RESUMEN
The amplitude of activation in brain resting state networks (RSNs), measured with resting-state functional magnetic resonance imaging, is heritable and genetically correlated across RSNs, indicating pleiotropy. Recent univariate genome-wide association studies (GWASs) explored the genetic underpinnings of individual variation in RSN activity. Yet univariate genomic analyses do not describe the pleiotropic nature of RSNs. In this study, we used a novel multivariate method called genomic structural equation modeling to model latent factors that capture the shared genomic influence on RSNs and to identify single nucleotide polymorphisms (SNPs) and genes driving this pleiotropy. Using summary statistics from GWAS of 21 RSNs reported in UK Biobank (N = 31,688), the genomic latent factor analysis was first conducted in a discovery sample (N = 21,081), and then tested in an independent sample from the same cohort (N = 10,607). In the discovery sample, we show that the genetic organization of RSNs can be best explained by two distinct but correlated genetic factors that divide multimodal association networks and sensory networks. Eleven of the 17 factor loadings were replicated in the independent sample. With the multivariate GWAS, we found and replicated nine independent SNPs associated with the joint architecture of RSNs. Further, by combining the discovery and replication samples, we discovered additional SNP and gene associations with the two factors of RSN amplitude. We conclude that modeling the genetic effects on brain function in a multivariate way is a powerful approach to learn more about the biological mechanisms involved in brain function.
Asunto(s)
Mapeo Encefálico , Red Nerviosa , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Mapeo Encefálico/métodos , Estudio de Asociación del Genoma Completo , Humanos , Imagen por Resonancia Magnética/métodos , Red Nerviosa/fisiologíaRESUMEN
Investigating the contribution of biology to human cognition has assumed a bottom-up causal cascade where genes influence brain systems that activate, communicate, and ultimately drive behavior. Yet few studies have directly tested whether cognitive traits with overlapping genetic underpinnings also rely on overlapping brain systems. Here, we report a step-wise exploratory analysis of genetic and functional imaging overlaps among cognitive traits. We used twin-based genetic analyses in the human connectome project (HCP) dataset (N â= â486), in which we quantified the heritability of measures of cognitive functions, and tested whether they were driven by common genetic factors using pairwise genetic correlations. Subsequently, we derived activation maps associated with cognitive tasks via functional imaging meta-analysis in BrainMap (N â= â4484), and tested whether cognitive traits that shared genetic variation also exhibited overlapping brain activation. Our genetic analysis determined that six cognitive measures (cognitive flexibility, no-go continuous performance, fluid intelligence, processing speed, reading decoding and vocabulary comprehension) were heritable (0.3 â< âh2 â< â0.5), and genetically correlated with at least one other heritable cognitive measure (0.2 â< âρg â< â0.35). The meta-analysis showed that two genetically-correlated traits, cognitive flexibility and fluid intelligence (ρg â= â0.24), also had a significant brain activation overlap (ρperm â= â0.29). These findings indicate that fluid intelligence and cognitive flexibility rely on overlapping biological features, both at the neural systems level and at the molecular level. The cross-disciplinary approach we introduce provides a concrete framework for data-driven quantification of biological convergence between genetics, brain function, and behavior in health and disease.
