Gene identification in cluster headache
Prosjekt
- Prosjektnummer
- 2008118
- Ansvarlig person
- Michael Bjørn Russell
- Institusjon
- Akershus universitetssykehus HF
- Prosjektkategori
- Nytt flerårig forskningsprosjekt
- Helsekategori
- Neurological
- Forskningsaktivitet
- 2. Aetiology
Rapporter
The Project has been expanded With several English families, and still work on identifing genes. Unfortunately we had not have success so far.1. Headache. 2010 Mar;50(3):374-82.
Familial cluster headache: demographic patterns in affected and nonaffected.
Sjöstrand C, Russell MB, Ekbom K, Waldenlind E.
MATERIALS AND METHODS: Affected CH patients and nonaffected first- and
second-degree relatives (n = 114) received a posted questionnaire. Information
from 83 subjects (42 affected and 41 first- and/or second-degree relatives) from
23 families was received. P < .05 was chosen to be significant.
RESULTS: Parental cigarette smoking during childhood and adolescence of patients
and controls and current or former smoking was significantly more common in CH
patients. Frequent alcohol intake (2-3 times/week or more) was significantly more
common in the affected group of CH patients. There were significant differences
as regards the life history of head trauma, but some of the affected had had the
trauma after the age of onset of CH. Interestingly, CH patients worked more
full-time than nonaffected.
CONCLUSION: Formerly described demographic relationships in CH regarding
cigarette smoking, alcohol consumption, and head trauma were also seen in our CH
patients and their nonaffected relatives. These findings might represent a gene
environment interaction in affected CH patients or it could be
personality-lifestyle-related phenomena or a combination of these mechanisms.
PMID: 19438738
2. Neurology. 2006; 66: 1888-93.
A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster
headache cohort.
Baumber L, Sjöstrand C, Leone M, Harty H, Bussone G, Hillert J, Trembath RC,
Russell MB.
OBJECTIVE: To investigate the molecular genetic basis of cluster headache (CH),
using a genome-wide scan and candidate gene strategy.
METHODS: Northern European CH families and a case-control cohort of Danish,
Swedish, and British origin (total n = 259 sporadic CH patients), including 267
control subjects matched for ancestry, participated in the study. A genome-wide
genetic screen using approximately 400 microsatellite markers was performed for
five informative Danish CH families. Additional markers were typed for those loci
generating statistical evidence suggestive of linkage, together with genotypes
for 111 individuals from further Danish and Italian kindreds. Sporadic CH
patients and controls were investigated by association analysis for variation in
the candidate gene, HCRTR2. Finally, complete HCRTR2 sequencing was undertaken
for eight independent probands.
RESULTS: Potential linkage was identified at four possible disease loci in Danish
kindreds, yet no single chromosome location generated a lod or NPL score of
recognized significance. No deleterious sequence variants of the HCRTR2 gene were
detected by comparison to wild-type sequence. Association of the HCRTR2 gene was
not replicated in this large dataset, even when the data were stratified into
distinct populations.
CONCLUSIONS: Cluster headache is a complex genetic disorder, with possible
phenotypic and genetic heterogeneity compounding attempts at gene identification.
PMID: 16801656
Cluster headache (CH) is a very severe type of headache. We have previously demonstrated that it is an inherited disorder. We still search for CH genes and have found several interesting spot to elucidate further.Cluster headache (CH) is regarded as the most severe of the primary headache syndromes and is widely considered to be a neurovascular disorder with activation of hypothalamic, trigeminovascular and cranial parasympathetic systems. A genetic predisposition to CH has long been debated. Genetic epidemiological studies have reported an increased risk of CH in relatives of CH sufferers. In addition, the familial clustering supports a model of autosomal dominant inheritance with reduced penetrance. Although some candidate gene studies have been performed, detecting associations with the HCRTR2 and ADH4 genes, these have been limited by small sample size. We have established a large cohort of CH families in which we have previously reported a genome-wide linkage scan. These data isolated a number of putative linkage loci; however, a single causative gene is yet to be identified, largely due to substantial genetic heterogeneity.
