Association analysis of STX1A gene variants in common forms of migraine.

OBJECTIVES: To examine the association of genetic variants in the syntaxin 1A gene (STX1A) with common forms of migraine, and perform a combined analysis of the data from the current study and previously published reports. METHODS: We investigated the parent-to-offspring transmission of rs6951030, rs4363087 and rs2293489 in 191 family trios, each with a proband with childhood-onset migraine, and performed a case-control analysis between the probands and 223 unrelated controls. In addition, we performed a combined data analysis with an overall sample of 567 migraine patients and 720 unrelated controls and performed a migraine-specific gene-network analysis. RESULTS: The transmission disequilibrium test revealed significant transmission distortion of rs4363087 in migraine overall (OR = 1.56, p = 0.006; p = 0.01 after correction for multiple testing) and migraine without aura (OR = 1.58, p = 0.01; corrected p = 0.04). Two-marker haplotype analysis revealed transmission distortion of A-G (rs6951030-rs4363087; OR = 1.47, p = 0.01) and A-C (rs4363087-rs2293489; OR = 0.66, p = 0.01). Combined analysis showed significant association of rs941298 with migraine overall (OR = 1.28, p = 0.004) and migraine without aura (OR = 1.3, p = 0.008). Network analysis identified 24 genes relating STX1A to other migraine candidate genes, including KCNK18 (TRESK channel) involved in the cytoplasmatic calcium signalling together with syntaxin 1A. CONCLUSION: Our results provide support for the hypothesis that STX1A represents a susceptibility gene for migraine.

No association between bipolar disorder risk polymorphisms in ANK3 and CACNA1C and common migraine.

BACKGROUND: Migraine and bipolar disorder are characterized by a high level of co-morbidity, and a common familial-genetic basis has recently been hypothesized for the 2 disorders. Genome-wide association studies have reported strong evidence of association between the polymorphisms rs10994336[T] in the ANK3 gene and rs1006737[A] in the CACNA1C gene and risk of bipolar disorder. OBJECTIVE: The aim of this study was to evaluate the hypothesis of a genetic linkage between migraine and bipolar disorder by investigating the familial transmission of the 2 bipolar disorder risk polymorphisms, in a sample of family trios with probands with childhood migraine, and unrelated controls. METHODS: Our sample comprised 192 family trios, each with a proband with childhood migraine (137 migraine without aura, 44 migraine with aura) and 228 unrelated controls. The markers rs10994336 and rs1006737 were genotyped using a TaqMan single nucleotide polymorphism Genotyping Assay. The transmission disequilibrium test analysis for the family trios and the case-control analysis were performed using the program UNPHASED. RESULTS: The allelic and genotypic transmission disequilibrium test analysis did not show any evidence of transmission distortion of the 2 markers in both migraine overall (rs10994336: OR = 1.61, P = .11; rs1006737: OR = 1.12, P = .49) and in the migraine without aura and migraine with aura subgroups. Likewise, the case-control analysis of alleles and genotypes frequencies did not show any evidence of association. CONCLUSION: In the present study, we did not find evidence for association between the bipolar disorder risk polymorphisms rs10994336 in the ANK3 gene and rs1006737 in the CACNA1C gene in migraine. However, as these are variants that have a small effect on the risk of bipolar disorder (OR < 1.5), we cannot exclude a similar small effect on migraine susceptibility with the present sample size.

Nuclear receptor rev-erb-{alpha} circadian gene variants and lithium carbonate prophylaxis in bipolar affective disorder.

Rev-erb-alpha is one of the key components of the mammalian circadian mechanism; recently, it was also reported to be involved in the biological action of lithium. We investigated whether polymorphisms in the Rev-erb- alpha gene are associated with the long-term efficacy of lithium carbonate therapy in bipolar affective disorder. Seven single nucleotide polymorphisms (SNPs) were genotyped in a well-characterized sample of patients from Sardinia, Italy, who were followed prospectively for up to 27 years. Genotypic and allelic analysis did not show evidence for association between the polymorphisms and the different levels of lithium response. Further analyses grouping the different levels of response demonstrated that when the patients were separated into groups of nonresponders versus individuals who have had at least a minor or modest improvement in frequency of episodes or admissions, there was a significant increase in the frequency of the T allele in the nonresponder group (p = 0.0008). Logistic regression analyses showed that patients carrying at least one copy of the T allele for the rs2314339 marker were shown to be approximately 3.5 times more likely to have no improvement or even a worsening of the illness (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.18-10.76). The results of this study may help to identify potential biological markers that can serve to predict the response of bipolar affective disorder patients to treatment, improving treatment efficacy.