Genomewide Significant Linkage to Migrainous Headache on Chromosome 5q21
2005; Elsevier BV; Volume: 77; Issue: 3 Linguagem: Inglês
10.1086/444510
ISSN1537-6605
AutoresDale R. Nyholt, Katherine I. Morley, Manuel A. R. Ferreira, Sarah E. Medland, Dorret I. Boomsma, Andrew C. Heath, Kathleen R. Merikangas, Grant W. Montgomery, Nicholas G. Martin,
Tópico(s)Neuroscience of respiration and sleep
ResumoFamilial typical migraine is a common, complex disorder that shows strong familial aggregation. Using latent-class analysis (LCA), we identified subgroups of people with migraine/severe headache in a community sample of 12,245 Australian twins (60% female), drawn from two cohorts of individuals aged 23–90 years who completed an interview based on International Headache Society criteria. We report results from genomewide linkage analyses involving 756 twin families containing a total of 790 independent sib pairs (130 affected concordant, 324 discordant, and 336 unaffected concordant for LCA-derived migraine). Quantitative-trait linkage analysis produced evidence of significant linkage on chromosome 5q21 and suggestive linkage on chromosomes 8, 10, and 13. In addition, we replicated previously reported typical-migraine susceptibility loci on chromosomes 6p12.2-p21.1 and 1q21-q23, the latter being within 3 cM of the rare autosomal dominant familial hemiplegic migraine gene (ATP1A2), a finding which potentially implicates ATP1A2 in familial typical migraine for the first time. Linkage analyses of individual migraine symptoms for our six most interesting chromosomes provide tantalizing hints of the phenotypic and genetic complexity of migraine. Specifically, the chromosome 1 locus is most associated with phonophobia; the chromosome 5 peak is predominantly associated with pulsating headache; the chromosome 6 locus is associated with activity-prohibiting headache and photophobia; the chromosome 8 locus is associated with nausea/vomiting and moderate/severe headache; the chromosome 10 peak is most associated with phonophobia and photophobia; and the chromosome 13 peak is completely due to association with photophobia. These results will prove to be invaluable in the design and analysis of future linkage and linkage disequilibrium studies of migraine. Familial typical migraine is a common, complex disorder that shows strong familial aggregation. Using latent-class analysis (LCA), we identified subgroups of people with migraine/severe headache in a community sample of 12,245 Australian twins (60% female), drawn from two cohorts of individuals aged 23–90 years who completed an interview based on International Headache Society criteria. We report results from genomewide linkage analyses involving 756 twin families containing a total of 790 independent sib pairs (130 affected concordant, 324 discordant, and 336 unaffected concordant for LCA-derived migraine). Quantitative-trait linkage analysis produced evidence of significant linkage on chromosome 5q21 and suggestive linkage on chromosomes 8, 10, and 13. In addition, we replicated previously reported typical-migraine susceptibility loci on chromosomes 6p12.2-p21.1 and 1q21-q23, the latter being within 3 cM of the rare autosomal dominant familial hemiplegic migraine gene (ATP1A2), a finding which potentially implicates ATP1A2 in familial typical migraine for the first time. Linkage analyses of individual migraine symptoms for our six most interesting chromosomes provide tantalizing hints of the phenotypic and genetic complexity of migraine. Specifically, the chromosome 1 locus is most associated with phonophobia; the chromosome 5 peak is predominantly associated with pulsating headache; the chromosome 6 locus is associated with activity-prohibiting headache and photophobia; the chromosome 8 locus is associated with nausea/vomiting and moderate/severe headache; the chromosome 10 peak is most associated with phonophobia and photophobia; and the chromosome 13 peak is completely due to association with photophobia. These results will prove to be invaluable in the design and analysis of future linkage and linkage disequilibrium studies of migraine. The classification of migraine has been impeded by the lack of pathognomonic markers, the co-occurrence of migraine subtypes and of migraine and tension-type headache within a single individual, and disputes over the validity of inclusion criteria and the boundaries between migraine and other headache subtypes (Merikangas et al. Merikangas et al., 1993Merikangas KR Whitaker AE Angst J Validation of diagnostic criteria for migraine in the Zürich longitudinal cohort study.Cephalalgia. 