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1.
Transl Psychiatry ; 9(1): 242, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582733

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder caused by an interplay of genetic and environmental factors. Epigenetics is crucial to lasting changes in gene expression in the brain. Recent studies suggest a role for DNA methylation in ADHD. We explored the contribution to ADHD of allele-specific methylation (ASM), an epigenetic mechanism that involves SNPs correlating with differential levels of DNA methylation at CpG sites. We selected 3896 tagSNPs reported to influence methylation in human brain regions and performed a case-control association study using the summary statistics from the largest GWAS meta-analysis of ADHD, comprising 20,183 cases and 35,191 controls. We observed that genetic risk variants for ADHD are enriched in ASM SNPs and identified associations with eight tagSNPs that were significant at a 5% false discovery rate (FDR). These SNPs correlated with methylation of CpG sites lying in the promoter regions of six genes. Since methylation may affect gene expression, we inspected these ASM SNPs together with 52 ASM SNPs in high LD with them for eQTLs in brain tissues and observed that the expression of three of those genes was affected by them. ADHD risk alleles correlated with increased expression (and decreased methylation) of ARTN and PIDD1 and with a decreased expression (and increased methylation) of C2orf82. Furthermore, these three genes were predicted to have altered expression in ADHD, and genetic variants in C2orf82 correlated with brain volumes. In summary, we followed a systematic approach to identify risk variants for ADHD that correlated with differential cis-methylation, identifying three novel genes contributing to the disorder.

2.
Genetics ; 213(2): 633-650, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31455722

RESUMO

Knowledge of the genetic basis underlying variation in response to environmental exposures or treatments is important in many research areas. For example, knowing the set of causal genetic variants for drug responses could revolutionize personalized medicine. We used Drosophila melanogaster to investigate the genetic signature underlying behavioral variability in response to methylphenidate (MPH), a drug used in the treatment of attention-deficit/hyperactivity disorder. We exposed a wild-type D. melanogaster population to MPH and a control treatment, and observed an increase in locomotor activity in MPH-exposed individuals. Whole-genome transcriptomic analyses revealed that the behavioral response to MPH was associated with abundant gene expression alterations. To confirm these patterns in a different genetic background and to further advance knowledge on the genetic signature of drug response variability, we used a system of inbred lines, the Drosophila Genetic Reference Panel (DGRP). Based on the DGRP, we showed that the behavioral response to MPH was strongly genotype-dependent. Using an integrative genomic approach, we incorporated known gene interactions into the genomic analyses of the DGRP, and identified putative candidate genes for variability in drug response. We successfully validated 71% of the investigated candidate genes by gene expression knockdown. Furthermore, we showed that MPH has cross-generational behavioral and transcriptomic effects. Our findings establish a foundation for understanding the genetic mechanisms driving genotype-specific responses to medical treatment, and highlight the opportunities that integrative genomic approaches have in optimizing medical treatment of complex diseases.

3.
Nat Neurosci ; 22(7): 1066-1074, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209380

RESUMO

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.


Assuntos
Abuso de Maconha/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Nicotínicos/fisiologia , Idade de Início , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Cognição/fisiologia , Estudos de Coortes , Fatores de Confusão (Epidemiologia) , Dinamarca , Escolaridade , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Transcriptoma
4.
Am J Psychiatry ; 176(8): 651-660, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164008

RESUMO

OBJECTIVE: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

6.
Am J Psychiatry ; 176(3): 228-238, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30818988

RESUMO

OBJECTIVE:: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder. METHODS:: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level. RESULTS:: Analyses revealed a significant negative genetic correlation between ADHD and ICV (rg=-0.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes. CONCLUSIONS:: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.

