cohort, the GABRA1 rs12658835 variant is associated with migraine with aura, whereas the rs35166395 variant is not. Familial predisposition is linked to more debilitating attacks and exertional exacerbation, highlighting the genetic factors that contribute to the severity of the phenotype and the potential GABAergic mechanisms involved in the pathophysiology of migraine with aura.

Anahtar Kelimeler

• Migraine
• Polimorphism
• GABRA1

GABRA1 Polimorfizmlerinin Auralı Migren ile İlişkisi: Türk Kohortunda Ön Nitelikli Olgu-Kontrol Çalışması

Öz

Amaç: Bu çalışmanın amacı, GABRA1 genindeki iki yaygın polimorfizmin (rs12658835, rs35166395) auralı migren ile ilişkisini saptamaktır. Ayrıca tetikleyici paternler ve aile öyküsü dâhil olmak üzere klinik özellikler incelenmiştir. Gereç ve Yöntem: Çok merkezli olgu–kontrol tasarımında (Atatürk Üniversitesi Tıp Fakültesi Nöroloji Anabilim Dalı ve Palandöken Devlet Hastanesi Nöroloji Polikliniği; 01.02.2013–01.06.2013) klinik olarak doğrulanmış auralı migren tanılı 108 birey ve demografik olarak eşleştirilmiş 107 sağlıklı kontrol çalışmaya alındı. Yapılandırılmış yüz yüze görüşmelerle sosyodemografik veriler, migren özellikleri, tetikleyiciler ve aile öyküsü kaydedildi. Periferik kandan genomik DNA izole edildi. GABRA1 rs12658835 ve rs35166395 için gerçek zamanlı PCR alel-ayrım kiti kullanılarak SNP genotiplemesi yapıldı. Laboratuvar personeli olgu/kontrol durumuna körlendi. Bulgular: Auralı migren grubu çoğunlukla kadındı (%82,4) ve ortalama yaş 33,8 ± 12,4 yıldı; kontrol grubunda yaş ve cinsiyet dağılımı benzerdi (her ikisi için p > 0,05, yaş için Mann–Whitney U). rs12658835 için auralı migren grubunda mutant genotip fazlalığı saptandı (%7,4; 8/108) ve bu fark kontrol grubuna kıyasla anlamlıydı (%0; 0/107; p = 0,007). rs35166395 genotip dağılımları (auralı migrende sırasıyla %60/%16/%24; kontrollerde %65/%13/%22) arasında anlamlı fark yoktu (p > 0,05). Auralı migren olgularında ailede migren öyküsü, aktiviteyi kısıtlayan ataklarla (toplam %69,4; OR ≈ 2,06; p = 0,02) ve fiziksel aktivite ile ağrı artışıyla (p = 0,02) ilişkili bulundu; diğer klinik özelliklerde cinsiyete göre belirgin fark saptanmadı. Sonuç: Bu Türk kohortunda GABRA1 rs12658835 varyantı auralı migren ile ilişkili bulunurken, rs35166395 ile ilişki izlenmedi. Ailevi yatkınlığın daha yıkıcı ataklar ve eforla alevlenme ile ilişkisi, fenotip şiddetine katkıda bulunan genetik etmenleri ve auralı migrenin patofizyolojisinde olası GABAerjik mekanizmaları desteklemektedir.

Anahtar Kelimeler

• Migren
• Polimorfizm
• GABRA1

Kaynakça

1. 1. Pizza V, Bisogno A, Lamaida E, et al. Migraine and coronary artery disease: an open study on the genetic polymorphism of the 5, 10 methylenetetrahydrofolate (MTHFR) and angiotensin I-converting enzyme (ACE) genes. Cent Nerv Syst Agents Med Chem. 2010;10(2):91-6.
2. 2. Moy BM, Bertucci HK, Lemma B, Rivas O. Hemiplegic Migraine in a Patient With Neurologic Symptoms After Regadenoson Administration. Clin Case Rep. 2025;13(7):e70611.
3. 3. Shrimpton M, Gasser YP, Sexton A, Malhotra A. Episodic headaches and cognitive decline: uncovering neuronal intranuclear inclusion disease in a young patient. BMJ Case Rep. 2025;18(1):e262351.
4. 4. Winsvold BS, Hagen K, Aamodt AH, Stovner LJ, Holmen J, Zwart JA. Headache, migraine and cardiovascular risk factors: the HUNT study. Eur J Neurol. 2011;18(3):504-11.
5. 5. Vinogradova LV, Suleymanova EM, Medvedeva TM. Transient loss of interhemispheric functional connectivity following unilateral cortical spreading depression in awake rats. Cephalalgia. 2021;41(3):353-65.
6. 6. Grecco MP, Pieroni M, Otero M, Ferreiro JL, Figuerola Mde L. Sporadic hemiplegic migraine and CREST syndrome. J Headache Pain. 2010;11(2):171-3.
7. 7. Bai YF, Chiu M, Chan ES, et al. Pathophysiology of and therapeutic options for a GABRA1 variant linked to epileptic encephalopathy. Mol Brain. 2019;12(1):92.
8. 8. Ligthart L, Huijgen A, Willemsen G, de Geus EJC, Boomsma DI. Are Migraine and Tension-Type Headache Genetically Related? An Investigation of Twin Family Data. Twin Res Hum Genet. 2018;21(2):112-8.

9. 9. Stewart WF, Wood C, Reed ML, Roy J, Lipton RB; AMPP Advisory Group. Cumulative lifetime migraine incidence in women and men. Cephalalgia. 2008;28(11):1170-8.
10. 10. Gallardo VJ, Gómez-Galván JB, Asskour L, et al. A study of differential microRNA expression profile in migraine: the microMIG exploratory study. J Headache Pain. 2023;24(1):11.
11. 11. Sutherland HG, Griffiths LR. Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders. Headache. 2017;57(4):537-69.
12. 12. Merikangas KR, Risch NJ, Merikangas JR, Weissman MM, Kidd KK. Migraine and depression: association and familial transmission. J Psychiatr Res. 1988;22(2):119-29.
13. 13. Gervil M, Ulrich V, Kyvik KO, Olesen J, Russell MB. Migraine without aura: a population-based twin study. Ann Neurol. 1999;46(4):606-11.
14. 14. Russell MB, Iselius L, Olesen J. Inheritance of migraine investigated by complex segregation analysis. Hum Genet. 1995;96(6):726-30.
15. 15. Stewart WF, Staffa J, Lipton RB, Ottman R. Familial risk of migraine: a population-based study. Ann Neurol. 1997;41(2):166-72.
16. 16. Cutrer FM, Smith JH. Human studies in the pathophysiology of migraine: genetics and functional neuroimaging. Headache. 2013;53(2):401-12.
17. 17. Plummer PN, Colson NJ, Lewohl JM, et al. Significant differences in gene expression of GABA receptors in peripheral blood leukocytes of migraineurs. Gene. 2011;490(1-2):32-6.
18. 18. Cutrer FM, Limmroth V, Moskowitz MA. Possible mechanisms of valproate in migraine prophylaxis. Cephalalgia. 1997;17(2):93-100. 19. Chaturvedi P, Khan R, Sahu P, Ludhiadch A, Singh G, Munshi A. Role of Omics in Migraine Research and Management: A Narrative Review. Mol Neurobiol. 2022;59(9):5809-34.
19. 20. García-Martín E, Martínez C, Serrador M, et al. Gamma-Aminobutyric Acid (Gaba) Receptors Rho (Gabrr) Gene Polymorphisms and Risk for Migraine. Headache. 2017;57(7):1118-35.