RESUMEN
The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.
Asunto(s)
Ansiedad/metabolismo , Predisposición Genética a la Enfermedad/genética , Proteínas de la Membrana/metabolismo , Polimorfismo de Nucleótido Simple/genética , Adulto , Animales , Ansiedad/genética , Ansiedad/patología , Ansiedad/fisiopatología , Modelos Animales de Enfermedad , Femenino , Lóbulo Frontal/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Proteínas de la Membrana/genética , Ratones , Persona de Mediana Edad , Fenotipo , Escalas de Valoración Psiquiátrica , ARN Mensajero/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P = 5.14e-08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P = 6.71e-08). Both SNPs lie in a region devoid of any protein-coding genes; however, they both show significant association with mRNA-expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible trans-regulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks.
Asunto(s)
Cromosomas Humanos Par 4 , Dislexia/genética , Potenciales Evocados Auditivos/genética , Transportador de Glucosa de Tipo 3/genética , Percepción del Habla/genética , Adolescente , Estudios de Casos y Controles , Niño , Variación Contingente Negativa/genética , Discriminación en Psicología/fisiología , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Valores de Referencia , Adulto JovenAsunto(s)
Dislexia/genética , Lateralidad Funcional/genética , Ligamiento Genético , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Linaje , Valores de Referencia , HermanosRESUMEN
Genes involved in serotonergic and dopaminergic neurotransmission have been hypothesized to affect different aspects of personality, but findings from genetic association studies did not provide conclusive results so far. In previous studies, however, only one or a few polymorphisms within single genes were investigated neglecting the possibility that the genetic associations might be more complex comprising several genes or gene regions. To overcome this limitation, we performed an extended genetic association study analyzing 17 serotonergic (SLC6A4, HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR6, MAOA, TPH1, TPH2) and dopaminergic genes (SLC6A3, DRD2, DRD3, DRD4, COMT, MAOA, TH, DBH), which have been previously reported to be implicated with personality traits. One hundred and ninety-five single nucleotide polymorphisms (SNPs) within these genes were genotyped with the Illumina BeadChip technology (HumanHap300, Human-1) in a sample of 366 mentally healthy Caucasians. Additionally, we tried to replicate our results in an independent sample of further 335 Caucasians. Personality traits in both samples were assessed with the German version of Cloninger's Tridimensional Personality Questionnaire. From 30 SNPs showing associations at a nominal level of significance, two intronic SNPs, rs2770296 and rs927544, both located in the HTR2A gene, withstood correction for multiple testing. These SNPs were associated with the personality trait novelty seeking. The effect of rs927544 could be replicated for the novelty seeking subscale extravagance, and the same SNP was also associated with extravagance in the combined samples. Our results show that HTR2A polymorphisms modulate facets of novelty seeking behaviour in healthy adults suggesting that serotonergic neurotransmission is involved in this phenotype.
Asunto(s)
Conducta Exploratoria/fisiología , Personalidad/genética , Receptor de Serotonina 5-HT2A/genética , Receptor de Serotonina 5-HT2A/fisiología , ADN/biosíntesis , ADN/genética , Dopamina/biosíntesis , Dopamina/genética , Dopamina/fisiología , Genotipo , Alemania/epidemiología , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple , Receptores Dopaminérgicos/biosíntesis , Receptores Dopaminérgicos/genética , Receptores de Serotonina/biosíntesis , Receptores de Serotonina/genética , Serotonina/biosíntesis , Serotonina/genética , Serotonina/fisiología , Transmisión Sináptica/genética , Transmisión Sináptica/fisiologíaRESUMEN
BACKGROUND: Restless legs syndrome (RLS) is associated with common variants in three intronic and intergenic regions in MEIS1, BTBD9, and MAP2K5/LBXCOR1 on chromosomes 2p, 6p and 15q. METHODS: Our study investigated these variants in 649 RLS patients and 1230 controls from the Czech Republic (290 cases and 450 controls), Austria (269 cases and 611 controls) and Finland (90 cases and 169 controls). Ten single nucleotide polymorphisms (SNPs) within the three genomic regions were selected according to the results of previous genome-wide scans. Samples were genotyped using Sequenom platforms. RESULTS: We replicated associations for all loci in the combined samples set (rs2300478 in MEIS1, p = 1.26 x 10(-5), odds ratio (OR) = 1.47, rs3923809 in BTBD9, p = 4.11 x 10(-5), OR = 1.58 and rs6494696 in MAP2K5/LBXCOR1, p = 0.04764, OR = 1.27). Analysing only familial cases against all controls, all three loci were significantly associated. Using sporadic cases only, we could confirm the association only with BTBD9. CONCLUSION: Our study shows that variants in these three loci confer consistent disease risks in patients of European descent. Among the known loci, BTBD9 seems to be the most consistent in its effect on RLS across populations and is also most independent of familial clustering.