To further delineate the genetic architecture underlying this condition, we have used an exome sequencing strategy in a subset of Northern European families. Exome target enrichment was performed for ten probands and paired-end sequence reads were generated on an Illumina Genome Analyzer IIx. Annotated variants were filtered to exclude synonymous polymorphisms and known or common variation, leaving a total of 1711 novel variants. Exome data from related affected subjects were examined to limit the analysis to variants segregating with the CH phenotype. A subsequent segregation analysis by Sanger sequencing in all family members reduced our candidate list to a total of 45 genes with novel variants (range: 1-13 genes per pedigree). These genes are now being screened in our extended cohort to provide further insight into the role of each gene in CH pathogenesis.
Whilst exome sequencing for gene identification in rare monogenic disorders is now well-established, approaches to detect pathogenic variation with complexities such as locus heterogeneity and incomplete penetrance remain challenging. We have used a combination of exome and Sanger sequencing to isolate novel coding variation segregating across CH families, highlighting the need for large homogeneous cohorts to elucidate the molecular genetic basis of CH. The significance of these variants in CH pathogenesis remains to be elucidated; however these results provide further evidence for a potential genetic predisposition to this debilitating disorder.
Still working and analysing the material, which has been expanded with cluster headache families from britain.
Cluster headache (CH) is a very severe type of headache. We have previously demonstrated that it is an inherited disorder. We still search for CH genes and have found several interesting spot to elucidate further.Cluster headache (CH) is regarded as the most severe of the primary headache syndromes and is widely considered to be a neurovascular disorder with activation of hypothalamic, trigeminovascular and cranial parasympathetic systems. A genetic predisposition to CH has long been debated. Genetic epidemiological studies have reported an increased risk of CH in relatives of CH sufferers. In addition, the familial clustering supports a model of autosomal dominant inheritance with reduced penetrance. Although some candidate gene studies have been performed, detecting associations with the HCRTR2 and ADH4 genes, these have been limited by small sample size. We have established a large cohort of CH families in which we have previously reported a genome-wide linkage scan. These data isolated a number of putative linkage loci; however, a single causative gene is yet to be identified, largely due to substantial genetic heterogeneity.
To further delineate the genetic architecture underlying this condition, we have used an exome sequencing strategy in a subset of Northern European families. Exome target enrichment was performed for ten probands and paired-end sequence reads were generated on an Illumina Genome Analyzer IIx. Annotated variants were filtered to exclude synonymous polymorphisms and known or common variation, leaving a total of 1711 novel variants. Exome data from related affected subjects were examined to limit the analysis to variants segregating with the CH phenotype. A subsequent segregation analysis by Sanger sequencing in all family members reduced our candidate list to a total of 45 genes with novel variants (range: 1-13 genes per pedigree). These genes are now being screened in our extended cohort to provide further insight into the role of each gene in CH pathogenesis.
Whilst exome sequencing for gene identification in rare monogenic disorders is now well-established, approaches to detect pathogenic variation with complexities such as locus heterogeneity and incomplete penetrance remain challenging. We have used a combination of exome and Sanger sequencing to isolate novel coding variation segregating across CH families, highlighting the need for large homogeneous cohorts to elucidate the molecular genetic basis of CH. The significance of these variants in CH pathogenesis remains to be elucidated; however these results provide further evidence for a potential genetic predisposition to this debilitating disorder.
Forskningsgruppen er International med samarbejde til London University, Karolinska Institut, Stockholm og Carlo Besta Institut, Milano. Foreløbig er det ikke identifisert gener for cluster headacheCluster headache (CH) is regarded as the most severe among the primary headache syndromes. It is characterised by recurrent, unilateral, relatively short-lived attacks of excruciating pain, often occurring with regular periodicity. Recent estimates suggest a disease prevalence of ~1 per 500 of the adult population and, although the aetiology and pathophysiology remain poorly characterised, CH is widely considered to be a neurovascular disorder with activation of hypothalamic, trigeminovascular and cranial parasympathetic systems.
Most commonly CH presents as a sporadic disorder. However, a number of observations including increased relative risk and twin concordance support a significant genetic component to disease predisposition1. We have previously described the results of a microsatellite-based genome-wide scan, in a large cohort of Northern European CH families2. This screen, using approximately 400 microsatellite markers, identified a number of loci generating putative evidence for linkage and provided evidence of possible phenotypic and genetic heterogeneity, suggesting CH to be a complex genetic disorder.
Association analysis of hypocretin/orexin pathway genes has identified a single SNP of the hypocretin receptor 2 (HCRTR2) gene, showing allelic association with the CH phenotype in Italian3 and German4 cohorts. However, this association was not replicated in our study2 and the polymorphism does not appear to be correlated with treatment response5. Most recently, an association between CH and variants within the alcohol dehydrogenase 4 (ADH4) gene has also been reported in an Italian cohort6. These data fit well with alcohol being a trigger factor for CH attacks; however, this association is yet to be replicated in an independent cohort.
