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Human Molecular Genetics, 2003, Vol. 12, No. 19 2511-2517
DOI: 10.1093/hmg/ddg252
© 2003 Oxford University Press

Significant linkage to migraine with aura on chromosome 11q24

Zameel M. Cader1,{dagger}, Sandra Noble-Topham2,{dagger}, David A. Dyment1, Stacey S. Cherny1, John D. Brown3, George P.A. Rice3 and George C. Ebers4,*

1Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK, 2Lawson Health Sciences Research Institute, London Health Sciences Centre, London, Canada, 3Department of Clinical Neurology, London Health Sciences Centre, London, Canada and 4Department of Clinical Neurology, Radcliffe Infirmary, Oxford OX2 6HE, UK

Received May 12, 2003; Revised July 9, 2003; Accepted July 21, 2003


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Migraine with aura (MA) is a prevalent neurological condition with strong evidence for a genetic basis. Familial hemiplegic migraine, a rare Mendelian form of MA, can be caused by mutations in the calcium channel gene, CACNA1A or in the ATP1A2 gene, a Na+/K+ pump. Susceptibility genes for the more prevalent forms of migraine have yet to be identified despite several reports of linkage including loci on 4q24, 1q31, 19p13 and Xq24–28. We have undertaken a genome-wide screen of 43 Canadian families, segregating MA with families chosen for an apparent autosomal dominant pattern of transmission. Diagnosis was based upon International Headache Society Criteria. Parametric linkage analysis revealed a novel locus on 11q24 with a two-point LOD score of 4.2 and a multi-point parametric LOD score of 5.6. We did not find any support for linkage at previously reported loci. The lack of consensus amongst linkage studies, including this study, is probably an indication of the heterogeneity that is inherent for MA. Nevertheless, the finding of a highly significant locus with a LOD score of 5.6 is powerful evidence that a gene increasing susceptibility to MA resides on 11q24. Several candidate genes map to this region of the genome including a number of ion channel genes such as GRIK4, SCNB2, KCNJ5 and KCNJ1.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Migraine is a common disorder affecting 15–20% of the population (1) and comprises a number of subtypes defined by the International Headache Society (IHS) (2). A proportion of migraine patients experience a phase of transient and reversible neurological symptoms such as flashing lights and visual scintillations preceding the typically severe, throbbing headache. This classical form of migraine, migraine with aura (MA), affects about 5% of the population (3).

There are several lines of evidence that support a genetic basis for migraine with aura, including familial aggregation of MA, twin studies and complex segregation analysis. The risk to first-degree relatives of MA probands is 3.8 relative to the general population in contrast to no increase in risk to the spouse of the proband (4). The monozygotic twin concordance at 50% is over twice the dizygotic concordance at 21% (5). Complex segregation analysis has indicated that the pattern of inheritance of MA is likely to be multifactorial (6). However, rare families with an autosomal dominant mode of inheritance cannot be excluded by this analysis. In addition, several monogenic disorders such as episodic ataxia (EA), CADASIL (cerebral autosomal dominant arteriopathy, subcortical infarcts and leucoencephalopathy) and familial hemiplegic migraine (FHM) express classical migraine as part of their phenotype (7–9).

The mapping of susceptibility loci for complex traits has been and continues to be a challenging problem in part because of the heterogeneity of such disorders. Mapping strategies that take advantage of linkage disequilibrium (LD) often require prior linkage studies to define a region where the disease-causing gene is likely to be located. For migraine, linkage analysis remains a powerful method for elucidating such loci with several sites of linkage reported. A recent genome-wide screen for families with MA in a Finnish population provides strong evidence for a susceptibility locus on 4q24 with a LOD score of 4.4 (10). However, causative mutations have so far only been characterized for the rare migraine variant, FHM (11,12). Linkage has also been identified for migraine at 1q31 (13), Xq24–28 (14) and to the FHM locus on 19p13 (15,16).