1993; 13: 47-53PubMed Google Scholar, Merikangas et al., 1994Merikangas KR Dartigues JF Whitaker A Angst J Diagnostic criteria for migraine: a validity study.Neurology. 1994; 44: 11-16Crossref PubMed Google Scholar). The two major subtypes of migraine defined by International Headache Society (IHS) criteria (Headache Classification Committee of the International Headache Society Headache Classification Committee of the International Headache Society, 1988Headache Classification Committee of the International Headache Society Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain.Cephalalgia. 1988; 8: 1-96Google Scholar), migraine without aura (MO) and migraine with aura (MA), frequently co-occur. A recent study found that 42% of individuals with active migraine with aura also reported having migraine attacks with no aura (Launer et al. Launer et al., 1999Launer LJ Terwindt GM Ferrari MD The prevalence and characteristics of migraine in a population-based cohort: the GEM study.Neurology. 1999; 53: 537-542Crossref PubMed Google Scholar). Moreover, MO and MA frequently coexist within the same family; a headache center in Italy reported that 45% of families with MA also had members with MO (Mochi et al. Mochi et al., 1993Mochi M Sangiorgi S Cortelli P Carelli V Scapoli C Crisci M Monari L Pierangeli G Montagna P Testing models for genetic determination in migraine.Cephalalgia. 1993; 13: 389-394Crossref PubMed Scopus (72) Google Scholar). The co-occurrence of the rare but severe familial hemiplegic form of migraine (FHM) and migraine with and without aura within families has also been reported (Joutel et al. Joutel et al., 1994Joutel A Ducros A Vahedi K Labauge P Delrieu O Pinsard N Mancini J Ponsot G Gouttiere F Gastaut JL Maziaceck J Weissenback J Bousser MG Tournier-Lasserve E Genetic heterogeneity of familial hemiplegic migraine.Am J Hum Genet. 1994; 55: 1166-1172PubMed Google Scholar; Ophoff et al. Ophoff et al., 1994Ophoff RA van Eijk R Sandkuijl LA Terwindt GM Grubben CP Haan J Lindhout D Ferrari MD Frants RR Genetic heterogeneity of familial hemiplegic migraine.Genomics. 1994; 22: 21-26Crossref PubMed Scopus (127) Google Scholar). Furthermore, changes in the presenting symptoms of migraine attacks, from hemiplegic to severe headache with or without aura in later life (Ophoff et al. Ophoff et al., 1994Ophoff RA van Eijk R Sandkuijl LA Terwindt GM Grubben CP Haan J Lindhout D Ferrari MD Frants RR Genetic heterogeneity of familial hemiplegic migraine.Genomics. 1994; 22: 21-26Crossref PubMed Scopus (127) Google Scholar), as well as the development of aura among subjects with MO and the converse (Ophoff et al. Ophoff et al., 1994Ophoff RA van Eijk R Sandkuijl LA Terwindt GM Grubben CP Haan J Lindhout D Ferrari MD Frants RR Genetic heterogeneity of familial hemiplegic migraine.Genomics. 1994; 22: 21-26Crossref PubMed Scopus (127) Google Scholar; Kallela et al. Kallela et al., 2001Kallela M Wessman M Havanka H Palotie A Farkkila M Familial migraine with and without aura: clinical characteristics and co-occurrence.Eur J Neurol. 2001; 8: 441-449Crossref PubMed Scopus (40) Google Scholar), suggest overlapping etiology. No study performed to date has led to the identification of a gene responsible for typical migraine. A gene on 19p13 has been identified for FHM1 (MIM 141500), a rare autosomal dominant subtype of migraine (Joutel et al. Joutel et al., 1993Joutel A Bousser M-G Biousse V Labauge P Chabriat H Nibbio A Maciazek J Meyer B Bach M-A Weissenbach J Lathrop GM Tournier-Lasserve E A gene for familial hemiplegic migraine maps to chromosome 19.Nat Genet. 