A clear application of genomic enrichment for high throughput sequencing is in the identification of disease causing mutations in Mendelian disorders. At the simplest level, enrichment and sequencing of the coding regions within a defined linkage interval will overcome the bottleneck currently associated with the sequencing phase of traditional positional cloning. The power of sequencing the whole exome is likely to also prove invaluable in unravelling the genetic architecture of Mendelian disorders in which linkage scans have revealed suggestive linkage to several genomic regions, due to small family size or complexities including incomplete penetrance and phenocopies. In these situations, the exome sequence of the most informative individual(s) has the capacity to enable the evaluation of all coding exons across such loci.
In addition to the utility of its combination with linkage based approaches, exome sequencing offers a revolutionary novel strategy for identifying disease causing genes. The approach, elegantly demonstrated in a recent proof-of-principle study at the University of Washington7, does not require large extended pedigrees but instead compares exome sequence variation of a small number of unrelated cases to identify gene(s) that are consistently the site of potentially pathogenic mutations. The study demonstrated that, in the absence of genetic heterogeneity, the causative gene in an autosomal dominant disorder can be identified with exome sequences from three unrelated affected individuals.
We are working for identification of genes that cause cluster headache, the most severe type of headache.Cluster headache (CH) is regarded as the most severe among the primary headache syndromes. It is characterised by recurrent, unilateral, relatively short-lived attacks of excruciating pain, often occurring with regular periodicity. Recent estimates suggest a disease prevalence of ~1 per 500 of the adult population and, although the aetiology and pathophysiology remain poorly characterised, CH is widely considered to be a neurovascular disorder with activation of hypothalamic, trigeminovascular and cranial parasympathetic systems.
Most commonly CH presents as a sporadic disorder. However, a number of observations including increased relative risk and twin concordance support a significant genetic component to disease predisposition1. We have previously described the results of a microsatellite-based genome-wide scan, in a large cohort of Northern European CH families2. This screen, using approximately 400 microsatellite markers, identified a number of loci generating putative evidence for linkage and provided evidence of possible phenotypic and genetic heterogeneity, suggesting CH to be a complex genetic disorder.
Association analysis of hypocretin/orexin pathway genes has identified a single SNP of the hypocretin receptor 2 (HCRTR2) gene, showing allelic association with the CH phenotype in Italian3 and German4 cohorts. However, this association was not replicated in our study2 and the polymorphism does not appear to be correlated with treatment response5. Most recently, an association between CH and variants within the alcohol dehydrogenase 4 (ADH4) gene has also been reported in an Italian cohort6. These data fit well with alcohol being a trigger factor for CH attacks; however, this association is yet to be replicated in an independent cohort.
Earlier this year, we completed a second, SNP-based genome-wide linkage study in a further collection of CH families, using the Illumina linkage panel IVb. Taken together with our previous report, this comprehensive combined dataset has isolated two distinct CH loci and we now seek to examine these linked regions in more detail.
A clear application of genomic enrichment for high throughput sequencing is in the identification of disease causing mutations in Mendelian disorders. At the simplest level, enrichment and sequencing of the coding regions within a defined linkage interval will overcome the bottleneck currently associated with the sequencing phase of traditional positional cloning. The power of sequencing the whole exome is likely to also prove invaluable in unravelling the genetic architecture of Mendelian disorders in which linkage scans have revealed suggestive linkage to several genomic regions, due to small family size or complexities including incomplete penetrance and phenocopies. In these situations, the exome sequence of the most informative individual(s) has the capacity to enable the evaluation of all coding exons across such loci.
In addition to the utility of its combination with linkage based approaches, exome sequencing offers a revolutionary novel strategy for identifying disease causing genes. The approach, elegantly demonstrated in a recent proof-of-principle study at the University of Washington7, does not require large extended pedigrees but instead compares exome sequence variation of a small number of unrelated cases to identify gene(s) that are consistently the site of potentially pathogenic mutations. The study demonstrated that, in the absence of genetic heterogeneity, the causative gene in an autosomal dominant disorder can be identified with exome sequences from three unrelated affected individuals.