Aside from the Finnish genome screen, the other linkage studies have included families segregating either MA or migraine without aura (MO), considering both as affected phenotypes. However the relationship of MA to MO is unclear and there continues to be debate as to whether they represent the same disorder. There are differences in the epidemiology (1,2), pathophysiology (17) and symptomology (17) between the two disorders and reports over co-occurrence are conflicting (18,19). The importance of resolving such issues cannot be understated as heterogeneity considerably weakens the power of linkage analysis.

In this paper, we report the results of a genome-wide screen in a Canadian population of extended families where we have identified a previously unreported locus for susceptibility to migraine with aura.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Two-point linkage analysis
The markers with scores greater than LOD=1.0 are listed in Table 1 and Figure 1 shows the maximum LOD score (Zmax) for each marker across the genome. The highest LOD score was obtained for marker GATA64D013 on 11q24. The Zmax was 4.24 at {Theta}=0.00. The adjacent markers, GATA23E06, 9 cM proximal, and UT2095, 18 cM distal to GATA64D03, had mildly raised LOD scores at 0.77 and 0.23 respectively.


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  		Table 1. Highest two-point LOD scores identified by genome screen
 


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  		Figure 1. Genome-wide maximum two-point LOD scores (Zmax).

 
The highest score next to 11q24 was 2.22, {Theta}=0.10, on chromosome 16, for marker GATA71H05. There were a cluster of scores greater than 1.0 located from 1p11–1p31, with marker GATA61A06 giving a score of 1.96 at {Theta}=0.05.

No markers spanning 4q24, 19p13 or 1q24–31 achieved an LOD score greater than one and were mostly less than -2.00. There were no significant two-point LOD scores for Xq24–q28.

Analysis in which MO was designated unknown affectation did not reveal any new significant linkage regions. The two-point LOD score for GATA64D03 was 3.4.

Multi-point linkage analysis
Multipoint linkage was performed on regions of chromosomes identified from the two-point linkage. 11q24 was the only region that showed a significant increase from the two-point LOD score (Fig. 2). The maximum multipoint score was 5.6 and was located over marker GATA64D03. Analysis with the linkage utility program HOMOG did not support heterogeneity at this locus. The LOD scores for chromosomes 1 and 16 dropped to below 1.0 with multipoint analysis.



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  		Figure 2. Multipoint LOD score for 11q23–24.

 
Multipoint LOD scores for 4q24, 19p13 and 1q24–31 were strongly negative (Fig. 3), and excluded these regions. Although some individual family LOD scores were positive, they were all below an LOD of 1.0 and HOMOG gave no evidence for heterogeneity within our study population for 4q24, 19p13 or 1q24–31. There were no significant multi-point LOD scores for Xq24–q28.



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  		Figure 3. Exclusion multipoint LOD score maps.

 
Under the alternative diagnostic scheme, where MO was classed as unknown affectation, the multipoint LOD score peak at 11q24 was 4.6.

Empirical significance values
Simulation studies were performed to assess the significance of these multipoint LOD scores and to calculate empirical P-value. Ten thousand replicates of the 43 families were simulated using SLINK (20,21) under the assumption that there was no linkage. The parametric model used for the linkage analysis and a single marker with a heterozygosity of 0.80 was used for the simulation.

No replicates reached an LOD score of 5.6, the multipoint LOD score identified for chromosome 11. This corresponds to a P-value of less than 0.0003. Only three replicates out of the 10 000 reached the 16q two-point LOD score of 2.22, giving an empirical P-value of less than 0.001. The P-value for a LOD of 1.96 on 1p31 was less than 0.002.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
There is now considerable evidence from several rigorous epidemiological studies that susceptibility to migraine with aura has a genetic basis. Familial aggregation for migraine with aura has been well documented and the relative risk to first-degree relatives of an MA proband is 3.8 (4). The risk to the spouse in contrast is not increased. The importance of genetics to the aetiology of MA is corroborated through twin studies in which the monozygotic proband-wise twin concordance is 50% for MA compared to a dizygotic concordance of 21% (5).

