RESUMO
Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To investigate whether common variants in ASTN2 contribute to ADHD disorder risk, we tested 63 SNPs spanning ASTN2 for association with ADHD and specific comorbid disorders in two samples: 171 families of children with ADHD and their parents (N = 592), and an adult sample comprising 604 adult ADHD cases and 974 controls. The C-allele of rs12376789 in ASTN2 nominally increased the risk for ADHD in the trio sample (p = 0.025). This was not observed in the adult case-control sample alone, but retained in the combined sample (nominal p = 0.030). Several other SNPs showed nominally significant association with comorbid disorders, especially anxiety disorder, in the childhood and adult ADHD samples. Some ASTN2 variants were nominally associated with personality traits in the adult ADHD sample and overlapped with risk alleles for comorbid disorders in childhood. None of the findings survived correction for multiple testing, thus, results do not support a major role of common variants in ASTN2 in the pathogenesis of ADHD, its comorbid disorders or ADHD associated personality traits.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Predisposição Genética para Doença/genética , Glicoproteínas/genética , Proteínas do Tecido Nervoso/genética , Transtornos da Personalidade/genética , Personalidade , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pais/psicologia , Adulto JovemRESUMO
Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (P(SR) = 0.00034, P(OR) = 0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Ligação Genética , Mapeamento Cromossômico , Cromossomos Humanos Par 16 , Genoma Humano , Humanos , Escore Lod , Probabilidade , População BrancaRESUMO
G protein-activated K+ channel 2 (GIRK2) and cAMP-response element binding protein (CREB1) are involved in synaptic plasticity and their genes have been implicated depression and memory processing. Excessive rumination is a core cognitive feature of depression which is also present in remission. High scores on the Ruminative Response Scale (RRS) questionnaire are predictive of relapse and recurrence. Since rumination involves memory, we tested the hypothesis that variation in the genes encoding GIRK2 (KCNJ6) and CREB1 mechanisms would influence RRS scores. GIRK2 and CREB1 polymorphisms were studied in two independent samples (n=651 and n=1174) from the general population. Strongly significant interaction between the TT genotype of rs2070995 (located in KCNJ6) and the GG genotype of rs2253206 (located in CREB1) on RRS were found in both samples. These results were validated in an independent third sample (n=565; individuals with personality disorders) showing significant main effect of the variants mentioned as well as significant interaction on a categorical diagnosis of Cluster C personality disorder (obsessional-compulsive, avoidant and dependent) in which rumination is a prominent feature. Our results suggest that genetic epistasis in post-receptor signaling pathways in memory systems may have relevance for depression and its treatment.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Depressão/psicologia , Transtorno Depressivo/psicologia , Epistasia Genética , Emoções Manifestas , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Adulto , Depressão/genética , Transtorno Depressivo/genética , Feminino , Genótipo , Alemanha , Humanos , Hungria , Masculino , Memória , Pessoa de Meia-Idade , Transtornos da Personalidade/genética , Fenótipo , Polimorfismo Genético , Reino Unido , Adulto JovemRESUMO
Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008-0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Bipolar/genética , GTP Fosfo-Hidrolases/genética , Estudos de Associação Genética/métodos , Transtornos da Personalidade/genética , Característica Quantitativa Herdável , Proteínas Supressoras de Tumor/genética , Adulto , Fatores Etários , Idoso , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno Bipolar/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos da Personalidade/epidemiologia , Adulto JovemRESUMO
A genome-wide association (GWA) study with pooled DNA in adult attention-deficit/hyperactivity disorder (ADHD) employing approximately 500K SNP markers identifies novel risk genes and reveals remarkable overlap with findings from recent GWA scans in substance use disorders. Comparison with results from our previously reported high-resolution linkage scan in extended pedigrees confirms several chromosomal loci, including 16q23.1-24.3 which also reached genome-wide significance in a recent meta-analysis of seven linkage studies (Zhou et al. in Am J Med Genet Part B, 2008). The findings provide additional support for a common effect of genes coding for cell adhesion molecules (e.g., CDH13, ASTN2) and regulators of synaptic plasticity (e.g., CTNNA2, KALRN) despite the complex multifactorial etiologies of adult ADHD and addiction vulnerability.