RESUMO
Positive affect denotes a state of pleasurable engagement with the environment eliciting positive emotion such as contentment, enthusiasm or happiness. Positive affect is associated with favorable psychological, physical and economic outcomes in many longitudinal studies. With a heritability of ⩽64%, positive affect is substantially influenced by genetic factors; however, our understanding of genetic pathways underlying individual differences in positive affect is still limited. Here, through a genome-wide association study of positive affect in African-American participants, we identify a single-nucleotide polymorphism, rs322931, significantly associated with positive affect at P<5 × 10-8, and replicate this association in another cohort. Furthermore, we show that the minor allele of rs322931 predicts expression of microRNAs miR-181a and miR-181b in human brain and blood, greater nucleus accumbens reactivity to positive emotional stimuli and enhanced fear inhibition. Prior studies have suggested that miR-181a is part of the reward neurocircuitry. Taken together, we identify a novel genetic variant for further elucidation of genetic underpinning of positive affect that mediates positive emotionality potentially via the nucleus accumbens and miR-181.
Assuntos
Emoções/fisiologia , Felicidade , MicroRNAs/genética , Prazer/fisiologia , Adulto , Negro ou Afro-Americano/genética , Alelos , Cromossomos Humanos Par 1 , Feminino , Frequência do Gene , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Íntrons , Masculino , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD.
Assuntos
Encéfalo/fisiopatologia , Moléculas de Adesão Celular Neuronais/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Negro ou Afro-Americano/genética , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Encéfalo/diagnóstico por imagem , Expressão Facial , Reconhecimento Facial , Medo , Feminino , Neuroimagem Funcional , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Reflexo de Sobressalto/fisiologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/fisiopatologia , População Branca/genética , Adulto JovemRESUMO
OBJECTIVE: Long-term antidepressant (AD) treatment for depression in bipolar disorder (BPD) patients is highly prevalent, but its benefits and risks remain uncertain, encouraging this meta-analysis of available research. METHOD: We reviewed randomized controlled trials for BPD involving >or=6 months of treatment with AD +/- mood stabilizer (MS) vs. placebo +/- MS, using meta-analyses to compare reported risks of new depression vs. mania. RESULTS: In seven trials (350 BPD patients) involving 12 contrasts, long-term treatments that included ADs yielded 27% lower risk of new depression vs. MS-only or no treatment [pooled relative risk, RR = 0.73; 95% CI 0.55-0.97; number-needed-to-treat (NNT) = 11], but 72% greater risk for new mania [RR = 1.72; 95% CI 1.23-2.41; number-needed-to-harm (NNH) = 7]. Compared with giving an MS-alone, adding an AD yielded neither major protection from depression (RR = 0.84; 95% CI 0.56-1.27; NNT = 16) nor substantial increase in risk of mania (RR = 1.37; 95% CI 0.81-2.33; NNH = 16). CONCLUSION: Long-term adjunctive AD treatment was not superior to MS-alone in BPD, further encouraging reliance on MSs as the cornerstone of prophylaxis.