FINAL REPORT: Identifying genetic differences between monozygotic twin pairs discordant for migraine via whole genome sequencing

Summary

To identify novel genetic mutations underlying migraine, this project performed whole genome sequencing (WGS) on identical twin pairs discordant for migraine (where one twin suffered from migraine and the other didn’t). In addition, this project aimed to compile a unique collection of discordant identical twin pairs that will serve as a model and resource for validation of previously implicated causal mutations of migraine and identification of epigenetic factors in migraine.

Hypothesis vs. Findings

We hypothesized that genetic (DNA sequence) mutations carried by migraine twins but not by unaffected co-twins have high potential to be causal for migraine, and WGS of discordant identical twin pairs would provide a novel approach to identify high impact de novo mutations contributing to migraine. In this study 15 identical twin pairs discordant in migraine were carefully selected. By analyzing WGS data from the 15 twin pairs, three de novo variants—two with pathogenic annotations—were identified in the migraine twins that were not observed in the unaffected twins.

We also conducted a pilot study of blood DNA methylation in these twins and found the ‘Voltage gated Potassium channels’ pathway—comprising three genes (KCNG2, KCNA3, KCNA1)—was the most significant pathway.

Application of the discordant identical twin model is an effective approach to validating previously reported disease-causing mutations and genes and has the potential to identify differentially methylated genes and pathways to help identify underlying biological mechanisms. It may also decrease the cost of detecting (post-zygotic) de novo mutations from WGS data compared to unrelated samples.

Unanswered Questions

Our findings show that comparing WGS data from identical twin pairs discordant for migraine can identify plausible causal mutations for migraine. However, to ultimately confirm the post-zygotic mutagenesis of these mutations, mutation validation by Sanger sequencing in the twins and their parents should ideally be performed. Meanwhile, in addition to DNA sequence variation, identical twin pairs may be discordant for migraine due to environmental factors, such as oxygen deficit during delivery, or epigenetic factors, such as DNA methylation.

What this Research Means to You

Twin studies have played an essential role in estimating phenotypic heritability (i.e., the relative contribution of genetic factors to the phenotypic variation observed in a population). Studies of phenotypically discordant identical twin pairs represent an elegant approach to identify epigenetic variation and post-zygotic mutations associated with inherited disorders. Our genome-wide search in a unique sample of identical twin pairs discordant for migraine provides a natural paradigm by which to identify de novo mutations associated with migraine. Migraine remains a complex disorder that is hard to diagnosis and treat. This research identified specific mutations that now can be further examined to see if they will lead to advances in diagnosing and designing individual treatment strategies for patients.