Latent Class and Genetic Analysis Does Not Support Migraine With Aura and Migraine Without Aura as Separate Entities Dale R. Nyholt, 1n Nathan G. Gillespie, 1 Andrew C. Heath, 2 Kathleen R. Merikangas, 3 David L. Duffy, 1 and Nicholas G. Martin 1 1 Queensland Institute of Medical Research, Brisbane, Queensland, Australia 2 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 3 Section on Developmental Genetic Epidemiology, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland Latent class and genetic analyses were used to identify subgroups of migraine sufferers in a community sample of 6,265 Australian twins (55% female) aged 25–36 who had completed an interview based on International Headache Society (IHS) criteria. Consistent with prevalence rates from other population-based studies, 703 (20%) female and 250 (9%) male twins satisfied the IHS criteria for migraine without aura (MO), and of these, 432 (13%) female and 166 (6%) male twins satisfied the criteria for migraine with aura (MA) as indicated by visual symptoms. Latent class analysis (LCA) of IHS symptoms identified three major symptomatic classes, representing 1) a mild form of recurrent nonmigrainous headache, 2) a moderately severe form of migraine, typically without visual aura symptoms (although 40% of individuals in this class were positive for aura), and 3) a severe form of migraine typically with visual aura symptoms (although 24% of individuals were negative for aura). Using the LCA classification, many more individuals were considered affected to some degree than when using IHS criteria (35% vs. 13%). Furthermore, genetic model fitting indicated a greater genetic contribution to migraine using the LCA classification (heritability, h 2 ¼0.40; 95% CI, 0.29–0.46) compared with the IHS classification (h 2 ¼0.36; 95% CI, 0.22–0.42). Exploratory latent class modeling, fitting up to 10 classes, did not identify classes corresponding to either the IHS MO or MA classification. Our data indicate the existence of a continuum of severity, with MA more severe but not etiologically distinct from MO. In searching for predisposing genes, we should therefore expect to find some genes that may underlie all major recurrent headache subtypes, with modifying genetic or environmental factors that may lead to differential expression of the liability for migraine. & 2004 Wiley-Liss, Inc. Key words: headache continuum; etiology; twins; heritability Grant sponsor: NIAAA (USA); Grant numbers: AA07728, AA10249, AA11998; Grant sponsor: NHMRC (Australia); Grant numbers: 941177, 951023, 241916, Peter Doherty Fellowship 159112. n Correspondence to: Dr. Dale Nyholt, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland 4029, Australia. E-mail: daleN@qimr.edu.au Received 10 June 2003; Accepted 20 August 2003 Published online 23 January 2004 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/gepi.10311 INTRODUCTION The classification of migraine has been impeded by the lack of pathognomonic markers for migraine, co-occurrence of migraine subtypes as well as migraine and tension-type headache within the same individual, and the lack of validity of inclusion criteria and thresholds for distinguishing disorder from nondisorder and the boundaries between migraine and other headache subtypes [Merikangas et al., 1993, 1994]. The nature of the association between two major subtypes of migraine defined by the International Headache Society (IHS) criteria [Headache Classification Committee of the International Headache Society, 1988], i.e., mi- graine without aura (MO) and migraine with aura (MA), was examined in several community, family, and twin studies. Russell and Olesen [1995] found that compared with the general population, the first-degree relatives of probands with MO had 1.86 (95% CI, 1.56–2.16) times the risk of MO and 1.44 (95% CI, 1.03–1.85) times the risk of MA, while the first-degree relatives of probands with MA had 3.79 (95% CI, 3.21–4.38) times the risk of MA and no increased risk of MO (1.02; 95% CI, 0.77–1.26). They concluded that MO and MA may have different etiologies and there- fore different modes of inheritance. However, this conclusion is difficult to reconcile with the high Genetic Epidemiology 26: 231–244 (2004) & 2004 Wiley-Liss, Inc.