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BACKGROUND: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM. METHODS: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders. RESULTS: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa. CONCLUSIONS: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.
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The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. The study sample (n = 513) was deeply phenotyped, consisting of 452 patients from tertiary care with mood disorders, anxiety disorders (ANX), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and/or substance use disorders (SUD) and 61 unaffected comparison individuals. We computed subject-specific polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions derived from a rich battery of psychopathology assessments. High PRSs for depression were unselectively associated with the diagnosis of SUD, ADHD, ANX, and mood disorders (p < 1e-4). In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems (R2 = 0.041, p = 5e-4) but not others. This study adds evidence to the ongoing discussion about the misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.
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Transtorno do Deficit de Atenção com Hiperatividade , Psiquiatria , Transtornos Relacionados ao Uso de Substâncias , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Psicopatologia , Transtornos de Ansiedade , Herança Multifatorial/genéticaRESUMO
The aetiology of autism spectrum disorder (ASD) is complex and, partly, accounted by genetic factors. Nonetheless, the genetic underpinnings of ASD are poorly defined. The presence of immune dysregulations in autistic individuals, and their families, supports a role of the immune system and its genetic regulators. Albeit immune responses belong either to the innate or adaptive arms, the overall immune system genetics is broad, and encompasses a multitude of functionally heterogenous pathways which may have different influences on ASD. Hence, to gain insights on the immunogenetic underpinnings of ASD, we conducted a systematic literature review of previous immune genetic and transcription studies in ASD. We defined a list of immune genes relevant to ASD and explored their neuro-immune function. Our review confirms the presence of immunogenetic variability in ASD, accounted by inherited variations of innate and adaptive immune system genes and genetic expression changes in the blood and post-mortem brain of autistic individuals. Besides their immune function, the identified genes control neurodevelopment processes (neuronal and synaptic plasticity) and are highly expressed in pre/peri-natal periods. Hence, our synthesis bolsters the hypothesis that perturbation in immune genes may contribute to ASD by derailing the typical trajectory of neurodevelopment. Our review also helped identifying some of the limitations of prior immunogenetic research in ASD. Thus, alongside clarifying the neurodevelopment role of immune genes, we outline key considerations for future work into the aetiology of ASD and possible novel intervention targets.
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BACKGROUND: Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD. METHODS: We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N = 2,258). Subsequently using Fisher's exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N = 23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N = 46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N = 46,350) and intracranial volume (N = 25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA. RESULTS: Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p = .0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p = .027), despite the absence of a significant genome-wide correlation (p = .81). CONCLUSIONS: This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD.
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Transtorno do Espectro Autista , Deficiência Intelectual , Humanos , Transtorno do Espectro Autista/genética , Encéfalo , Serina-Treonina Quinases TOR/genética , Predisposição Genética para DoençaRESUMO
Here we review the motivation for creating the enhancing neuroimaging genetics through meta-analysis (ENIGMA) Consortium and the genetic analyses undertaken by the consortium so far. We discuss the methodological challenges, findings, and future directions of the genetics working group. A major goal of the working group is tackling the reproducibility crisis affecting "candidate gene" and genome-wide association analyses in neuroimaging. To address this, we developed harmonized analytic methods, and support their use in coordinated analyses across sites worldwide, which also makes it possible to understand heterogeneity in results across sites. These efforts have resulted in the identification of hundreds of common genomic loci robustly associated with brain structure. We have found both pleiotropic and specific genetic effects associated with brain structures, as well as genetic correlations with psychiatric and neurological diseases.
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Encéfalo , Genética , Estudo de Associação Genômica Ampla , Transtornos Mentais , Metanálise como Assunto , Doenças do Sistema Nervoso , Neuroimagem , Encéfalo/anatomia & histologia , Encéfalo/diagnóstico por imagem , Humanos , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/genética , Transtornos Mentais/patologia , Estudos Multicêntricos como Assunto , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologiaRESUMO
Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000-3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure.
