Trait Components Provide Tools to Dissect the Genetic Susceptibility of Migraine

Anttila, Verneri; Kallela, Mikko; Oswell, Greg; Kaunisto, Mari A.; Nyholt, Dale R.; Hämäläinen, Eija; Havanka, Hannele; Ilmavirta, Matti; Terwilliger, Joseph D.; Sobel, Eric M.; Peltonen, Leena; Kaprio, Jaakko; Färkkilä, Markus; Wessman, Maija; Palotie, Aarno

doi:10.1086/504814

Cited by 69 publications

(93 citation statements)

References 47 publications

(75 reference statements)

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“…To our knowledge, the suggestive peak on chromosome 20 has not been reported before. This study also replicated the significant peak on chromosome 5q21 and the highly suggestive peak on 10q22 Anttila et al, 2006]. These results provide important replication and support for the presence of migraine susceptibility genes within these regions, and will be useful in guiding future research efforts in the area of gene-finding.…”

Section: Discussionsupporting

confidence: 73%

“…A potentially interesting finding is the linkage for moderate/severe pain intensity on chromosome 10 (highest LOD ¼ 2.13, nominal pointwise P ¼ 0.0009), approximately 30 cM away from the linkage peak (marker D10S2327), but overlapping the 95% CI, in the region reported in Australian (highly suggestive linkage for LCA migraine) and Finnish (nearly suggestive linkage for phonophobia) genome scans Anttila et al, 2006]. In addition, on chromosome 5, a LOD score of 1.97 (pointwise P ¼ 0.001) was found for photo-/phonophobia, at marker D5S2501.…”

Section: Discussionmentioning

confidence: 87%

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A genome‐wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

Ligthart

Nyholt

Hottenga

et al. 2008

American J of Med Genetics Pt B

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Latent class analysis was performed on migraine symptom data collected in a Dutch population sample (N ¼ 12,210, 59% female) in order to obtain empirical groupings of individuals suffering from symptoms of migraine headache. Based on these heritable groupings (h 2 ¼ 0.49, 95% CI: 0.41-0.57) individuals were classified as affected (migrainous headache) or unaffected. Genomewide linkage analysis was performed using genotype data from 105 families with at least 2 affected siblings. In addition to this primary phenotype, linkage analyses were performed for the individual migraine symptoms. Significance levels, corrected for the analysis of multiple traits, were determined empirically via a novel simulation approach. Suggestive linkage for migrainous headache was found on chromosomes 1 (LOD ¼ 1.63; pointwise P ¼ 0.0031), 13 (LOD ¼ 1.63; P ¼ 0.0031), and 20 (LOD ¼ 1.85; P ¼ 0.0018). Interestingly, the chromosome 1 peak was located close to the ATP1A2 gene, associated with familial hemiplegic migraine type 2 (FHM2). Individual symptom analysis produced a LOD score of 1.97 (P ¼ 0.0013) on chromosome 5 (photo/ phonophobia), a LOD score of 2.13 (P ¼ 0.0009) on chromosome 10 (moderate/severe pain intensity) and a near significant LOD score of 3.31 (P ¼ 0.00005) on chromosome 13 (pulsating headache). These peaks were all located near regions previously reported in migraine linkage studies. Our results provide important replication and support for the presence of migraine susceptibility genes within these regions, and further support the utility of an LCA-based phenotyping approach and analysis of individual symptoms in migraine genetic research. Additionally, our novel ''2-step'' analysis and simulation approach provides a powerful means to investigate linkage to individual trait components.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 87%

A genome‐wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

Ligthart

Nyholt

Hottenga

et al. 2008

American J of Med Genetics Pt B

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“…However, Nyholt et al [27] & Lea et al [28] had further dissected the common types of migraine according to latent class analysis (LCA) [27,28]. Another approach, trait component analysis (TCA), based on individual patient responses instead of clinical diagnoses was adopted by Antilla and colleagues in 2006 in order to classify patients into groups for genetic analysis [29].…”