Cluster headache is an autosomal dominant inherited disorder in 5-10% of those with cluster headache. The remaining 90% are sporadic cases.Klasehodepine (clustre headache) er karakterisert ved voldsomme anfall av hodepine rundt det ene øye ledsaget av autonome fenomener. Anfallene kommer 1-8 gange i døgnet i perioder av vanligvis 1-3 måneder varighet. Heretter kan pasienten være symptomfri i lange perioder. Noen få har kronisk klasehodepine med anfall hver dag året rundt. Klasehodepine forekommer hos 1-2‰ av befolkningen. Klasehodepine ble tidligere betraktet som en sporadisk lidelse. Ansøkers forskningsgruppe påviste som den første at første grads slektninger til personer med klasehodepine har en signifikant økt forekomst av klasehodepine sammenliknet med befolkningen. Dette funn er siden ble reprodusert i flere studier. Ansøker forskningsgruppe foretokk siden enn kompleks segregationsanalyse som understøtter at klasehodepine er autosomalt dominant lidelse i 5-10% av familiene. Etterfølgende analyse av kliniske karakteristika i familiene med klasehodepine påviste ingen spesifikke intra- eller interfamiliære karakteristika. I 2005 ble det påvist en assosiasjon mellom en polymorfisme i hypocretin reseptor 2 genet og klasehodepine. Vi kunne ikke reprodusere dette funn og fant ingen mutasjoner ved sekvensering av genet i 8 uavhengige probander. Assosiasjonen i hypocretin receptor 2 genet er siden gjenfunnet av andre. Ansøkers forskningsgruppe fortokk siden en genome-wide skanning av fem informative klasehodepine familier uten at finne sikker linkage. Klasehodepine er en kompleks genetisk lidelse med fenotypisk og genetisk heterogenitet.
Forskningsgruppen har samarbeide med Medical Genetic, London University. Det er siden søknaden ble innvilget sket store fremskridt innenfor molekylær genetiske metoder, som er blevet mye mer effektive og mer rimelig i relasjon til kostnader. Vi jobber med en ny utviklet metode Exome sequencing som er yderst effektiv når det gjelder komplekse genetiske liderser som cluster headache. Når relevante genområder er identifisert, anvendes vanlige genetiske metoder som sekvensering mv. Vi håper at identifisere et eller flere gener for cluster headache med denne metode.
Candidate genes for cluster headache is under investigation. The molecular genetic analyses are currently run.Cluster headache is an autosomal dominant disorder in some families. The penetrance varies between 0.17-0.21. The majority are sprodic cases. The Cluster Headache Consortium have collected familial cluster headache families in Denmark, Italy and Sweden. We use human material DNA and the project has been approved by the Danish, Italian and Swedish authorities. In order to continue our search for genes we need further financing.
Three genes have been identified for familial hemiplegic migraine. They are all ion-channel genes and it is likely cluster headache is also caused by an ion-channel gene, due to the cluster headache occurs in attacks on/off.
The literature provide som evidence that a mutation in a clock gene can cause cluster headache, but other studies including our can not confirm these data.
We have so far had several publication on cluster headache in international journal such as Lancet Neurology, Neurology, Journal of Medical Genetics, Journal of Neurolgy, Neurosurgery and Psychiatry, Eurpean Journal of Neurology etc.
We hope that Helse SørØst continues to support our research. Even if our result should turn out to be negative, they will be of importance. However, we hope to hit one or more positive results, since the method we apply is suitable to identify gene mutation in the single family. This is rather important, since cluster headache most likely is a genetic heterogenous disorder.
Along with the genetics, we are also
working on a symptomatic cluster headache secondary to pressure from a. cerebelli superior on the trigeminal nerve.
Vitenskapelige artikler
Sjöstrand Christina, Russell Michael Bjørn, Ekbom Karl, Waldenlind Elisabet
Familial Cluster Headache: Demographic Patterns in Affected and Nonaffected.
Headache 2009 Apr. Epub 2009 apr 27
PMID: 19438738
Southgate L et al.
Elucidating the molecular genetic basis of cluster headache: delineation of the genetic architecture by exome sequencing
Abstract på Hodepinekongress London 2012
Deltagere
- Michael Bjørn Russell Prosjektleder
- Laura Southgate Forsker (annen finansiering)
- Richard Trembath Prosjektleder
- Christina Sjöstran Forsker (annen finansiering)
- Massimo Leone Forsker (annen finansiering)
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