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2.
Am J Med Genet B Neuropsychiatr Genet ; 168B(5): 327-36, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25988933

RESUMO

Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N = 147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N = 147, ß = 31.34, P = 1.28 × 10(-8) ) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N = 2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N = 2006, P = 0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N = 157, P = 0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N = 53, P < 0.05) in the GTP replication sample. These data identify a genome-wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder.


Assuntos
Epigênese Genética/genética , Face/fisiologia , Medo , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Metilação de DNA , Expressão Facial , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Locos de Características Quantitativas/genética , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/psicologia , Veteranos/psicologia
3.
Alcohol Alcohol ; 43(5): 505-15, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18477577

RESUMO

AIMS: To develop a panel of markers able to extract full haplotype information for candidate genes in alcoholism, other addictions and disorders of mood and anxiety. METHODS: A total of 130 genes were haplotype tagged and genotyped in 7 case/control populations and 51 reference populations using Illumina GoldenGate SNP genotyping technology, determining haplotype coverage. We also constructed and determined the efficacy of a panel of 186 ancestry informative markers. RESULTS: An average of 1465 loci were genotyped at an average completion rate of 91.3%, with an average call rate of 98.3% and replication rate of 99.7%. Completion and call rates were lowered by the performance of two datasets, highlighting the importance of the DNA quality in high throughput assays. A comparison of haplotypes captured by the Addictions Array tagging SNPs and commercially available whole-genome arrays from Illumina and Affymetrix shows comparable performance of the tag SNPs to the best whole-genome array in all populations for which data are available. CONCLUSIONS: Arrays of haplotype-tagged candidate genes, such as this addictions-focused array, represent a cost-effective approach to generate high-quality SNP genotyping data useful for the haplotype-based analysis of panels of genes such as these 130 genes of interest to alcohol and addictions researchers. The inclusion of the 186 ancestry informative markers allows for the detection and correction for admixture and further enhances the utility of the array.


Assuntos
Comportamento Aditivo/genética , Mapeamento Cromossômico/métodos , Haplótipos , Polimorfismo de Nucleotídeo Único , Alelos , Comportamento Aditivo/etnologia , Estudos de Casos e Controles , Genoma Humano , Genótipo , Humanos , Sitios de Sequências Rotuladas
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