Migraine loci idenfied by genome-wide linkage studies

By February 2009, eleven genome-wide linkage studies have been published identifying 16 suggestive or significant migraine loci based on the migraine end-diagnosis, TCA or LCA (Table 10). In four of them significant linkage between the end-diagnosis of MA or MO and loci at 4q21−q24, 6p12−p21, 11q24 and 14q21−q22 has been identified (Wessman et al. 2002, Björnsson et al. 2003, Carlsson et al. 2003, Cader et al. 2003, Soragna et al. 2003). The more recent studies have used different phenotyping strategies, such as TCA and LCA, to identify loci for different migraine trait components or symptom groups. In TCA the IHS based symptoms are used as traits (Anttila et al. 2006), and in LCA individuals are divided in four groups based on the severity of migraine symptoms (Nyholt et al. 2004). These studies have identified significant loci at 4q24, 5q21, 10q22–q23, 17p13 and several other suggestive loci (Nyholt et al. 2005, Lea et al. 2005, Anttila et al. 2006 and 2008, Ligthart et al. 2008).

So far, only in two studies have fine-mapping results for the linked regions at 6p12–p21 and 10q22–q23 been reported (Norberg et al. 2006, Anttila et al. 2008), but both of them failed to show significant association in the studied regions. However, the emerging consistency between linkage results and with both the increasing number of studies and phenotyping strategies has strengthened the confidence that the majority of significant linkage findings are true positives. It is especially encouraging when samples with different nationalities have been used. The advantage of using different phenotyping strategies has been obvious when these methods were compared in a study by Anttila and co-workers 2008 on a sample of 1,675 individuals from 210 migraine families. They found that the most heavily replicated locus on 10q22–q23 would have been identified only in one study instead of four studies (Nyholt et al.

2005, Anttila et al. 2006, 2008, Ligthart et al. 2008) if only the MA end diagnosis based phenotype was used.

Linkage studies on migraine have also shown that gender-specific genetic factors have a role in migraine pathophysiology as has been suggested by epidemiological studies.

Female-specific contribution has been detected in two populations: at loci 10q22-q23 and 18q12 in Finns, and at 4q21 in Icelanders (Björnsson et al. 2003, Anttila et al. 2006, 2008).

Table 10. The loci showing best evidence for linkage in the genome wide linkage studies on migraine. Loci showing significant, suggestive or replicated evidence of linkage are bolded, underlined or italicized, respectively.

Reference Trait ¹ No of

families No of

affecteds ² Nationality Locus Wessman et

unilaterality Finnish 10q22–q23

pulsation Australian 10q22–q23

pulsation Finnish 2p12

pain intensity Australian 8q12

pulsation Finnish Xp22

attack length Finnish 18q12

pain intensity Australian 14q21

Ligthart et al.

No, number; MA, migraine with aura; MO, migraine without aura; LCA, latent class analysis; TCA, trait component analysis; na, not available

1) In TCA the trait that showed the best linkage signal on a locus is given, 2) Number of affected individuals that has been used as primary selection criterion for the study, 3) Slightly relaxed criteria of MO, 4) The same families as in Wessman et al. 2002, 5) The significance of this locus was not defined.

An eye-catching feature in replicated migraine loci on 1q21–q23, 4q21–q24, 5q21–q22, 6p12–

p21, 10q22–q23, 13q21, 14q21–q22 and 18q12 (Table 10) is the phenotypic heterogeneity in the linked traits. This inconsistency between traits may be due to susceptibility variant(s) that in these loci predispose to several symptom-specific processes (Anttila et al. 2008). For example, the first MA locus on 4q was replicated in the Icelandic MO sample based on the overlapping NPL results on 4q21–q24 (Wessman et al. 2002, Björnsson et al. 2003). Although the analyzed end-diagnosis was different, MA versus MO, the TCA analyses on the same Finnish families showed linkage to 4q21–q24 with age at onset, photophobia, phonophobia and unilaterilaty traits (Anttila et al. 2006) that are shared in migraine headache of both MA and MO. Furthermore, both the Icelandic and Finnish study also showed linkage on the 18q12 region that was further confirmed and replicated in the Finnish TCA study on individuals affected with MA and/or MO with normal attack length of 4–72 h (Anttila et al. 2006, 2008).

The use of the LCA method has shown overlapping results at 1q21–1q23 and 13q21 (Nyholt et al. 2005, Ligthart et al. 2008), but the specific characteristics of each of the latent groups have not been reported, and thus, the predisposing trait components cannot be determined.

It is interesting that the pulsating migraine headache trait has been the most successful symptom for a locus identification on 2p12, 10q22–q23, 13q21, 17p13 and Xp22 (Anttila et al. 2008) even though the trait has not shown consistency between the studies. It can be an easily identified clinical symptom, but the pulsating migraine pain may indicate a role of neurovascular mechanisms in migraine. Another interesting feature in the genome-wide linkage studies on migraine is the almost total lack of overlapping results among common migraine, especially MA, and FHM loci. Suggestive evidence of linkage has been identified in only two LCA studies for the FHM2 region (Table 10, Nyholt et al. 2005, Ligthart et al.

2008), but the role of aura in these loci was not established. The Danish linkage study on the FHM families suggested a possibility of locus heterogeneity in FHM (Thomsen et al. 2007) and interestingly one of their nominal linkage signals is located in the proximity of the 10q21–

q22 locus that has been linked to several common migraine traits (Anttila et al. 2008). The recent linkage study on a Spanish FHM family affected also with MA and MO showed significant linkage on 14q32 (Cuenca-León et al. 2009). Further studies will show whether the additional FHM loci predispose also to common migraine.