Journal
CEPHALALGIA
Volume 38, Issue 3, Pages 466-475Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/0333102417695105
Keywords
Migraine; genome-wide association study; DLG2; GFRA1; Taiwan; Han Chinese; Asian
Categories
Funding
- Ministry of Education, Aim for the Top University Plan
- Brain Research Center, National Yang-Ming University
- Taipei Veterans General Hospital [V100E6- 001, V101E7-003, V102E9-001, V103E9-006, V104E9-001, V105E9-001-MY2-1]
- Ministry of Science and Technology of Taiwan [MOST 104-2314-B-010-015-MY2, MOST 103-2321-B-010-017]
- 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]
- 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 [IBMS-CRC103-P04, 104-2314-B-001-003]
- Taiwan Han Chinese Cell and Genome Bank of Academia Sinica
- Translational Resource Center for Genomic Medicine of National Research Program for Biopharmaceuticals (NRPB), Taiwan
- 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]
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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 x 10(-12), odds ratio [OR] = 2.42), and also another locus (rs3781545in GFRA1) with suggestive significance (p = 1.27 x 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 x 10(-5); risk allele: T) and rs1172113 in LRP1 (OR = 1.23, 95% CI = 1.04-1.45, P-permutation = 2.9 x 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.
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