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Evolução Biológica , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiologia , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Testes Genéticos/métodos , Humanos , Imageamento por Ressonância Magnética/tendências , Herança Multifatorial/genética , Tamanho do Órgão/genética , Locos de Características Quantitativas/genéticaRESUMO
BACKGROUND: Type 2 diabetes mellitus (T2DM) is linked with several neurodegenerative and psychiatric disorders, either as a comorbid condition or as a risk factor. We aimed to expand the evidence by examining associations with a broad range of brain disorders (psychiatric and neurological disorders, excluding late-onset neurodegenerative disorders), while also accounting for the temporal order of T2DM and these brain disorders. METHODS: In a population-based cohort-study of 1,883,198 Danish citizens, born 1955-1984 and followed until end of 2016, we estimated associations between T2DM and 16 brain disorders first diagnosed between childhood and mid-adulthood. We calculated odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) in temporally ordered analyses (brain disorder diagnosis after T2DM and vice versa), adjusted for sex, age, follow-up, birth year, and parental factors. RESULTS: A total of 67,660 (3.6%) of the study population were identified as T2DM cases after age 30 and by a mean age of 45 years (SD of 8 years). T2DM was associated with most psychiatric disorders. Strongest associations were seen with other (i.e. non-anorectic) eating disorders (OR [95% CI]: 2.64 [2.36-2.94]) and schizophrenia spectrum disorder (2.73 [2.63-2.84]). Among neurological disorders especially inflammatory brain diseases (1.73 [1.57-1.91]) and epilepsy (1.67 [1.60-1.75]) were associated with T2DM. Most associations remained in both directions in the temporally ordered analyses. For most psychiatric disorders, associations were strongest in females. CONCLUSIONS: T2DM was associated with several psychiatric and neurological disorders, and most associations were consistently found for both temporal order of disorders. This suggests a shared etiology of T2DM and those brain disorders. This study can form the starting point for studies directed at further elucidating potential causal links between disorders and shared biological mechanisms.
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Diabetes Mellitus Tipo 2 , Epilepsia , Adulto , Criança , Estudos de Coortes , Dinamarca , Feminino , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.
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The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer's disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields' genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10-16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.
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Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Hipocampo/anatomia & histologia , Hipocampo/patologia , Neuroimagem , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Esquizofrenia/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico por imagem , Adulto JovemRESUMO
Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (ß = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (ß = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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Transtorno Autístico/genética , Gânglios da Base/patologia , Transtornos Cromossômicos/genética , Variações do Número de Cópias de DNA/genética , Deficiência Intelectual/genética , Adulto , Transtorno do Espectro Autista/genética , Encéfalo/patologia , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Bases de Dados Factuais , Feminino , Globo Pálido/patologia , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/genética , Tamanho do Órgão/genética , Putamen/patologia , Esquizofrenia/genéticaRESUMO
OBJECTIVE: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Núcleo Caudado , Criança , Humanos , Imageamento por Ressonância MagnéticaRESUMO
The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
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Encéfalo/anatomia & histologia , Variação Genética/genética , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Apoptose/genética , Núcleo Caudado/anatomia & histologia , Criança , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Loci Gênicos/genética , Hipocampo/anatomia & histologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Tamanho do Órgão/genética , Putamen/anatomia & histologia , Caracteres Sexuais , Crânio/anatomia & histologia , Adulto JovemRESUMO
BACKGROUND: The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. METHODS: Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8-26 years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. RESULTS: Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity-impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. CONCLUSIONS: NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies.
