Ester Saus

Additional support for the association of SLITRK1 var321 and Tourette syndrome

We identified SLIT and NTRK-like 1 (SLITRK1) as a candidate gene for Tourette syndrome (TS) based on the mapping of a de novo chr13 inversion, the finding of a rare frameshift mutation in a family with TS, and the association of a functional rare 3′UTR variant (var321) corresponding to highly conserved miRNA binding domain.1 This rare allele was identified in 2 of 174 individuals with TS and was not present in 2148 controls (P = 0.0056). Based on the absence of haplotype sharing between the var321 probands, we concluded that the alleles were likely to represent independent mutations, further supporting the association. In this study, we present additional data based on genome-wide genotyping, multidimensional scaling analysis (MDS), and dense haplotype mapping, providing additional evidence in favor of these initial conclusions.

Copy number polymorphism of the salivary amylase gene: implications in human nutrition research.

The salivary α-amylase is a calcium-binding enzyme that initiates starch digestion in the oral cavity. The α-amylase genes are located in a cluster on the chromosome that includes salivary amylase genes (AMY1), two pancreatic α-amylase genes (AMY2A and AMY2B) and a related pseudogene. The AMY1 genes show extensive copy number variation which is directly proportional to the salivary α-amylase content in saliva. The α-amylase amount in saliva is also influenced by other factors, such as hydration status, psychosocial stress level, and short-term dietary habits. It has been shown that the average copy number of AMY1 gene is higher in populations that evolved under high-starch diets versus low-starch diets, reflecting an intense positive selection imposed by diet on amylase copy number during evolution. In this context, a number of different aspects can be considered in evaluating the possible impact of copy number variation of the AMY1 gene on nutrition research, such as issues related to human diet gene evolution, action on starch digestion, effect on glycemic response after starch consumption, modulation of the action of α-amylases inhibitors, effect on taste perception and satiety, influence on psychosocial stress and relation to oral health.

Suicide attempts in bulimia nervosa: Personality and psychopathological correlates

BACKGROUND Little evidence exists about suicidal acts in eating disorders and its relation with personality. We explored the prevalence of lifetime suicide attempts (SA) in women with bulimia nervosa (BN), and compared eating disorder symptoms, general psychopathology, impulsivity and personality between individuals who had and had not attempted suicide. We also determined the variables that better correlate with of SA. METHOD Five hundred sixty-six BN outpatients (417 BN purging, 47 BN non-purging and 102 subthreshold BN) participated in the study. RESULTS Lifetime prevalence of suicide attempts was 26.9%. BN subtype was not associated with lifetime SA (p=0.36). Suicide attempters exhibited higher rates on eating symptomatology, general psychopathology, impulsive behaviors, more frequent history of childhood obesity and parental alcohol abuse (p<0.004). Suicide attempters exhibited higher scores on harm avoidance and lower on self-directedness, reward dependence and cooperativeness (p<0.002). The most strongly correlated variables with SA were: lower education, minimum BMI, previous eating disorder treatment, low self-directedness, and familial history of alcohol abuse (p<0.006). CONCLUSION Our results support the notion that internalizing personality traits combined with impulsivity may increase the probability of suicidal behaviors in these patients. Future research may increase our understanding of the role of suicidality to work towards rational prevention of suicidal attempts.

Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 x 10(-4)) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 x 10(-5)) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.

A haplotype of glycogen synthase kinase 3β is associated with early onset of unipolar major depression.

Recent findings suggest that glycogen synthase kinase 3β (GSK3β) may play a role in the pathophysiology and treatment of mood disorders. Various genetic studies have shown the association of GSK3β polymorphisms with different mood disorder phenotypes. We hypothesized that genetic variants in the GSK3β gene could partially underlie the susceptibility to mood disorders. We performed a genetic case–control study of 440 psychiatrically screened control subjects and 445 mood disorder patients [256 unipolar major depressive disorder (MDD) and 189 bipolar disorder (BD)]. We genotyped a set of 11 single nucleotide polymorphisms (SNPs) and determined the relative frequency of a known copy number variant (CNV) overlapping the GSK3β by quantitative real‐time polymerase chain reaction (PCR). We found no evidence of association with MDD or BD diagnosis, and we further investigated the age at onset (AAO) of the disorder and severity of depressive index episode. We found that rs334555, located in intron 1 of GSK3β, was nominally associated with an earlier AAO of the disease in MDD (P = 0.001). We also identified a haplotype containing three SNPs (rs334555, rs119258668 and rs11927974) associated with AAO of the disorder (permutated P = 0.0025). We detected variability for the CNV, but we could not detect differences between patients and controls for any of the explored phenotypes. This study presents further evidence of the contribution of GSK3β to mood disorders, implicating a specific SNP and a haplotype with an earlier onset of the disorder in a group of well‐characterized patients with unipolar MDD. Further replication studies in patients with the same phenotypic characteristics should confirm the results reported here.

Role of the neurotrophin network in eating disorders' subphenotypes: Body mass index and age at onset of the disease

Eating disorders (ED) are severe psychiatric diseases that most likely result from, and are sustained by socio-cultural, psychological and biological factors. We explored whether members of the neurotrophin family are disease-modifying factors of quantitative traits, potentially contributing to the outcome or prognosis of the disease. We studied lifetime minimum and maximum body mass index (minBMI and maxBMI) and age at onset of the disease in a sample of 991 ED patients from France, Germany, Italy and Spain and analysed 183 genetic variants located in 10 candidate genes encoding different neurotrophins and their receptors. We used a hierarchical model approach to include prior genetic knowledge of the specific and found that variants in CNTF, in its receptor CNTFR, and in NTRK2 were significantly associated with a lower age at onset of the ED. In addition, one variant in NTRK1 was associated with a higher minBMI. The results suggest that for these two subphenotypes, CNTF, CNTFR, NTRK1 and NTRK2 might act as disease-modifying factors and add preliminary evidence to the global hypothesis that EDs are the result of complex interactions and reciprocal controls between the immune, endocrine and central nervous systems.