1993; 5: 40-45Crossref PubMed Scopus (366) Google Scholar; Ophoff et al. Ophoff et al., 1996Ophoff RA Terwindt GM Vergouwe MN van Eijk R Oefner PJ Hoffman SM Lamerdin JE Mohrenweiser HW Bulman DE Ferrari M Haan J Lindhout D van Ommen GJ Hofker MH Ferrari MD Frants RR Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutation in the Ca2+ channel gene CACNL1A4.Cell. 1996; 87: 543-552Abstract Full Text Full Text PDF PubMed Scopus (2028) Google Scholar). Mutations in this gene, CACNA1A (MIM 601011), a brain-specific P/Q-type calcium-channel gene, account for only a small fraction of all patients with migraine and for 50% of families with the FHM subtype (Ducros et al. Ducros et al., 2001Ducros A Denier C Joutel A Cecillon M Lescoat C Vahedi K Darcel F Vicaut E Bousser MG Tournier-Lasserve E The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.N Engl J Med. 2001; 345: 17-24Crossref PubMed Scopus (437) Google Scholar). Another 20% of families with FHM show linkage to 1q21-31 (FHM2 [MIM 602481] and FHM3 [MIM 607516]) (Ducros et al. Ducros et al., 1997Ducros A Joutel A Vahedi K Cecillon M Ferreira A Bernard E Verier A Echenne B Lopez de Manain A Boussier MG Tournier-Lasserve E Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and evidence of further heterogeneity.Ann Neurol. 1997; 42: 885-890Crossref PubMed Scopus (203) Google Scholar; Gardner et al. Gardner et al., 1997Gardner K Barmada M Ptacek LJ Hoffman EP A new locus for hemiplegic migraine maps to chromosome 1q31.Neurology. 1997; 49: 1231-1238Crossref PubMed Scopus (176) Google Scholar). In a recent breakthrough, missense mutations in a chromosome 1q23 gene, ATP1A2 (MIM 182340), which encodes a Na+, K+-ATPase, were identified in four distinct pedigrees with FHM (De Fusco et al. De Fusco et al., 2003De Fusco M Marconi R Silvestri L Atorino L Rampoldi L Morgante L Ballabio A Aridon P Casari G Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2.Nat Genet. 2003; 33: 192-196Crossref PubMed Scopus (753) Google Scholar; Vanmolkot et al. Vanmolkot et al., 2003Vanmolkot KR Kors EE Hottenga JJ Terwindt GM Haan J Hoefnagels WA Black DF Sandkuijl LA Frants RR Ferrari MD Van Den Maagdenberg AM Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial neonatal convulsions.Ann Neurol. 2003; 54: 360-366Crossref PubMed Scopus (300) Google Scholar). Several studies have suggested that the 19p13 CACNA1A locus may also be involved in nonhemiplegic migraine (MGR5 [MIM 607508]) (May et al. May et al., 1995May A Ophoff RA Terwindt GM Urban C van Eijk R Haan J Diener HC Lindhout D Frants RR Sandkuijl LA Ferrari MD van Eijk R Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura.Hum Genet. 1995; 96: 604-608Crossref PubMed Scopus (175) Google Scholar; Ophoff et al. Ophoff et al., 1997Ophoff RA Terwindt GM Vergouwe MN Frants RR Ferrari MD Involvement of a Ca2+ channel gene in familial hemiplegic migraine and migraine with and without aura.Headache. 1997; 37: 479-485Crossref PubMed Scopus (43) Google Scholar; Nyholt et al. Nyholt et al., 1998bNyholt DR Lea RA Goadsby PJ Brimage PJ Griffiths LR Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity.Neurology. 1998; 50: 1428-1432Crossref PubMed Scopus (128) Google Scholar; Terwindt et al. Terwindt et al., 2001Terwindt GM Ophoff RA van Eijk R Vergouwe MN Haan J Frants RR Sandkuijl LA Ferrari MD Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura.Neurology. 2001; 56: 1028-1032Crossref PubMed Scopus (121) Google Scholar), although contradictory data have also been reported (Hovatta et al. Hovatta et al., 1994Hovatta I Kallela M Farkkila M Peltonen L Familial migraine: exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p.Genomics. 1994; 23: 707-709Crossref PubMed Scopus (83) Google Scholar; Jones et al. Jones et al., 2001Jones KW Ehm MG Pericak-Vance MA Haines JL Boyd PR Peroutka SJ Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus.Genomics. 2001; 78: 150-154Crossref PubMed Scopus (61) Google Scholar). Recently, loci at 1q31 (MGR6 [MIM 607516]) (Lea et al. Lea et al., 2002Lea RA Shepherd GA Curtain RP Nyholt DR Quinlan S Brimage PJ Griffiths LR A typical migraine susceptibility region localizes to chromosome 1q31.Neurogenetics. 