|rs10504861 is a SNP located on Chromosome 8q21 that was found to be associated with elevated incidence of migraine without aura in genome-wide association studies (GWAS).|
|(A;A)||2||Reduced risk of migraine without aura|
|(A;G)||2||Reduced risk of migraine without aura|
|(G;G)||1||Major allele, normal risk of migraine|
|Trait||Migraine without aura|
|Title||Genome-wide meta-analysis identifies new susceptibility loci for migraine.|
|Odds Ratio||1.16 [1.10-1.23]|
rs10504861 is a SNP located on Chromosome 8q21 that was found to be associated with elevated incidence of migraine without aura in genome-wide association studies (GWAS). Migraine is a common but often incapacitating disease that affects up to 20% of the population, and affects 3-4 times as many women as men [PMID 16426991]. Migraine can be classified into two main types: migraine with auras and migraines without auras. Migraine with auras accounts for a third of cases, where individuals experience a transient neurological symptom such as a visual, sensory, language or motor disturbance prior to an impending migraine attack [PMID 14979299]. Migraines are thought to be caused by a mixture of genetic and environmental factors, with about two-thirds of patients reporting family history [PMID 20572569].
rs10504861’s association with migraine without aura was first identified in a meta-analysis GWAS published in 2013[PMID 23793025], which pooled 23,285 cases and 95,425 controls. rs10504861 was shown to be significantly associated with migraine without aura, where the minor allele (T) is protective (p = 1.32 × 10−8, OR = 0.86; 95%CI: 0.81 – 0.91). However, this SNP did not pass genome-wide significance threshold when studying its association with all migraine cases (p-value not reported).
A smaller clinic-based replication study was conducted in Spain in 2014 [PMID 25388962], which recruited 512 migraine cases and 535 ethnically-matched controls; females made up three-quarters of both groups. 13 SNPs were genotyped in an attempt to replicate previous findings. Interestingly, this study reports a significant association between the rs10504861 SNP and migraine (with and without auras) under a recessive model (corrected p = 0.0288, OR = 0.26, 95%CI not reported). The minor allele is similarly shown to be protective.
A similar small-scale replication study was performed in Denmark in 2015 [PMID 25667298]. This study recruited 1806 cases and 6415 controls, and performed genotyping on 12 SNPs. In this study, rs10504861 was not found to be statistically associated with migraines without aura (p=0.95, OR = 0.99, 95%CI: 0.89-1.14) or migraines in general (p=0.5, OR=0.97, 95%CI: 0.88-1.07).
The inconclusive results above suggest that rs10504861 may only be associated with a specific sub-classification of migraine, where statistical significance is reached only in a very large cohort study. A hypothesis-driven study on a more detailed sub-classification of migraine in women suggests that rs10504861 is preferentially associated with active migraines [PMID 24852292].
The SNP is located 200kb away from the matrix metalloproteinase MMP16. Metalloproteinases are a diverse family of protease enzymes involved in the breakdown of extracellular matrix in normal physiological processes. Notably, the protein encoded by MMP16, MT3-MMP, cleaves low-density lipoprotein receptor protein, LRP1 [PMID 14645246]. A SNP within LRP1 (rs11172113) has previously been reported to be associated with migraine in a genome-wide association study [PMID 21666692]. In addition, MT3-MMP has recently been shown to be involved in basal NgR1 (Nogo-66 receptor) shedding in cortical neurons, thereby increasing axonal and synaptic plasticity [PMID 22311207]. Though no conclusive evidence exist for the mechanism mitigating association of MMP16 to migraines, these two implications offer plausible explanations for biological implication of rs10504861 in migraine pathology.
[PMID 23793025] Genome-wide meta-analysis identifies new susceptibility loci for migraine.
[PMID 20572569] Migraine update. Diagnosis and treatment.
[PMID 22311207] The Nogo-66 receptor family in the intact and diseased CNS.
[PMID 21666692] Genome-wide association study reveals three susceptibility loci for common migraine in the general population.
[PMID 24852292] Selectivity in genetic association with sub-classified migraine in women.
[PMID 25667298] The association between candidate migraine susceptibility loci and severe migraine phenotype in a clinical sample.
[PMID 16426991] Chronic disorders with episodic manifestations: focus on epilepsy and migraine.
[PMID 14979299] The International Classification of Headache Disorders: 2nd edition.
[PMID 14645246] The low density lipoprotein receptor–related protein LRP is regulated by membrane type-1 matrix metalloproteinase (MT1-MMP) proteolysis in malignant cells.
[PMID 25388962] Replication study of previous migraine genome-wide association study findings in a Spanish sample of migraine with aura.
[PMID 26231841] Association of genetic loci for migraine susceptibility in the she people of China