Asunto(s)
Cognición/fisiología , Función Ejecutiva/fisiología , Patrón de Herencia/genética , Inteligencia/genética , Adulto , Comprensión/fisiología , Conectoma , Femenino , Humanos , Masculino , Metaanálisis como Asunto , Tiempo de Reacción/genética , Adulto JovenRESUMEN
We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10-7) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in "SNAP" (Soluble NSF attachment protein) Receptor" (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r2 = - 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Proteínas del Tejido Nervioso/genética , Proteínas R-SNARE/genética , ARN Largo no Codificante/genética , Adulto , Animales , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Estudios de Cohortes , ADN sin Sentido/genética , ADN sin Sentido/metabolismo , Femenino , Predisposición Genética a la Enfermedad/genética , Genética de Población/métodos , Estudio de Asociación del Genoma Completo , Genotipo , Células HEK293 , Humanos , Masculino , Ratones , Fenotipo , Polimorfismo de Nucleótido Simple/genética , ARN Largo no Codificante/metabolismo , Factores de RiesgoRESUMEN
Autism spectrum disorders (ASDs) and autistic traits in the general population may share genetic susceptibility factors. In this study, we investigated such potential overlap based on common genetic variants. We developed and validated a self-report questionnaire of autistic traits in adults. We then conducted genome-wide association studies (GWASs) of six trait scores derived from the questionnaire through exploratory factor analysis in 1981 adults from the general population. Using the results from the Psychiatric Genomics Consortium GWAS of ASDs, we observed genetic sharing between ASDs and the autistic traits 'childhood behavior', 'rigidity' and 'attention to detail'. Gene-set analysis subsequently identified 'rigidity' to be significantly associated with a network of ASD gene-encoded proteins that regulates neurite outgrowth. Gene-wide association with the well-established ASD gene MET reached significance. Taken together, our findings provide evidence for an overlapping genetic and biological etiology underlying ASDs and autistic population traits, which suggests that genetic studies in the general population may yield novel ASD genes.
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Trastorno del Espectro Autista/genética , Trastorno Autístico/genética , Adulto , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/fisiopatología , Trastorno Autístico/etiología , Trastorno Autístico/fisiopatología , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Fenotipo , Proteínas Proto-Oncogénicas c-met/genética , Autoinforme , Encuestas y CuestionariosRESUMEN
De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.
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Encéfalo/anatomía & histología , Discapacidad Intelectual/genética , Megalencefalia/genética , Mutación , Proteína Homóloga de Ras Enriquecida en el Cerebro/genética , Serina-Treonina Quinasas TOR/metabolismo , Animales , Movimiento Celular , Tamaño de la Célula , Células Cultivadas , Humanos , Discapacidad Intelectual/patología , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Tamaño de los Órganos , Convulsiones/genética , Transducción de Señal/genética , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Pez Cebra/genéticaRESUMEN
This corrects the article DOI: 10.1038/mp.2017.98.
RESUMEN
Identifying genetic variants contributing to attention-deficit/hyperactivity disorder (ADHD) is complicated by the involvement of numerous common genetic variants with small effects, interacting with each other as well as with environmental factors, such as stress exposure. Random forest regression is well suited to explore this complexity, as it allows for the analysis of many predictors simultaneously, taking into account any higher-order interactions among them. Using random forest regression, we predicted ADHD severity, measured by Conners' Parent Rating Scales, from 686 adolescents and young adults (of which 281 were diagnosed with ADHD). The analysis included 17 374 single-nucleotide polymorphisms (SNPs) across 29 genes previously linked to hypothalamic-pituitary-adrenal (HPA) axis activity, together with information on exposure to 24 individual long-term difficulties or stressful life events. The model explained 12.5% of variance in ADHD severity. The most important SNP, which also showed the strongest interaction with stress exposure, was located in a region regulating the expression of telomerase reverse transcriptase (TERT). Other high-ranking SNPs were found in or near NPSR1, ESR1, GABRA6, PER3, NR3C2 and DRD4. Chronic stressors were more influential than single, severe, life events. Top hits were partly shared with conduct problems. We conclude that random forest regression may be used to investigate how multiple genetic and environmental factors jointly contribute to ADHD. It is able to implicate novel SNPs of interest, interacting with stress exposure, and may explain inconsistent findings in ADHD genetics. This exploratory approach may be best combined with more hypothesis-driven research; top predictors and their interactions with one another should be replicated in independent samples.