2002; 4: 17-22Crossref PubMed Scopus (65) Google Scholar), Xq (MGR2 [MIM 300125]) (Nyholt et al. Nyholt et al., 1998aNyholt DR Dawkins JL Brimage PJ Goadsby PJ Nicholson GA Griffiths LR Evidence for an X-linked genetic component in familial typical migraine.Hum Mol Genet. 1998; 7: 459-463Crossref PubMed Scopus (87) Google ScholarNyholt et al., 2000Nyholt DR Curtain RP Griffiths LR Familial typical migraine: significant linkage and localisation of a gene to Xq24-28.Hum Genet. 2000; 107: 18-23PubMed Google Scholar; Oterino et al. Oterino et al., 2001Oterino A Monton F Cid C Ruiz-Lavilla N Gardner K Barmada M Pascual J A new locus for migraine with aura on Xq13.Cephalalgia. 2001; 21: 346Google Scholar), and 15q11-q13 (MGR7 [MIM 609179]) (Russo et al. Russo et al., 2005Russo L Mariotti P Sangiorgi E Giordano T Ricci I Lupi F Chiera R Guzzetta F Neri G Gurrieri F A new susceptibility locus for migraine with aura in the 15q11-q13 genomic region containing three GABA-A receptor genes.Am J Hum Genet. 2005; 76: 327-333Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar) have been implicated in typical familial migraine. In addition, a number of association studies have shown linkage and/or linkage disequilibrium between various gene loci and either MA or MO (Pardo et al. Pardo et al., 1995Pardo J Carracedo A Munoz I Castillo J Lema M Noya M Genetic markers: association study in migraine.Cephalalgia. 1995; 15: 200-204Crossref PubMed Scopus (21) Google Scholar; Peroutka et al. Peroutka et al., 1997Peroutka SJ Wilhoit T Jones K Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles.Neurology. 1997; 49: 201-206Crossref PubMed Scopus (159) Google Scholar; Del Zompo et al. Del Zompo et al., 1998Del Zompo M Cherchi A Palmas MA Ponti M Bocchetta A Gessa GL Piccardi MP Association between dopamine receptor genes and migraine without aura in a Sardinian sample.Neurology. 1998; 51: 781-786Crossref PubMed Scopus (118) Google Scholar; Ogilvie et al. Ogilvie et al., 1998Ogilvie AD Russell MB Dhall P Battersby S Ulrich V Smith CA Goodwin GM Harmar AJ Olesen J Altered allelic distributions of the serotonin transporter gene in migraine without aura and migraine with aura.Cephalalgia. 1998; 18: 23-26Crossref PubMed Scopus (92) Google Scholar; Kowa et al. Kowa et al., 2000Kowa H Yasui K Takeshima T Urakami K Sakai F Nakashima K The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine.Am J Med Genet. 2000; 96: 762-764Crossref PubMed Google Scholar; Lea et al. Lea et al., 2000Lea RA Dohy A Jordan K Quinlan S Brimage PJ Griffiths LR Evidence for allelic association of the dopamine β-hydroxylase gene (DBH) with susceptibility to typical migraine.Neurogenetics. 2000; 3: 35-40PubMed Google Scholar; Paterna et al. Paterna et al., 2000Paterna S Di Pasquale P D'Angelo A Seidita G Tuttolomondo A Cardinale A Maniscalchi T Follone G Giubilato A Tarantello M Licata G Angiotensin-converting enzyme gene deletion polymorphism determines an increase in frequency of migraine attacks in patients suffering from migraine without aura.Eur Neurol. 2000; 43: 133-136Crossref PubMed Scopus (116) Google Scholar; McCarthy et al. McCarthy et al., 2001McCarthy LC Hosford DA Riley JH Bird MI White NJ Hewett DR Peroutka SJ et al.Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine.Genomics. 2001; 78: 135-149Crossref PubMed Scopus (109) Google Scholar; Tzourio et al. Tzourio et al., 2001Tzourio C El Amrani M Poirier O Nicaud V Bousser MG Alperovitch A Association between migraine and endothelin type A receptor (ETA −231 A/G) gene polymorphism.Neurology. 2001; 56: 1273-1277Crossref PubMed Scopus (106) Google Scholar; Yilmaz et al. Yilmaz et al., 2001Yilmaz M Erdal ME Herken H Cataloluk O Barlas O Bayazit YA Significance of serotonin transporter gene polymorphism in migraine.J Neurol Sci. 2001; 186: 27-30Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar; Rainero et al. Rainero et al., 2002Rainero I Pinessi L Salani G Valfre W Rivoiro C Savi L Gentile S Giudice RL Grimaldi LM A polymorphism in the interleukin-1alpha gene influences the clinical features of migraine.Headache. 2002; 42: 337-340Crossref PubMed Scopus (22) Google Scholar; Trabace et al. Trabace et al., 2002Trabace S Brioli G Lulli P Morellini M Giacovazzo M Cicciarelli G Martelletti P Tumor necrosis factor gene polymorphism in migraine.Headache. 