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Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Óxido Nítrico Sintase Tipo I/genética , Substância Branca/anatomia & histologia , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Criança , Imagem de Tensor de Difusão , Feminino , Genótipo , Humanos , Masculino , Caracteres Sexuais , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto JovemRESUMO
Schizophrenia is associated with brain structural abnormalities including gray and white matter volume reductions. Whether these alterations are caused by genetic risk variants for schizophrenia is unclear. Previous attempts to detect associations between polygenic factors for schizophrenia and structural brain phenotypes in healthy subjects have been negative or remain non-replicated. In this study, we used genetic risk scores that were based on the accumulated effect of selected risk variants for schizophrenia belonging to specific biological systems like synaptic function, neurodevelopment, calcium signaling, and glutamatergic neurotransmission. We hypothesized that this "biologically informed" approach would provide the missing link between genetic risk for schizophrenia and brain structural phenotypes. We applied whole-brain voxel-based morphometry (VBM) analyses in two population-based target samples and subsequent regions of interest (ROIs) analyses in an independent replication sample (total N = 2725). No consistent association between the genetic scores and brain volumes were observed in the investigated samples. These results suggest that in healthy subjects with a higher genetic risk for schizophrenia additional factors apart from common genetic variants (e.g., infection, trauma, rare genetic variants, or gene-gene interactions) are required to induce structural abnormalities of the brain. Further studies are recommended to test for possible gene-gene or gene-environment effects. © 2017 Wiley Periodicals, Inc.
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Encéfalo/fisiopatologia , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Adulto , Encéfalo/anatomia & histologia , Mapeamento Encefálico/métodos , Feminino , Previsões , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Tamanho do Órgão/genética , Fatores de RiscoRESUMO
BACKGROUND: Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample. METHODS: We performed voxel-based morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered. RESULTS: Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 [range 8-30] yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results. LIMITATIONS: Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional. CONCLUSION: Brain areas involved in decision making, motivation, cognitive control and motor functioning were smaller in participants with ADHD than in controls. Investigation of unaffected siblings indicated familiality of 4 of the structural brain differences, supporting their potential in molecular genetic analyses in ADHD research.
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Transtorno do Deficit de Atenção com Hiperatividade/patologia , Encéfalo/patologia , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Encefalopatias/patologia , Mapeamento Encefálico , Criança , Cognição/fisiologia , Estudos Transversais , Tomada de Decisões/fisiologia , Feminino , Substância Cinzenta/patologia , Humanos , Inteligência/fisiologia , Imageamento por Ressonância Magnética , Masculino , Motivação/fisiologia , Tamanho do Órgão , Desempenho Psicomotor/fisiologia , Psicotrópicos/uso terapêutico , Irmãos , Adulto JovemRESUMO
Elucidating genetic mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) has been challenging. Relatively unexplored is the fact that genetic mechanisms can differ with age. The current study explored the association between dopaminergic and serotonergic genes, ADHD symptoms, and neurocognitive functioning in relation to age. Associations of three genetic ADHD risk factors, DAT1, DRD4, and 5-HTT with symptoms and six neurocognitive measures were explored in two samples of the NeuroIMAGE study: 756 children, adolescents, and young adults with ADHD, their siblings, and controls (M age 17 years, SD 3.2), and 393 parents with and without ADHD (M age 48 years, SD 4.8). Association analyses were performed in both samples, and effects were compared to address dichotomous age effects. Gene*age interactions were examined to address continuous age effects. Moderating effects of age were found for DRD4-7R carriership and ADHD symptoms in the adult group only; in the adolescents the 5-HTT LL genotype was differentially associated with inhibition and with motor timing at different ages, and to inhibition in adults; DAT1 10-6 haplotype carriership showed differential working memory performance depending on age. None of our effects survived correction for multiple comparisons. Our results are preliminary, but may point to differential genotype-phenotype associations at different ages. This can be seen as a proof of concept for the importance of age in dopaminergic and serotonergic genetic association analyses. Our findings are consistent with the idea that genetic and neurocognitive mechanisms underlying ADHD may change throughout life. © 2015 Wiley Periodicals, Inc.