7.
Acta Oncol ; 58(5): 537-547, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30822178

RESUMO

Background: Cancer-related cognitive impairment (CRCI) is a commonly reported complaint among non-CNS cancer patients. Even subtle CRCI may have detrimental effects on quality of life and identifying patients at increased risk for CRCI to improve survivorship care is important. In the present paper, we systematically reviewed available studies of possible genetic risk factors for developing CRCI. Methods: Keyword-based systematic searches were undertaken on 24 July 2018 in PubMed, Web of Science, The Cochrane Library, and CINAHL. Three authors independently evaluated full-texts of identified papers and excluded studies with registration of reasons. Seventeen studies reporting results from 14 independent samples were included for review. Two authors independently quality assessed the included studies. The review was preregistered with PROSPERO (CRD42018107689). Results: Ten studies investigated apolipoprotein E (APOE), with four studies reporting that carrying at least one risk allele (APOE4 (ε4)) was associated with CRCI, while six studies found no association. The remaining identified genetic risk variants associated with CRCI located in: COMT, four DNA repair genes, five oxidative stress genes, 22 genes related to breast cancer phenotype, and GNB3. No associations were found between CRCI and genes coding for interleukin-6 (IL6), tumor necrosis factor alpha (TNF), interleukin 1 beta (IL1B), and brain-derived neurotropic factor (BDNF). With the exception of APOE, the genetic risk factors had only been investigated in one or two studies each. Conclusions: Overall, the available evidence of possible genetic risk factors for CRCI is limited. While some research suggests a role for the ε4 allele, the literature is generally inconsistent, and the currently available evidence does not allow clear-cut conclusions regarding the role of genetic factors in the development of CRCI. Larger genetic studies and studies investigating additional genetic variants are needed to uncover genetic risk factors for CRCI.

8.
Nat Genet ; 51(4): 659-674, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30911161

RESUMO

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.


Assuntos
Encéfalo/fisiopatologia , Expressão Gênica/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Risco , Transcriptoma/genética
9.
Nat Genet ; 51(3): 431-444, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804558

RESUMO

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dinamarca , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Herança Multifatorial/genética , Fenótipo , Fatores de Risco
10.
Mol Psychiatry ; 2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610198

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a severely impairing neurodevelopmental disorder with a prevalence of 5% in children and adolescents and of 2.5% in adults. Comorbid conditions in ADHD play a key role in symptom progression, disorder course and outcome. ADHD is associated with a significantly increased risk for substance use, abuse and dependence. ADHD and cannabis use are partly determined by genetic factors; the heritability of ADHD is estimated at 70-80% and of cannabis use initiation at 40-48%. In this study, we used summary statistics from the largest available meta-analyses of genome-wide association studies (GWAS) of ADHD (n = 53,293) and lifetime cannabis use (n = 32,330) to gain insights into the genetic overlap and causal relationship of these two traits. We estimated their genetic correlation to be r2 = 0.29 (P = 1.63 × 10-5) and identified four new genome-wide significant loci in a cross-trait analysis: two in a single variant association analysis (rs145108385, P = 3.30 × 10-8 and rs4259397, P = 4.52 × 10-8) and two in a gene-based association analysis (WDPCP, P = 9.67 × 10-7 and ZNF251, P = 1.62 × 10-6). Using a two-sample Mendelian randomization approach we found support that ADHD is causal for lifetime cannabis use, with an odds ratio of 7.9 for cannabis use in individuals with ADHD in comparison to individuals without ADHD (95% CI (3.72, 15.51), P = 5.88 × 10-5). These results substantiate the temporal relationship between ADHD and future cannabis use and reinforce the need to consider substance misuse in the context of ADHD in clinical interventions.

11.
Transl Psychiatry ; 9(1): 35, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679418

RESUMO

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10-8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10-5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10-6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Escolaridade , Linguagem , Alfabetização , Herança Multifatorial , Adolescente , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Inteligência , Masculino , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Análise de Regressão , Medição de Risco , Reino Unido
12.
Nat Genet ; 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478444

RESUMO

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

13.
Biol Psychiatry ; 83(12): 1044-1053, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29325848

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. METHODS: We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). RESULTS: Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15). CONCLUSIONS: Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