2002; 42: 341-345Crossref PubMed Scopus (50) Google Scholar; Kusumi et al. Kusumi et al., 2003Kusumi M Ishizaki K Kowa H Adachi Y Takeshima T Sakai F Nakashima K Glutathione S-transferase polymorphisms: susceptibility to migraine without aura.Eur Neurol. 2003; 49: 218-222Crossref PubMed Scopus (15) Google Scholar; Mochi et al. Mochi et al., 2003Mochi M Cevoli S Cortelli P Pierangeli G Soriani S Scapoli C Montagna P A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes.Neurol Sci. 2003; 23: 301-305Crossref PubMed Scopus (48) Google Scholar; Colson et al. Colson et al., 2004Colson NJ Lea RA Quinlan S MacMillan J Griffiths LR The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups.Neurogenetics. 2004; 5: 129-133Crossref PubMed Scopus (87) Google Scholar, Colson et al., 2005Colson NJ Lea RA Quinlan S MacMillan J Griffiths LR Investigation of hormone receptor genes in migraine.Neurogenetics. 2005; 6: 17-23Crossref PubMed Scopus (60) Google Scholar). Unfortunately, most of these studies have remained single reports and await confirmatory replication studies or have been contradicted by studies done by other groups. The first genomewide linkage screen for typical familial MA genes was conducted by a group in Helsinki (Wessman et al. Wessman et al., 2002Wessman M Kallela M Kaunisto MA Marttila P Sobel E Hartiala J Oswell G Leal SM Papp JC Hamalainen E Broas P Joslyn G Hovatta I Hiekkalinna T Kaprio J Ott J Cantor RM Zwart JA Ilmavirta M Havanka H Farkkila M Peltonen L Palotie A A susceptibility locus for migraine with aura, on chromosome 4q24.Am J Hum Genet. 2002; 70: 652-662Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). They studied a sample of 50 Finnish families (comprising 252 individuals with MA) and found significant evidence for linkage on 4q24 (MGR1 [MIM 157300]). Interestingly, a genomewide scan in Iceland of 289 patients with MO also showed significant linkage to the chromosome 4q region (Bjornsson et al. Bjornsson et al., 2003Bjornsson A Gudmundsson G Gudfinnsson E Hrafnsdottir M Benedikz J Skuladottir S Kristjansson K Frigge ML Kong A Stefansson K Gulcher JR Localization of a gene for migraine without aura to chromosome 4q21.Am J Hum Genet. 2003; 73: 986-993Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar), further supporting the existence of trait loci common to both major IHS classes of migraine. Three additional published genomewide screens have identified several new loci, with significant linkage on 6p12.2-p21.1 (MGR3 [MIM 607498]) (Carlsson et al. Carlsson et al., 2002Carlsson A Forsgren L Nylander PO Hellman U Forsman-Semb K Holmgren G Holmberg D Holmberg M Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.Neurology. 2002; 59: 1804-1807Crossref PubMed Scopus (77) Google Scholar), 11q24 (Cader et al. Cader et al., 2003Cader ZM Noble-Topham S Dyment DA Cherny SS Brown JD Rice GP Ebers GC Significant linkage to migraine with aura on chromosome 11q24.Hum Mol Genet. 2003; 12: 2511-2517Crossref PubMed Scopus (73) Google Scholar), and 14q21.2-q22.3 (MGR4 [MIM 607501]) (Soragna et al. Soragna et al., 2003Soragna D Vettori A Carraro G Marchioni E Vazza G Bellini S Tupler R Savoldi F Mostacciuolo ML A locus for migraine without aura maps on chromosome 14q21.2-q22.3.Am J Hum Genet. 2003; 72: 161-167Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar), suggesting additional migraine genes in these regions. Hence, there is a growing body of evidence supporting the existence of both phenotypic and genetic heterogeneity, with multiple genes contributing to migraine susceptibility. To diagnose migrainous headache more accurately and to examine whether MO and MA are two separate entities or not, we recently performed latent-class analysis (LCA)—a statistical method best characterized as a categorical analog of factor analysis for finding subtypes of related cases (latent classes) from multivariate categorical data (Rindskopf and Rindskopf Rindskopf and Rindskopf, 1986Rindskopf D Rindskopf W The value of latent class analysis in medical diagnosis.Stat Med. 1986; 5: 21-27Crossref PubMed Scopus (204) Google Scholar)—to investigate the presence and composition of migraine symptom subgroups in our twin sample (Nyholt et al. Nyholt et al., 2004Nyholt DR Gillespie NA Heath AC Merikangas KR Duffy DL Martin NG Latent class analysis does not support migraine with aura and migraine without aura as separate entities.Genet Epidemiol. 