Tooth agenesis affects 20% of the world population, and maxillary lateral incisors agenesis (MLIA) is one of the most frequent subtypes, characterized by the absence of formation of deciduous or permanent lateral incisors. Odontogenesis is a complex mechanism regulated by sequential and reciprocal epithelial-mesenchymal interactions, controlled by activators and inhibitors involved in several pathways. Disturbances in these signaling cascades can lead to abnormalities in odontogenesis, resulting in alterations in the formation of the normal teeth number. Our aim was to study a large number of genes encoding either transcription factors or key components in signaling pathways shown to be involved in tooth odontogenesis. We selected 8 genes-MSX1, PAX9, AXIN2, EDA, SPRY2, TGFA, SPRY4, and WNT10A-and performed one of the largest case-control studies taking into account the number of genes and variants assessed, aiming at the identification of MLIA susceptibility factors. We show the involvement of PAX9, EDA, SPRY2, SPRY4, and WNT10A as risk factors for MLIA. Additionally, we uncovered 3 strong synergistic interactions between MLIA liability and MSX1-TGFA, AXIN2-TGFA, and SPRY2-SPRY4 gene pairs. We report the first evidence of the involvement of sprouty genes in MLIA susceptibility. This large study results in a better understanding of the genetic components and mechanisms underlying this trait.

Migraine is a common neurological disorder with a global prevalence around 10% [1]. Several studies showed that migraine is influenced by genetic and environmental factors [2]. The female-to-male ratio of migraine prevalence is 3- to 4-fold higher among women than men[3]. The role of common variants of GABA genes in the X-chromosome in migraine susceptibility was assessed, aiming to explain the differences in disease frequency between males and females. An association study with 188 unrelated cases and 287 migraine-free controls age- and ethnic matched was performed. The case-control ratio was 1:1.5. Candidate genes were selected based on their possible role in pathophysiology of migraine.Thirty-two tagging SNPs were selected in three genes (GABRE, GABRA3 and GABRQ) and genotyping was performed by SNaPshot. Allelic, genotypic and haplotypic frequencies were compared between cases and controls and multiple testing corrections were performed. Also, gene-gene interactions were analyzed. The Results for allelic associations revealed five nominal significant associations and three trends for association. In what concerns genotypic frequencies, four noteworthy results were found in GABRE and GABRA3 genes. After multiple testing correction, two allelic associations remained significant (GABRA3 and GABRE) and one genotypic association resisted to Bonferroni correction (GABRE), all in the females group. No significant results were found in the haplotypic analyses but an additive effect was observed between two SNPs of GABRA3 and two of GABRE. These findings show, for the first time, evidence of a possible involvement of common variants in GABA receptors in migraine susceptibility and in gender-specific liability.

In spite of recent developments, data regarding the genes responsible for the less severe forms of hypodontia are still scarce and controversial. This study addressed the hypothesis that agenesis of maxillary lateral incisors (MLIA) is a distinct type of hypodontia, by evaluating its familial aggregation and the occurrence of other types of ageneses or microdontia in probands' relatives. Sixty-two probands with MLIA were identified, and information was collected on 142 first-degree relatives. Relative risk (RR) was calculated and compared by re-assessment of data previously published for the Swedish, Utah, and Israeli populations, for the same trait. A RR of 15 was obtained in the Portuguese, 16 in the Swedish, 12 in Utah, and 5 in the Israeli population. Our results support a significant familial aggregation of MLIA, show that MLIA almost never segregates with other forms of agenesis, and suggest that microdontia of maxillary lateral incisors is part of the same phenotype.