14.
Psychiatry Res ; 251: 255-260, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28219025

RESUMO

Disruptive behavior disorders (DBDs), inclusive of oppositional defiant disorder (ODD) and conduct disorder (CD), are associated with outcomes likely to increase risk of mortality. Using Danish National Registers, a total of 1.92 million individuals including 9495 individuals with DBDs diagnosed by specialist services were followed from their first birthday to 2013. Those with and without DBDs were compared using mortality rate ratios (MRRs) estimated using Poisson regression and adjusted for calendar period, age, sex, family history of psychiatric disorders, maternal age at time of birth, paternal age at time of birth, parental education status, and parental employment status. Over the course of follow up, which totalled 24.9 million person-years, 5580 cohort members died including 78 individuals with DBDs. The mortality rate per 10,000 person-years was 9.66 for individuals with DBDs compared to 2.22 for those with no diagnosis. This corresponded to a fully adjusted MRR of 2.57 (95% confidence interval 2.04-3.20). Comorbid substance use disorder and attention-deficit/hyperactivity disorder resulted in the highest MRR across all categories. These findings demonstrate the excess mortality associated with DBDs.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/diagnóstico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/mortalidade , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/mortalidade , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/psicologia , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Transtorno da Conduta/diagnóstico , Transtorno da Conduta/mortalidade , Transtorno da Conduta/psicologia , Dinamarca , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pais/psicologia , Risco , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/mortalidade , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto Jovem
15.
Brain Imaging Behav ; 11(3): 769-783, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27240852

RESUMO

Evidence suggests that testicular cancer (TC) and its treatment are associated with cognitive impairment. However, the underlying neural substrate and biological mechanisms are poorly understood. This study aimed to investigate changes in cognition and brain grey matter (GM) morphology in TC patients undergoing treatment, and to explore associations with immune markers, endocrine markers, and genotype. Sixty-five patients with stage I-III TC underwent assessment after surgery but prior to further treatment and again 6 months after. Twenty-two patients received chemotherapy (+CT), while 43 did not (-CT). Assessments included neuropsychological testing, whole-brain magnetic resonance imaging, and blood samples. Twenty-five healthy controls (HCs) underwent neuropsychological testing with a matching time interval. A regression-based approach was used to determine cognitive changes and longitudinal voxel-based morphometry (VBM) was performed to investigate changes in GM density in the TC groups. Compared with the HCs, both TC groups showed higher rates of cognitive decline (p < 0.05). A trend towards greater decline was observed in + CT (63.6 %) compared with -CT patients (39.5 %) (p = 0.07). VBM revealed widespread GM reductions in both TC groups, but a group-by-time interaction analysis revealed prefrontal reductions specific to the + CT group (p = 0.02), which were associated with poorer cognitive performance. Poorer cognitive performance was also associated with an increase in tumor necrosis factor alpha in + CT patients. Furthermore, an interaction effect was found between the APOE ε4 genotype and chemotherapy on cognitive performance with ε4 carriers performing significantly worse. These findings provide novel evidence of changes in cognition and brain morphology in TC patients undergoing treatment.


Assuntos
Apolipoproteínas E/genética , Encéfalo/diagnóstico por imagem , Cognição , Substância Cinzenta/diagnóstico por imagem , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/terapia , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Proteína C-Reativa/metabolismo , Cognição/fisiologia , Seguimentos , Humanos , Interleucina-6/sangue , Imagem por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Orquiectomia , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/psicologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue
16.
Exp Gerontol ; 84: 96-100, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27612602

RESUMO

Mutations in progranulin are a major cause of frontotemporal lobe degeneration (FTLD). Hence, plasma progranulin is an attractive biomarker in FTLD but poorly reflects levels in cerebrospinal fluid (CSF), suggesting tissue-specific regulation of progranulin levels. Sortilin was recently identified as a progranulin scavenger receptor that destines it for lysosomal degradation. Proteolysis or alternative splicing generates soluble sortilin variants that retain progranulin binding and potentially functions as a decoy receptor. In the present study, we analyzed soluble sortilin and progranulin in plasma and CSF in 341 aging individuals. We found that soluble sortilin exists in CSF in ten-fold molar excess compared to progranulin and observed a highly significant positive correlation between soluble sortilin and progranulin levels in CSF but not in plasma. However, carriers of the minor allele of SNP rs646776 in SORT1 encoding sortilin displayed significantly increased soluble sortilin and reduced progranulin specifically in plasma but not in CSF. Taken together, our findings suggest that soluble sortilin may affect progranulin levels in both a tissue-specific and genotype-dependent manner.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Envelhecimento/genética , Peptídeos e Proteínas de Sinalização Intercelular/líquido cefalorraquidiano , Proteínas Adaptadoras de Transporte Vesicular/sangue , Proteínas Adaptadoras de Transporte Vesicular/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Envelhecimento/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Dinamarca , Feminino , Degeneração Lobar Frontotemporal/genética , Genótipo , Humanos , Modelos Lineares , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Progranulinas
17.
Am J Med Genet B Neuropsychiatr Genet ; 171(8): 1013-1022, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27255576

