HCRTR2 and Cluster headache: Since there is no major gene effect for the orexin loci linked to migraine, the orexins have tended to be studied more frequently in cluster headache, where a model of complex genetic traits suggests multifactorial involvement that may include orexin loci. Numerous common polymorphisms of HCRTR1 and HCRTR2 have been studied in cluster headache (below), though the frequency and physiological significance of these variants is still being investigated (Rainero et al., 2004; Schürks et al., 2007a; Rainero et al., 2011b).