Significant linkage to migraine with aura on chromosome 11q24

Cader, M Z; Noble-Topham, S E; Dyment, David A.; Cherny, Stacey S.; Brown, John; Rice, George P.; Ebers, George C.

doi:10.1093/hmg/ddg252

Cited by 81 publications

(38 citation statements)

References 54 publications

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“…Both forms have a strong genetic basis with complex inheritance [Estevez and Gardner, 2004;Palotie et al, 2002], but according to recent epidemiological data the genetic background of MA is stronger than that of MO [Russell and Olesen, 1995]. Recently, several loci for MA and MO have been identified by genome-wide linkage analyses in single extended pedigrees [Carlsson et al, 2002;Soragna et al, 2003] or a collection of multiplex families (MIM]s 157300, 607498, and 607501) [Bjornsson et al, 2003;Cader et al, 2003;Wessman et al, 2002]. Yet the genes involved in common forms of migraine are unknown.…”

Section: Introductionmentioning

confidence: 99%

Rare missense variants inATP1A2 in families with clustering of common forms of migraine

Todt

Dichgans²,

Jurkat‐Rott

et al. 2005

Hum. Mutat.

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Migraine is a recurrent neurovascular disease. Its two most common forms-migraine without aura (MO) and migraine with aura (MA)-both show familial clustering and a complex pattern of inheritance. Familial hemiplegic migraine (FHM) is a rare monogenic subform caused by mutations in the calcium channel gene CACNA1A or the Na(+)/K(+)-ATPase gene ATP1A2. An involvement of FHM genes in the pathogenesis of common forms of migraine is not proven. We therefore systematically screened ATP1A2 in families with several members affected by MA and/or MO. We identified two novel missense alterations [c.520G>A (p.E174 K) and c.1544G>A (p.C515Y)] in two out of 45 families, which were not found in 520 control chromosomes. Functional studies of these variants in Xenopus oocytes by two-electrode voltage clamp measurements and radiochemical determination of ATPase activity showed that C515Y leads to a complete loss of function comparable with the effect of FHM-mutations whereas for E174 K no functional alteration could be found in the in vitro assays. In conclusion we propose that rare variants in ATP1A2 are involved in the susceptibility to common forms of migraine, because of 1) the absence of alterations in controls, 2) the particular pattern of segregation in both families, 3) the high conservation of mutated residues in Na(+)/K(+)-ATPases, 4) the functional effect of C515Y, and 5) the involvement of ATP1A2 in a monogenic form of migraine.

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Section: Introductionmentioning

confidence: 99%

Rare missense variants inATP1A2 in families with clustering of common forms of migraine

Todt

Dichgans²,

Jurkat‐Rott

et al. 2005

Hum. Mutat.

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“…However, the sequence screen cannot exclude possible intronic mutation that could cause MA in our MA families. Mapping studies of MA show many loci that implies polygenetic nature [Nyholt et al, 2000;Jones et al, 2001;Carlsson et al, 2002;Lea et al, 2002;Wessman et al, 2002;Cader et al, 2003;Soragna et al, 2003;Lea et al, 2005;Russo et al, 2005], and twin studies show clear environmental influence [Ulrich et al, 1999a]. Such multifactorial nature of the disease and the limited power of our data (only promoter and exons sequenced) do not rule out that the CACNA1A or ATP1A2 genes may be involved in MA as a complex trait in some families.…”

Section: Discussionmentioning

confidence: 58%

The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura

Kirchmann

Thomsen

Olesen

2006

American J of Med Genetics Pt B

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Epidemiological studies indicate that migraine with typical aura (MA) has a major genetic component but the genes for MA have not been identified. However, the autosomal dominantly inherited familial hemiplegic migraine (FHM) is often caused by mutations in the CACNA1A or ATP1A2 genes. The aim of the study was to investigate if the CACNA1A or ATP1A2 genes are involved in MA with an apparently autosomal dominant mode of inheritance. From a clinic population diagnosed by a trained physician we recruited 34 extended families (comprising 174 MA patients) with an apparently autosomal dominant mode of inheritance of MA. We performed a linkage analysis of 161 of 174 MA patients and 79 unaffected relatives using a framework marker set of 44 markers for chromosome 1 and 22 markers for chromosome 19. Linkage analysis was made with a non-parametric or autosomal dominant parametric model, either allowing for heterogeneity or not, using an affected only analysis. We identified no linkage to CACNA1A and ATP1A2 loci on chromosome 19 or 1, respectively. Additionally, at least two patients from each family and 92 healthy, unrelated controls were selected for a sequence analysis. We sequenced the 48 exons of CACNA1A and the 23 exons of ATP1A2, including promoter and flanking intron sequences. No polymorphism was identified in the CACNA1A or ATP1A2 genes with a strong correlation to MA. Our study shows that the CACNA1A or ATP1A2 genes are probably not involved in MA. To identify the genes involved in the common forms of migraine, future genetic studies should focus on MA and migraine without aura (MO) and not FHM.

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“…The 11q24 region is implicated in mental retardation 62 and migraine. 63 The significant SNP in the GWAS rs677035 is located between FLI1 and KCNJ1. Previously, we have found linkage to other potassium channel genes including KCNJ2, KCNJ6 and KCNJ16, 27 making KCNJ1 the most interesting gene in the region.…”

Section: Discussionmentioning

confidence: 99%

Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions

et al. 2012

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Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N ¼ 6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (NB17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD ¼ 4.67) and to chromosome 19q13 (rs628604, LOD ¼ 3.55); of extraversion to 14q32 (ATGG002, LOD ¼ 3.3); and of agreeableness to 3p25 (rs709160, LOD ¼ 3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD ¼ 4.07) and 15q14 (rs1055356, LOD ¼ 3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value ¼ 2.6 Â 10 À06 , KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene.

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Significant linkage to migraine with aura on chromosome 11q24

Cited by 81 publications

References 54 publications

Rare missense variants inATP1A2 in families with clustering of common forms of migraine

Rare missense variants inATP1A2 in families with clustering of common forms of migraine

The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura

Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions

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