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INTRODUCTION: The role of the serotonin transporter gene polymorphism 5-HTTLPR in attention-deficit/hyperactivity disorder (ADHD) is unclear. Heterogeneity of findings may be explained by gene-environment interactions (GxE), as it has been suggested that S-allele carriers are more reactive to psychosocial stress than L-allele homozygotes. This study aimed to investigate whether 5-HTTLPR genotype moderates the effects of stress on ADHD in a multisite prospective ADHD cohort study. METHODS: 5-HTTLPR genotype, as well as the number of stressful life events in the past 5 years and ongoing long-term difficulties, was determined in 671 adolescents and young adults with ADHD, their siblings, and healthy controls (57.4% male, average age 17.3 years). Linear mixed models, accounting for family relatedness, were applied to investigate the effects of genotype, experienced stress, and their interaction on ADHD severity at time point T2, while controlling for ADHD severity at T1 (mean follow-up time 5.9 years) and for comorbid internalizing problems at T2. RESULTS: The interaction between genotype and stress significantly predicted ADHD severity at T2 (p = .006), which was driven by the effect on hyperactivity-impulsivity (p = .004). Probing of the interaction effect made clear that S-allele carriers had a significantly more positive correlation between stress and ADHD severity than L-allele homozygotes. CONCLUSION: The results show that the interaction between 5-HTTLPR and stress is a mechanism involved particularly in the hyperactivity/impulsivity dimension of ADHD, and that this is independent of comorbid internalizing problems. Further research into the neurobiological mechanisms underlying this interaction effect is warranted.
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Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Interação Gene-Ambiente , Acontecimentos que Mudam a Vida , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Feminino , Seguimentos , Humanos , Masculino , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Índice de Gravidade de Doença , Irmãos , Adulto JovemRESUMO
Recent advancements in psychiatric genetics have sparked a lively debate on the opportunities and pitfalls of incorporating polygenic scores into clinical practice. Yet, several ethical concerns have been raised, casting doubt on whether further development and implementation of polygenic scores would be compatible with providing ethically responsible care. While these ethical issues warrant thoughtful consideration, it is equally important to recognize the unresolved need for guidance on heritability among patients and their families. Increasing the availability of genetic counseling services in psychiatry should be regarded as a first step toward meeting these needs. As a next step, future integration of novel genetic tools such as polygenic scores into genetic counseling may be a promising way to improve psychiatric counseling practice. By embedding the exploration of polygenic psychiatry into the supporting environment of genetic counseling, some of the previously identified ethical pitfalls may be prevented, and opportunities to bolster patient empowerment can be seized upon. To ensure an ethically responsible approach to psychiatric genetics, active collaboration with patients and their relatives is essential, accompanied by educational efforts to facilitate informed discussions between psychiatrists and patients.
Assuntos
Transtornos Mentais , Psiquiatria , Humanos , Transtornos Mentais/genética , Psiquiatras , Herança Multifatorial/genética , Assistência Centrada no PacienteRESUMO
The brain's default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. In the present study, we examined the genetic relationship between sociability and DMN-related resting-state functional magnetic resonance imaging (rs-fMRI) traits. To this end, we used genome-wide association summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits (N=34,691-342,461). First, we examined global and local genetic correlations between sociability and the rs-fMRI traits. Second, to assess putatively causal relationships between the traits, we conducted bi-directional Mendelian randomisation (MR) analyses. Finally, we prioritised genes influencing both sociability and rs-fMRI traits by combining three methods: gene-expression eQTL MR analyses, the CELLECT framework using single-nucleus RNA-seq data, and network propagation in the context of a protein-protein interaction network. Significant local genetic correlations were found between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the frontal/cingulate and angular/temporal cortices. Sociability affected 12 rs-fMRI traits when allowing for weakly correlated genetic instruments. Combing all three methods for gene prioritisation, we defined 17 highly prioritised genes, with DRD2 and LINGO1 showing the most robust evidence across all analyses. By integrating genetic and transcriptomics data, our gene prioritisation strategy may serve as a blueprint for future studies. The prioritised genes could be explored as potential biomarkers for social dysfunction in the context of neuropsychiatric disorders and as drug target genes.
RESUMO
The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.