Although migraine is a feature of several rare Mendelian disorders including CADASIL (8), MELAS (22), EA-2 (7) and FHM (9), the genetic mutations conferring susceptibility to migraine with aura remains elusive. Episodes of migraine with aura much like classical migraine can be seen in patients with the mitochondrial disorder, MELAS, and magnetic resonance spectroscopy has shown mitochondrial abnormalities in migraineurs (23). A family with only migraine with prolonged aura has also been found to have mutations in Notch3, which is also known to cause CADASIL (24). However, generally, the genetic abnormalities associated with MELAS and CADASIL do not appear to be present in families with classical migraine (25,26). Nevertheless, the presence of migraine in such a diverse set of Mendelian disorders would suggest that the migraine phenotype is an end-product of a variety of aetiological pathways.

Characterization of familial hemiplegic migraine has been particularly rewarding and has led to extrapolations that MA is also an ion channel disorder or channelopathy. Linkage in FHM families was first identified to 19p13 and , subsequently, mutations were found in the coding region of CACNA1A (11), the alpha subunit of a P/Q type calcium channel. The majority of the mutations in CACNA1A alter the channel kinetics, but both gain and loss of function effects can occur and yet cause the same phenotype (27,28). This highlights the complexity of ion channel interactions and would suggest that the MA phenotype could arise through multiple pathways. Moreover, spinocerebellar ataxia type 6 (SCA6), a triplet repeat disorder (29) and episodic ataxia type 2 (EA-2), where the mutations tend to cause premature protein truncation (30), are both allelic disorders of CACNA1A. FHM, EA2 and SCA6 also show phenotypic overlap (31).

There is clearly a close relationship between FHM and MA and some FHM families mutations in CACNA1A are expressed as classical migraine alone (32). It is therefore not surprising that a number of studies have examined further the genetic relationship between the CACNA1A locus and classical migraine. The results of such studies, however, provide conflicting evidence (14,15,33,34) and we have previously shown exclusion of linkage of 19p13 in a Canadian dataset (35). Hence CACNA1A does not appear to be a major susceptibility locus for MA.

FHM illustrates the recurring theme of genetic heterogeneity in ion channel disorders. In addition to the 19p13 linkage, a proportion of FHM families are linked to other loci including two loci on chromosome 1 (36,37), while a proportion of FHM families are unlinked to these loci. Recently mutations have been identified in the ATP1A2 gene which is a Na+/K+ ion transporter located on 1q23 (12). Hence with locus heterogeneity apparent for many Mendelian disorders, a similar situation would not be unexpected for a complex trait such as MA. The very large number of ion channel genes across the genome would allow for MA to arise by a number of distinct genetic mutations.

The existence of a subset of MA families where there is a major gene operating is not precluded, however, and provides a rationale for linkage studies. Although the pattern of inheritance for migraine with aura is not clear, the identification of pedigrees showing three or four generations of transmission is a contrast to most other complex traits (38). Hence major monogenic loci may exist for MA in what a priori would be expected to be a very heterogenous population. Linkage analysis has been very successful for the characterization of Mendelian traits. For complex traits, success has depended crucially on the selection of ‘Mendelian’-like families, as in the identification of BRCA1 in familial breast cancer (39). Similarly, identification of major loci in Alzheimer's disease relied on selection of large kindreds with early onset forms of this disorder (40).

We therefore ascertained large multigenerational families with an apparent Mendelian pattern of transmission of migraine with aura. A genome search was performed using 395 microsatellite markers in 43 large kindreds segregating MA. We chose to designate only migraine with aura as affected as the relationship to migraine without aura remains unclear. In addition, the offspring of matings where one or both parents suffer with MO have no increase in risk of MA (unpublished data). The rate of MO in our families was comparable to the rate in the general population (1,3). By using parametric analysis in large families with MA affected and all other subjects unaffected, we employed a powerful method of identifying major MA loci in these families.

The results of our two-point screen revealed a LOD score of 4.2 at marker GATA64D03 on 11q24. The flanking markers were inconclusive for linkage and this is probably a reflection of the genetic distance between these markers and GATA64D03. To further evaluate this region, multipoint analysis was performed using SIMWALK 2.8 and the LOD score increased to 5.6 with this peak coinciding with the peak two point LOD score on 11q24. Hence our data would strongly support the presence of a migraine susceptibility gene on 11q24 with a 1-LOD support interval extending over a range of 12 cM. When MO individuals were designated as unknown affectation, there were no new significant linkage regions and, as might be expected, the LOD scores at GATA64D03 were reduced for both the two-point and multipoint analysis.

