Although the biological causes and triggers of the migraine headache remain mysterious, investigators now have at least five genetic suspects in the lineup.

Few common medical maladies remain as vexingly mysterious as the migraine headache, as 28 million American sufferers can attest.

The migraine is a debilitating disorder that affects approximately 14 percent of adults, recently recognized as the seventh disabler in the "Global Burden of Disease Survey 2010" and perhaps the most costly neurological disorder, sending millions of Americans to bed every year and quite a few of them to the emergency room.

Although no reliable biomarkers have been found to allow the study of the condition during or between episodic attacks, researchers have now identified five genetic regions linked to the onset of migraine, which may lead to better understanding the biological triggers.

"This study has greatly advanced our biological insight about the cause of migraine," Aarno Palotie, of the Wellcome Trust Sanger Institute, told reporters. "Migraine and epilepsy are particularly difficult neural conditions to study — between episodes the patient is basically healthy so it's extremely difficult to uncover biochemical clues."

The researchers discovered the underlying predilections for the condition by comparing the results from 29 genomic studies, including more than 100,000 samples from migraine patients and others, finding some regions of susceptibility near a network of genes sensitive to oxidative stress, a biochemical process resulting in dysfunction of cells.

"We have proven that this is the most effective approach to study this type of neurological disorder and understand the biology that lies at the heart of it," Palotie said.

The researchers believes many of the genes in these five regions may be interconnected and could possibly be disrupting the internal regulation of tissue and cells in the brain, causing some of the symptoms of migraine, according to Gisela Terwindt, of Leiden University Medical Centre, who co-authored the study.

"We could not have made discoveries by studying smaller groups of individuals," she said. "This large-scale method of studying over 100,000 samples of healthy and affected people means we can tease out the genes that are important suspects and follow them up in the lab."

Aside from the five regions implicated in the condition, researchers identified an additional 134 genetic regions possibly associated with migraine susceptibility, though with weaker statistical evidence. Whether these regions might underlie migraine susceptibility or not must still be investigated, though similar studies have shown genetic areas with weaker statistical connections playing a more or less equal role in the underlying biology of a particular disease or disorder.

Although migraine remains poorly understood by science, the sequence variants uncovered by this large analysis may lead to further studies into the pathophysiology of the condition, researchers said.

Source: Anttila, Verneri, Winsvold, Bendik S., Gormley, Padhraig. Genome-Wide Meta-Analysis Identifies New Susceptibility Loci For Migraine. Nature Genetics. 2013.