BACKGROUND: Recent studies suggested a role for hypocretins in the neurobiology of Major Mood Disorders (MMD). The purpose of this study was to investigate hypocretin involvement in MMD evaluating whether particular alleles or genotypes of the hypocretin pathway genes (HCRT, HCRTR1 and HCRTR2) would modify the occurrence and clinical features of the disease. METHODS: We selected for the study 229 MMD patients and 259 healthy age-, sex- and ethnicity-matched controls. Cases and controls were genotyped for several single-nucleotide polymorphisms (SNPs) of the HCRT, HCRTR1, and HCRTR2 genes. RESULTS: We found that allelic and genotypic frequencies of the rs2271933 G>A polymorphism (Ile408Val) in the HCRTR1 gene were significantly different between cases and controls (p=0.003 and p=0.0004, respectively). The carriage of the A allele was associated with a significantly increased disease risk (OR:1.60, 95% C.I. 1.22-2.10). In addition, we found a significant association between HCRTR1 haplotypes and the disease (permutation p<0.0001). In the analysis of subgroups we confirmed the association only in patients with unipolar depression. LIMITATIONS: Our sample was relatively small and included only cases and controls recruited from Northern Italy. Analysis of the disease subgroups warrants reexamination with more subjects. Finally, the effects of the rs2271933 G>A polymorphism on the hypocretin-1 receptor function are unknown. CONCLUSIONS: Our study suggests that the HCRTR1 gene or a linked locus may modulate the risk for Major Mood Disorders and supports recent studies suggesting an involvement of hypocretin neurotransmitter system in affective disorders.
BACKGROUND: Recent studies suggested a role for hypocretins in the neurobiology of Major Mood Disorders (MMD). The purpose of this study was to investigate hypocretin involvement in MMD evaluating whether particular alleles or genotypes of the hypocretin pathway genes (HCRT, HCRTR1 and HCRTR2) would modify the occurrence and clinical features of the disease. METHODS: We selected for the study 229 MMD patients and 259 healthy age-, sex- and ethnicity-matched controls. Cases and controls were genotyped for several single-nucleotide polymorphisms (SNPs) of the HCRT, HCRTR1, and HCRTR2 genes. RESULTS: We found that allelic and genotypic frequencies of the rs2271933 G>A polymorphism (Ile408Val) in the HCRTR1 gene were significantly different between cases and controls (p=0.003 and p=0.0004, respectively). The carriage of the A allele was associated with a significantly increased disease risk (OR:1.60, 95% C.I. 1.22-2.10). In addition, we found a significant association between HCRTR1 haplotypes and the disease (permutation p<0.0001). In the analysis of subgroups we confirmed the association only in patients with unipolar depression. LIMITATIONS: Our sample was relatively small and included only cases and controls recruited from Northern Italy. Analysis of the disease subgroups warrants reexamination with more subjects. Finally, the effects of the rs2271933 G>A polymorphism on the hypocretin-1 receptor function are unknown. CONCLUSIONS: Our study suggests that the HCRTR1 gene or a linked locus may modulate the risk for Major Mood Disorders and supports recent studies suggesting an involvement of hypocretin neurotransmitter system in affective disorders.
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