No other region of the genome exceeded the accepted threshold for linkage at 3.30 for the autosomes or 2.00 for chromosome X. However the simulation studies would suggest that chromosome 16 may also be highly significant, given our genetic model and pedigree structure. This region therefore warrants closer evaluation and we plan to genotype further microsatellite markers in the area. Although chromosome 1 did not yield an LOD score greater than 2.00, which would indicate a suggestive linkage, the observed clustering of several two point LOD scores greater than 1.5 suggests that this region also merits further genotyping. There were no significant LOD scores on Xq24–q28 for either the two-point or multipoint linkage analyses.

The Finnish genome screen in 50 families with MA identified 4q24 as a linked locus (10). Their maximum multipoint LOD score with an affected only analysis was 4.4 under heterogeneity, with an {alpha} of 0.2–0.45. Our genome screen did not provide any evidence to support linkage at this locus as the multipoint LOD score in this region was less than -7.00, thereby indicating exclusion of linkage. Equally, no individual families in our dataset had multipoint LOD scores suggestive of linkage. Multipoint exclusion is highly sensitive to the model specified and spurious exclusions are common (41). However, examination of our two-point LOD scores on 4q24 for all families combined and individually did not support linkage at this site. The Finnish data suggests that only about 25–50% of their families are linked at 4q24 and it may be that our families simply represent a group that does not harbour this particular susceptibility locus. Other reported sites of linkage for MA include 1q31 (12), 19p13 (14,15) and Xq22–38 (13) and we again found no support for linkage in these regions.

A unified model of pathogenesis is lacking, but ion channels represent a means of integrating a number of key features of migraine. In common with the channelopathy paradigm, migraine has a young age of onset, is paroxysmal, has similar triggering factors to other ion channel disorders and responds to similar drugs. Ion channels are typically heteromeric membrane complexes with a diverse range of gating mechanisms (reviewed in 42). They are of central importance in excitable cells determining background membrane excitability, action potential generation and are part of several signal transduction pathways including those that mediate neurotransmitter release. Mutations in ion channel genes may thus alter the activation state of specific neuronal pathways or the excitability of the cortex generally and perhaps increase liability to phenomenon such as cortical spreading depression (CSD), an experimental model of migraine aura (43).

The cytogenetic region linked to MA on 11q24 that we identified harbours several ion channel genes such as KCNJ1, KCNJ5, SCNB2 and GRIK4, KCNJ1 and KCNJ5 are inwardly rectifying potassium channels expressed in the cerebral cortex (44,45). Mutations in neuronally expressed potassium channels cause autosomal dominant paroxysmal movement disorders such as benign familial neonatal convulsions and episodic ataxia type 1 (46). SCNB2 is a voltage-gated sodium channel beta subunit expressed ubiquitously in the brain (47). Neuronal sodium channels are heterotrimeric complexes composed of a pore-forming alpha subunit and two beta subunits which modify the properties of the alpha subunit (47). Sodium channels are also associated with generalized epilepsy with febrile seizures and the periodic paralyses (46). GRIK4 is a kainite glutamate receptor which has an extensive central nervous system distribution (48). Moreover, migraine may respond to therapies such as lamotrigine targeted at the glutamate axis by causing an inhibition of glutamate release by acting on voltage sensitive sodium channels (49).

Ion channels are choice candidates but other proteins may have direct or indirect interactions with ion channels. Genes expressed in cerebral blood vessels, genes which are part of the serotonin pathway and genes involved in inflammation may also contain important migraine-causing polymorphisms. Weak and conflicting associations with MA have been reported for several genes including endothelin type A receptor (50), dopamine receptors (51,52) and the serotonin transporter (53). DRD2 at 11q23 is nearby our region of linkage although association studies have provided mixed results as to its involvement with MA (51,52).

