Rs10504861

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. 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. Migraines are thought to be caused by a mixture of genetic and environmental factors, with about two-thirds of patients reporting family history.

rs10504861’s association with migraine without aura was first identified in a meta-analysis GWAS published in 2013, 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, 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. 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.

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. A SNP within LRP1 (rs11172113) has previously been reported to be associated with migraine in a genome-wide association study. 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. 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.

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The low density lipoprotein receptor–related protein LRP is regulated by membrane type-1 matrix metalloproteinase (MT1-MMP) proteolysis in malignant cells.

Replication study of previous migraine genome-wide association study findings in a Spanish sample of migraine with aura.