2004; 26: 231-244Crossref PubMed Scopus (91) Google Scholar). Migraine data were obtained during the course of an extensive, semistructured telephone interview that included diagnostic assessments of migraine. Participants answering "yes" to the question of whether they have ever had migraine or recurrent attacks of headache then answered a number of questions, relating to their headaches, that were developed by an experienced migraine researcher (K.R.M.) on the basis of IHS diagnostic criteria (tables Table 1, Table 2). The interview yielded diagnoses for MO and MA, with the use of visual prodromal symptoms as an index of MA.Table 1IHS Diagnostic Criteria for MOCriteria for MOA. At least five attacks fulfilling B through DB. Headache lasting 4–72 h (untreated or unsuccessfully treated)C. Headache has at least two of the following characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate/severe (a) or prohibitive (b) intensity (inhibits or prohibits daily activities) 4. Aggravation by walking stairs or by similar routine physical activitiesD. During headache at least one of the following is present: 1. Nausea and/or vomiting 2. Photophobia (a) and phonophobia (b)Note.—Excerpted from IHS classification of headache (Headache Classification Committee of the International Headache Society Headache Classification Committee of the International Headache Society, 1988Headache Classification Committee of the International Headache Society Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain.Cephalalgia. 1988; 8: 1-96Google Scholar). Open table in a new tab Table 2The 10 Symptom Response Variables Based on IHS Diagnostic CriteriaAbbreviation for VariableCodeaCodes correspond to the outline of diagnostic criteria in table 1.Description>5 EpisodesAAt least five migraines/episodes of headache during lifetime4–72 hBAverage typical migraine/headache lasts between 4 and 72 hUnilateralC1Headache usually occurs on one side of the headPulsatingC2Usual headache pain is described as throbbing, pulsating, or poundingModerate/severeC3aPain associated with headache is described as moderate or severeProhibitiveC3bHeadaches inhibit or prohibit daily activitiesNausea/vomitingD1Associated and recurrent attacks of nausea, vomiting, or diarrheaPhotophobiaD2aEnhanced sensitivity to lightPhonophobiaD2bEnhanced sensitivity to noiseAura…Associated and recurrent visual problems such as blurring, showers of light, blind spots, or double visiona Codes correspond to the outline of diagnostic criteria in table 1. Open table in a new tab Note.— Excerpted from IHS classification of headache (Headache Classification Committee of the International Headache Society Headache Classification Committee of the International Headache Society, 1988Headache Classification Committee of the International Headache Society Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain.Cephalalgia. 1988; 8: 1-96Google Scholar). In our younger cohort of twins born in 1964–1971 (3,438 females and 2,774 males), the use of IHS diagnostic criteria yielded an MO prevalence of 15.3% (20.4% female; 9.0% male), which is comparable to that found in other large epidemiologic studies in similar Western populations (Stewart et al. Stewart et al., 1992Stewart WF Lipton RB Celentano DD Reed ML Prevalence of migraine headache in the United States: relation to age, income, race, and other sociodemographic factors.JAMA. 1992; 267: 64-69Crossref PubMed Scopus (1431) Google Scholar), including a recent population-based Australian study (the Blue Mountains Eye Study [n=3,654]) that found that 22% of women and 9.6% of men satisfied the IHS criteria for MO (Wang et al. Wang et al., 1997Wang JJ Mitchell P Smith W Is there an association between migraine headache and open-angle glaucoma?. Findings from the Blue Mountains Eye Study.Ophthalmology. 