RESUMO
BACKGROUND: Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD. METHODS: Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT. RESULTS: A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5' region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplo-type block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2. LIMITATIONS: The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype. CONCLUSION: The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Criança , Manual Diagnóstico e Estatístico de Transtornos Mentais , Família , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Caracteres SexuaisRESUMO
OBJECTIVE: To investigate the association between a Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia. METHODS: 408 schizophrenic patients and 172 control subjects were compared with regard to their DRD3 Ser9Gly genotypic and allelic frequencies. In addition, we carried out a family-based association study including 183 pedigrees (472 subjects) using the transmission disequilibrium test (TDT). RESULTS: No significant differences of genotype or homozygosity distribution were identified between patients and controls. When patients were stratified according to gender, response to treatment, age at onset, no significant differences were observed. Neither allele A (Ser), or G (Gly) were preferentially transmitted from parents to affected offspring. CONCLUSION: The hypothesis that the DRD3 Ser9Gly polymorphism plays a predisposing role in schizophrenia is not supported by this study.
Assuntos
Frequência do Gene , Polimorfismo Genético , Receptores de Dopamina D3/genética , Esquizofrenia/genética , Adulto , Antipsicóticos/uso terapêutico , Estudos de Casos e Controles , Manual Diagnóstico e Estatístico de Transtornos Mentais , Família , Feminino , Ligação Genética , Marcadores Genéticos , Predisposição Genética para Doença/genética , Genótipo , Glicina/genética , Haplótipos/genética , Homozigoto , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Serina/genética , População Branca/genéticaRESUMO
BACKGROUND: Several lines of evidence support the association between low or lowered levels of serum total cholesterol and suicide. Genetic epidemiological studies suggest that genes predispose to suicide. Given that genes control many aspects of cholesterol biosynthesis and metabolism, one approach through which to explore the putative association between low cholesterol and suicide is through genetic studies. METHODS: We examined the potential role of five genes encoding proteins involved in cholesterol biosynthesis and transport in a total sample of 305 male Caucasian subjects, consisting of 145 suicide completers and 160 controls. We investigated variation in the HMG CoA reductase (HMGCR), 7-dehydrocholesterol reductase (DHCR7), lipoprotein lipase (LPL), low-density lipoprotein receptor (LDLR), and apolipoprotein E (APOE) genes. RESULTS: We were unable to detect significant differences in allele or genotype frequencies between the suicide cases and controls for any of the genes studied. No relationship was found between genotype and impulsivity or aggression as measured using the BIS and BDHI, respectively. LIMITATIONS: The limitations of this study are consistent with the typical limitations inherent in most genetic association studies involving complex behavioral traits. CONCLUSION: Although these genes are unlikely to play a major role in susceptibility to suicide, further studies in a larger sample are necessary to reveal the smaller genetic effects, if present.
Assuntos
Colesterol/biossíntese , Colesterol/genética , Suicídio , Adulto , Agressão , Estudos de Casos e Controles , Colesterol/sangue , Variação Genética , Genótipo , Humanos , Comportamento Impulsivo , Masculino , Reação em Cadeia da Polimerase , Fatores de RiscoRESUMO
OBJECTIVE: Previous findings indicate that women with Bulimia Nervosa (BN), when compared to women with no eating disorder (NED), tend to display elevated methylation in the promoter region of the DRD2 gene. The preceding would be compatible with evidence of generally reduced dopamine activity in people with BN. However, altered DNA methylation has also been associated with adverse environmental exposures (such as to childhood abuse) and with psychiatric disturbances (such as Borderline Personality Disorder: BPD). In this study, we examined the extent to which DRD2 methylation was associated with the presence or absence of a bulimic eating disorder, to childhood abuse exposure, or to comorbid BPD. METHOD: Women with a bulimia-spectrum disorder (BSD) and women with NED were assessed for childhood traumata, eating-disorder symptoms and BPD, and provided blood samples for methylation analyzes. RESULTS: BSD and NED groups did not differ as to mean percent DRD2 promoter methylation. However, among the women with a BSD, those with BPD showed small, but significant increases in DRD2 methylation levels compared to women with NED (as indicated by Hochberg's post-hoc tests). Similarly, women with a BSD who reported a history of childhood sexual abuse showed a trend-level elevation of DRD2 methylation compared to our NED group. DISCUSSION: Our findings imply that, in people with a BSD, increased methylation of the DRD2 gene promoter may be more strongly characteristic of comorbid psychopathology than it is a global correlate of the eating disorder per se. We discuss theoretical implications of our findings.