RESUMO

The demographic history of the isolated population of the Faroe Islands may have induced enrichment of variants rarely seen in outbred European populations, including enrichment of risk variants for panic disorder (PD). PD is a common mental disorder, characterized by recurring and unprovoked panic attacks, and genetic factors have been estimated to explain around 40% of the risk. In this study the potential enrichment of PD risk variants was explored based on whole-exome sequencing of 54 patients with PD and 211 control individuals from the Faroese population. No genome-wide significant associations were found, however several single variants and genes showed strong association with PD, where DGKH was found to be the strongest PD associated gene. Interestingly DGKH has previously demonstrated genome-wide significant association with bipolar disorder as well as evidence of association to other mental disorders. Additionally, we found an enrichment of PD risk variants in the Faroese population; variants with otherwise low frequency in more outbreed European populations. © 2016 Wiley Periodicals, Inc.


Assuntos
Diacilglicerol Quinase/genética , Transtorno de Pânico/genética , Adulto , Dinamarca , Diacilglicerol Quinase/metabolismo , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Masculino , Transtorno de Pânico/psicologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
18.
Genetics ; 203(4): 1901-13, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27317683

RESUMO

Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies.


Assuntos
Estudo de Associação Genômica Ampla/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Vitamina A/genética , Simulação por Computador , Genoma Humano , Humanos , Modelos Genéticos , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Vitamina A/metabolismo
19.
Genome Med ; 8(1): 53, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-27142060

RESUMO

BACKGROUND: The bromodomain containing 1 (BRD1) gene has been implicated with transcriptional regulation, brain development, and susceptibility to schizophrenia and bipolar disorder. To advance the understanding of BRD1 and its role in mental disorders, we characterized the protein and chromatin interactions of the BRD1 isoforms, BRD1-S and BRD1-L. METHODS: Stable human cell lines expressing epitope tagged BRD1-S and BRD1-L were generated and used as discovery systems for identifying protein and chromatin interactions. Protein-protein interactions were identified using co-immunoprecipitation followed by mass spectrometry and chromatin interactions were identified using chromatin immunoprecipitation followed by next generation sequencing. Gene expression profiles and differentially expressed genes were identified after upregulating and downregulating BRD1 expression using microarrays. The presented functional molecular data were integrated with human genomic and transcriptomic data using available GWAS, exome-sequencing datasets as well as spatiotemporal transcriptomic datasets from the human brain. RESULTS: We present several novel protein interactions of BRD1, including isoform-specific interactions as well as proteins previously implicated with mental disorders. By BRD1-S and BRD1-L chromatin immunoprecipitation followed by next generation sequencing we identified binding to promoter regions of 1540 and 823 genes, respectively, and showed correlation between BRD1-S and BRD1-L binding and regulation of gene expression. The identified BRD1 interaction network was found to be predominantly co-expressed with BRD1 mRNA in the human brain and enriched for pathways involved in gene expression and brain function. By interrogation of large datasets from genome-wide association studies, we further demonstrate that the BRD1 interaction network is enriched for schizophrenia risk. CONCLUSION: Our results show that BRD1 interacts with chromatin remodeling proteins, e.g. PBRM1, as well as histone modifiers, e.g. MYST2 and SUV420H1. We find that BRD1 primarily binds in close proximity to transcription start sites and regulates expression of numerous genes, many of which are involved with brain development and susceptibility to mental disorders. Our findings indicate that BRD1 acts as a regulatory hub in a comprehensive schizophrenia risk network which plays a role in many brain regions throughout life, implicating e.g. striatum, hippocampus, and amygdala at mid-fetal stages.


Assuntos
Encéfalo/metabolismo , Transtornos Mentais/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Mapeamento de Interação de Proteínas/métodos , Proteoma/metabolismo , Encéfalo/crescimento & desenvolvimento , Linhagem Celular , Montagem e Desmontagem da Cromatina , Imunoprecipitação da Cromatina , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Espectrometria de Massas , Regiões Promotoras Genéticas , Isoformas de Proteínas/metabolismo , Proteoma/genética
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