Section: Discussionmentioning

confidence: 99%

Clinical Characteristics of Migraine in Twelve Sudanese families

ELmagzoub¹,

Ibrahim²,

Abdalla³

2017

JNSK

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Introduction: Migraine headache is characterized by certain clinical features that were compiled according to certain criteria set by the international headache society (IHS) so as to provide a standardized definition, diagnosis and classification of headaches for both clinical practice and research studies. Aims:The aim of this study is to determine the clinical characteristics of migraine in Sudanese families and whether they adhere to international criteria set by the IHS. Patients and Methods:Following the description of the clinically diagnosed index case, a detailed validated questionnaire based on the IHS was distributed to all family members affected as well as non-affected after giving an informed consent. The responding family members were then classified as migraineurs and nonmigraineurs after analysis of the questionnaire and confirmation of the diagnosis by two neurologists. Results:From the 175 subjects who agreed to participate (from twelve pedigrees) 107 were migraineurs (70.1% females, 29.9 % males). Both migraine with aura (MA) and migraine without aura(MO) co-exist in the same family and even in the same individual with the most common migraine type being MO (51.4%,N=55), followed by MA+MO (32.7%, N=35) and MA (15.9 %, N=17). Unilateral location, presence of nausea, photophobia and aggravation by exercise showed significant results (P value 0.000). Conclusions:The presentation of migraine headache showed results similar to that described by the HIS 2nd edition in most of the criteria and differed in others. Comorbidity with a number of diseases and migraine coexist.

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“…Our analysis of component phenotypes of bipolar disorder is an attempt to identify specific diagnostic entities that correlate with allelic over-transmission across sample panels, which, to our knowledge, is the first such exploration in bipolar disorder. Genetic analysis of multiple component phenotypes in a complex disease has been reported recently, for example, in migraine (Anttila et al, 2006) and hypertension (Wallace et al, 2006). This approach necessarily entails multiple tests whose mutual dependency is difficult to assess.…”

Section: Discussionmentioning

confidence: 99%

Sequence variation in DOCK9 and heterogeneity in bipolar disorder

Detera‐Wadleigh

Liu

Maheshwari

et al. 2007

Psychiatric Genetics

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a Background Linkage of bipolar disorder to a broad region on chromosome 13q has been supported in several studies including a meta-analysis on genome scans. Subsequent reports have shown that variations in the DAOA (G72) locus on 13q33 display association with bipolar disorder but these may not account for all of the linkage evidence in the region.Objective To identify additional susceptibility loci on 13q32-q33 by linkage disequilibrium mapping and explore the impact of phenotypic heterogeneity on association.Methods In the initial phase, 98 single nucleotide polymorphism (SNPs) located on 13q32-q33 were genotyped on 285 probands with bipolar disorder and their parents were drawn from families in the NIMH Genetics Initiative consortium for bipolar disorder (NIMH1-4) and two other series. Fine scale mapping using one family series (NIMH1-2) as the test sample was targeted on a gene that displayed the highest evidence of association. A secondary analysis of familial component phenotypes of bipolar disorder was conducted.Results Three of seven SNPs in DOCK9, a gene that encodes an activator of the Rho-GTPase Cdc42, showed significant excess allelic transmission (P = 0.0477 -0.00067). Fine scale mapping on DOCK9 yielded evidence of association at nine SNPs in the gene (P = 0.02 -0.006). Follow-up tests detected excess transmission of the same allele of rs1340 in two out of three other sets of families. The association signals were largely attributable to maternally transmitted alleles (rs1927568: P = 0.000083; odds ratio = 3.778).A secondary analysis of familial component phenotypes of bipolar disorder detected significant association across multiple DOCK9 markers for racing thoughts, psychosis, delusion during mania and course of illness indicators.Conclusion These results suggest that DOCK9 contributes to both risk and increased illness severity in bipolar disorder. We found evidence for the effect of phenotypic heterogeneity on association. To our knowledge this is the first report to implicate DOCK9 or the Rho-GTPase pathway in the etiology of bipolar disorder.

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Trait Components Provide Tools to Dissect the Genetic Susceptibility of Migraine

Cited by 69 publications

References 47 publications

A genome‐wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

A genome‐wide linkage scan provides evidence for both new and previously reported loci influencing common migraine

Clinical Characteristics of Migraine in Twelve Sudanese families

Sequence variation in DOCK9 and heterogeneity in bipolar disorder

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