1997; 104: 1714-1719Abstract Full Text PDF PubMed Google Scholar). The total same-sex DZ relative risks (RRs)—applicable to first-degree relatives in the general population—associated with the IHS groups were surprisingly similar, with an RR of 1.53 (95% CI 0.61–3.83) for MO-MO and 1.77 (95% CI 1.00–3.13) for MA-MA (Nyholt et al. Nyholt et al., 2004Nyholt DR Gillespie NA Heath AC Merikangas KR Duffy DL Martin NG Latent class analysis does not support migraine with aura and migraine without aura as separate entities.Genet Epidemiol. 2004; 26: 231-244Crossref PubMed Scopus (91) Google Scholar). LCA, performed using the Latent GOLD 2.0 package (Statistical Innovations), identified one asymptomatic class (CL0) and three major symptomatic classes (fig. 1), representing a mild form of recurrent nonmigrainous headache (CL1); a moderately severe form of migraine, typically without visual aura, loading (i.e., had endorsement probability ⩾0.5) on all IHS MO symptoms except unilateral location and nausea/vomiting (CL2); and a severe form of migraine, typically with visual aura, loading on all IHS symptoms (CL3). Of particular importance is that although aura was often associated with other and more severe neurological symptoms and was predominantly found in latent class CL3, almost one quarter of CL3 individuals did not report aura. Furthermore, aura was present in 39.3% of individuals in CL2. Therefore, the LCA did not specifically separate MO from MA. Instead, the LCA classifications are based on the severity and combination of symptoms and do not support the hypothesis that MO and MA are separate subtypes. Moreover, both traditional (principal components) factor analysis using SPSS and latent factor analysis using Latent GOLD indicated that a single major factor best fit the data, supporting the existence of a severity continuum from mild to severe headache, of which the LCA classes and IHS classes MO and MA are a part. In other words, an individual's liability to migraine is of a single dimension representing the contribution of all genetic and environmental influences; individuals whose liability exceeds a certain threshold manifest the disorder, with the more severely affected individuals assumed to have a higher liability than the less severely affected individuals. Also consistent with the threshold model is that three times as many females than males had migraine; thresholds for females were significantly lower than those for males. Therefore, in searching for predisposing genes, we should expect to find some trait loci common to both major classes of IHS migraine, with perhaps additional loci, or more-severe alleles, associated with more-severe types, such as MA or CL3 (Nyholt et al. Nyholt et al., 2004Nyholt DR Gillespie NA Heath AC Merikangas KR Duffy DL Martin NG Latent class analysis does not support migraine with aura and migraine without aura as separate entities.Genet Epidemiol. 2004; 26: 231-244Crossref PubMed Scopus (91) Google Scholar). We classified 407 individual twins (203 female [5.9% of total female sample]; 204 male [7.4% of total male sample]) in CL1, 1,267 twins (781 [22.7%] female; 486 [17.5%] male) in CL2, and 991 twins (793 [23.1%] female; 198 [7.1%] male) in CL3. Therefore, the prevalence of migrainous headache identified by LCA classification (hereafter, "LCA migraine," which represents CL2 and CL3) was 36.5% (45.8% female; 24.7% male). Using the total same-sex data, the relative risks associated with the LCA groups were 1.40 (95% CI 1.03–1.90) for CL2-CL2 and 2.18 (95% CI 1.57–3.03) for CL3-CL3 (Nyholt et al. Nyholt et al., 2004Nyholt DR Gillespie NA Heath AC Merikangas KR Duffy DL Martin NG Latent class analysis does not support migraine with aura and migraine without aura as separate entities.Genet Epidemiol. 2004; 26: 231-244Crossref PubMed Scopus (91) Google Scholar). Importantly, these data did not support the presence of genetic sex-specific effects (i.e., effects expressed in one sex but not in the other) or significant sex differences in the magnitude of genetic influences (i.e., sex limitation) on risk of migraine. The ability of LCA to weight each symptom by use of endorsement frequencies and to obtain for each symptom response profile the associated posterior
Referência(s)