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Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Estrés Psicológico/genética , Telomerasa/genética , Adolescente , Proteínas de Arabidopsis , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/psicología , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Liasas Intramoleculares , Masculino , Sistema Hipófiso-Suprarrenal/fisiopatología , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología , Adulto JovenRESUMEN
Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno Autístico/genética , Ácido Glutámico/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Adolescente , Sistema de Transporte de Aminoácidos y+L , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/psicología , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/psicología , Trastorno Autístico/metabolismo , Trastorno Autístico/psicología , Proteínas de Unión al Calcio/genética , Niño , Preescolar , Femenino , Cadenas Ligeras de la Proteína-1 Reguladora de Fusión , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , Receptores AMPA/genética , Receptores de GABA-A/genética , Receptores de Glutamato Metabotrópico/genética , Receptores de N-Metil-D-Aspartato/genética , Índice de Severidad de la EnfermedadRESUMEN
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Secuenciación del Exoma , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo Genético/genética , Adulto , Encéfalo/metabolismo , Femenino , Sitios Genéticos/genética , Variación Genética , Genotipo , Humanos , Masculino , Sistemas de Lectura Abierta/genéticaRESUMEN
The glucocorticoid receptor plays a pivotal role in the brain's response to stress; a haplotype of functional polymorphisms in the NR3C1 gene encoding this receptor has been associated with attention-deficit hyperactivity disorder (ADHD). The serotonin transporter (5-HTT) gene polymorphism 5-HTTLPR is known to influence the relation between stress exposure and ADHD severity, which may be partly because of its reported effects on glucocorticoid levels. We therefore investigated if NR3C1 moderates the relation of stress exposure with ADHD severity and brain structure, and the potential role of 5-HTTLPR. Neuroimaging, genetic and stress exposure questionnaire data were available for 539 adolescents and young adults participating in the multicenter ADHD cohort study NeuroIMAGE (average age: 17.2 years). We estimated the effects of genetic variation in NR3C1 and 5-HTT, stress exposure and their interactions on ADHD symptom count and gray matter volume. We found that individuals carrying the ADHD risk haplotype of NR3C1 showed significantly more positive relation between stress exposure and ADHD severity than non-carriers. This gene-environment interaction was significantly stronger for 5-HTTLPR L-allele homozygotes than for S-allele carriers. These two- and three-way interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex and angular gyrus. Our findings illustrate how genetic variation in the stress response pathway may influence the effects of stress exposure on ADHD severity and brain structure. The reported interplay between NR3C1 and 5-HTT may further explain some of the heterogeneity between studies regarding the role of these genes and hypothalamic-pituitary-adrenal axis activity in ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Encéfalo/anatomía & histología , Encéfalo/fisiopatología , Receptores de Glucocorticoides/genética , Estrés Psicológico/genética , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/patología , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Interacción Gen-Ambiente , Variación Genética , Haplotipos , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Sistema Hipófiso-Suprarrenal/fisiopatología , Polimorfismo de Nucleótido Simple , Receptores de Glucocorticoides/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estrés Psicológico/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Impairment of response inhibition has been implicated in attention-deficit/hyperactivity disorder (ADHD). Dopamine neurotransmission has been linked to the behavioural and neural correlates of response inhibition. The current study aimed to investigate the relationship of polymorphisms in two dopamine-related genes, the catechol-O-methyltransferase gene (COMT) and the dopamine transporter gene (SLC6A3 or DAT1), with the neural and behavioural correlates of response inhibition. METHOD: Behavioural and neural measures of response inhibition were obtained in 185 adolescents with ADHD, 111 of their unaffected siblings and 124 healthy controls (mean age 16.9 years). We investigated the association of DAT1 and COMT variants on task performance and whole-brain neural activation during response inhibition in a hypothesis-free manner. Additionally, we attempted to explain variance in previously found ADHD effects on neural activation during response inhibition using these DAT1 and COMT polymorphisms. RESULTS: The whole-brain analyses demonstrated large-scale neural activation changes in the medial and lateral prefrontal, subcortical and parietal regions of the response inhibition network in relation to DAT1 and COMT polymorphisms. Although these neural activation changes were associated with different task performance measures, no relationship was found between DAT1 or COMT variants and ADHD, nor did variants in these genes explain variance in the effects of ADHD on neural activation. CONCLUSIONS: These results suggest that dopamine-related genes play a role in the neurobiology of response inhibition. The limited associations between gene polymorphisms and task performance further indicate the added value of neural measures in linking genetic factors and behavioural measures.