The results of this genome-wide screen have provided a starting point to search for disease susceptibility genes in our Canadian MA families. We believe that with a maximum LOD score of 5.6 on 11q24, there is strong evidence for this novel region containing a gene with a major role to play in the pathogenesis of migraine with aura.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
Ascertainment of study subjects
Forty-three unrelated probands with migraine with aura and a positive family history for MA were identified from a large neurology practice and from returned questionnaires mailed in January 1998 to subscribers to The Migraine Association of Canada newsletter. Subjects were interviewed via telephone by a neurologist using a validated migraine questionnaire (2). Headache type was classified using the IHS diagnostic criteria for MA (1.2), MO (1.1) and migraine aura without headache (1.2.5). In selecting families where there were parent-to-child transmissions we aimed to obtain pedigrees in which MA appeared to be behave in an autosomal dominant manner.

Additional information was also collected: headache diagnosis by a physician or neurologist, the type of migraine medication used, migraine trigger(s) and the diagnosis of co-segregating paroxysmal neurological disorders (e.g. epilepsy, ataxia) and co-morbid medical conditions (e.g. stroke, depression).

Individuals with MA or co-occurrence of MA and MO or migraine aura without headache were considered affected and individuals with MO or no migraine headache were considered as unaffected. Two-hundred and forty-eight of a total of 575 individuals were classified as MA. Fifty-eight individuals had MO. The female to male ratio of affected individuals was 3 to 1.

Genotyping
A total of 420 individuals were genotyped. Genomic DNA was extracted from fresh blood using a phenol chloroform extraction method as described previously (19). Fluorescent genotyping was performed at the NHLBI Mammalian Genotyping Service at the Center for Medical Genetics, Marshfield Medical Research Foundation (54). CEPH pedigree members were included as controls for allele sizing and genotyping accuracy. The Marshfield panel 10 marker set (55) (www.marshfieldclinic.org), consisting mainly of tri- and tetra-nucleotide markers, with an average marker spacing of 9 cM for the 376 autosomal markers and 19 markers on chromosome X, were used. The average heterozygosity of the autosomal markers was 0.75±0.07 and the chromosome X markers was 0.73±0.07 (56).

The validity of the specified sibling relationships were evaluated using the Graphical Representation of Relationship Errors programme, GRR (57). Mendelian errors were identified in the completed autosomal genotype data using the PEDCHECK utility (58) and these errors (269 errors/151 528 total genotypes=0.18% error rate) were corrected by entering the genotype data as unknown for that individual and marker.

Parametric linkage analysis
Two-point linkage.
The genotype data was analysed using FASTLINK 5.21 (59,60). An autosomal dominant mode of inheritance was assumed. A disease allele frequency of 0.05 was specified and the allele frequencies for the microsatellite markers were calculated from all genotyped individuals. Three liability classes were used to account for age dependent penetrance. Class1 had a penetrance of 50% with a phenocopy rate of 5%; class 2 had a penetrance of 35% and phenocopy rate of 3.5%; and class 3 had a penetrance of 7% with a phenocopy rate of 1%.

Analysis was also performed in which individuals with MO were designated as unknown affectation.

Multipoint linkage.
Simwalk 2.8 (61) was used to estimate multi-point LOD scores in regions with suggestive two point LOD scores. The genetic model was specified as for the two point analysis. Genehunter Plus (62,63) was used to calculate multi-point LOD scores for chromosome X.


   ACKNOWLEDGEMENTS
 
We thank The Migraine Association of Canada and greatly appreciate the voluntary participation of the families in this study. We thank the following individuals for their contributions: Dr Patti Mandalfino, Dr Dean Wingerchuk, Pam Schoffer, Tracey Bentall, Roopa Ganapathy, Holly Armstrong, Bev Scott Harriett Margalias and Cathy Burgard.


   FOOTNOTES
 
* To whom correspondence should be addressed at: Department of Clinical Neurology, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK. Tel: +44 1865224492; Fax: +44 1865224757; Email: george.ebers{at}clneuro.ox.ac.uk Back

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 

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