RESUMEN
Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C subunit of the voltage-gated L-type calcium channel Cav1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Cav1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene × environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Cav1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Cav1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.
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Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/fisiología , Trastornos Mentales/genética , Adulto , Negro o Afroamericano , Animales , Trastorno Bipolar/genética , Canales de Calcio/genética , Trastorno Depresivo Mayor/genética , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Humanos , Masculino , Ratones/embriología , Ratones Transgénicos/genética , Neuronas/metabolismo , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genéticaRESUMEN
Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.
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Trastorno Bipolar/etnología , Trastorno Bipolar/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Hipocampo/patología , Polimorfismo de Nucleótido Simple/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Estudios de Casos y Controles , Biología Computacional , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Fenotipo , ARN Mensajero/metabolismo , Población Blanca/genéticaRESUMEN
Background: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes. Methods: We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts (n pooled=5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years. Outcomes: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS. Interpretation: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia. Funding: HorizonEurope; European Research Council.
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Importance: Understanding antidepressant mechanisms could help design more effective and tolerated treatments. Objective: Identify DNA methylation (DNAm) changes associated with antidepressant exposure. Design: Case-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS. Setting: Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR. Participants: Participants with DNAm data and self-report/prescription derived antidepressant exposure. Main Outcomes and Measures: Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N exposed = 661, N unexposed = 9,575) alongside MBD-Seq in NESDA (N exposed = 398, N unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions. Results: The self-report MWAS (N = 16,536, N exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N exposed = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 -8 ), respectively. The top locus was cg26277237 ( KANK1, p self-report = 9.3x10 -13 , p prescription = 6.1x10 -3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p adj = 5.0x10 -3 ) alongside significant enrichment for genes expressed in the amygdala, the "synaptic vesicle membrane" gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (N studies = 9, N = 10,236, N exposed = 661, f3 = 0.196, p < 1x10 -4 ). Conclusions and Relevance: Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments. 3 Key Points: Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to KANK1 and DGUOK-AS1. A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10 -4 ) in a meta-analysis of external datasets. Meaning: Antidepressant exposure is associated with hypermethylation at KANK1 and DGUOK-AS1 , which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.
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BACKGROUND: Depression frequently co-occurs with somatization, and somatic complaints have been reported as a vulnerability marker for affective disorders observable before disease onset. Somatization is thought to result from an increased attention to somatic sensations, which should be reflected in long-latency somatosensory evoked electroencephalogram (EEG) potentials (SSEPs) at the physiological level. Previous studies revealed that SSEPs are altered in depressed patients and suggested late SSEP components as vulnerability markers for affective disorders. Neurotransmitters such as serotonin, γ-aminobutyric acid (GABA) and the neuropeptide substance P may play an important role for both affective disorders and somatosensory processing. Method We investigated the associations between SSEPs and polymorphisms within candidate genes of the serotonergic, GABAergic as well as the substance P system in subjects at high risk for affective disorders. The sample was composed of high-risk families participating in the Munich Vulnerability Study and genetic association analyses were calculated using qfam (family-based association tests for quantitative traits) implemented in PLINK 1.05. RESULTS: We observed significant associations (false discovery rate <0.05) withstanding correction for multiple testing between late SSEP components (response strength 170-370 ms after stimulation) and four single nucleotide polymorphisms within the GABA transaminase (ABAT) gene region coding for a protein responsible for GABA degradation. No effects were found with the classical disease trait approach, suggesting SSEP marker specificity of the observed associations. CONCLUSIONS: Our findings point to a possible role of ABAT gene-regulated GABA catabolism for an altered processing of somatosensory stimuli as a potential vulnerability marker for affective disorders.
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4-Aminobutirato Transaminasa/genética , Potenciales Evocados Somatosensoriales/genética , Trastornos del Humor/genética , Regiones no Traducidas 3' , Adulto , Electroencefalografía , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Humor/enzimología , Trastornos del Humor/psicología , Polimorfismo de Nucleótido Simple , Trastornos Somatomorfos/genética , Trastornos Somatomorfos/psicologíaRESUMEN
OBJECTIVE: To identify clinical variables and genetic variations within monoaminergic genes known to be implicated in pain perception that are associated with the occurrence of somatization symptoms in patients with major depression. METHOD: Somatization was evaluated using the respective subscale of the Symptom Checklist SCL-90-R. Six monoaminergic genes were identified showing an involvement in pain perception and somatization according to the literature: COMT, HTR2A, SLC6A2, SLC6A4, DRD4, and TPH1. One hundred and eighteen single nucleotide polymorphisms (SNPs) within these genes were genotyped using Illumina BeadChips in a sample of 398 at least moderately to severely depressed in-patients participating in the Munich Antidepressant Response Signature (MARS) project. RESULTS: Thirty SNPs exhibit nominally significant associations with somatization. One SNP (rs9534505) located in intron 2 of the HTR2A gene withstood correction for multiple testing. Clinical data provide further evidence for strong impact of somatization on the presentation of depressive symptoms and description of a patient subgroup with unfavorable clinical outcome. CONCLUSION: Our results demonstrate the influence of a HTR2A polymorphism on aspects of somatization in major depression, which co-occurs with an unfavorable antidepressant treatment outcome. These results confirm and expand previous findings on somatization as a risk factor for treatment outcome in major depression.
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Trastorno Depresivo Mayor/genética , Trastornos Somatomorfos/genética , Adulto , Anciano , Anciano de 80 o más Años , Antidepresivos/uso terapéutico , Catecol O-Metiltransferasa/genética , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/psicología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/genética , Percepción del Dolor , Polimorfismo de Nucleótido Simple/genética , Escalas de Valoración Psiquiátrica , Receptor de Serotonina 5-HT2A/genética , Receptores de Dopamina D4/genética , Trastornos Somatomorfos/etiología , Trastornos Somatomorfos/psicología , Resultado del Tratamiento , Triptófano Hidroxilasa/genética , Adulto JovenRESUMEN
Various studies have investigated whether single nucleotide polymorphisms (SNPs) in the gene purinergic receptor P2X7 (P2RX7), and rs2230912 specifically, were associated with mood disorders. While some studies found positive evidence, a large number of studies reported no significant associations. In a previously published meta-analysis, Feng et al. did not find a significant association and only moderate odds ratios (ORs) in case-control studies. They reported significant findings only for family-based studies. We revisited this finding and conducted a meta-analysis including 8,652 cases and 11,153 controls, adding unpublished results from the Munich Antidepressant Response Signature (MARS) study. We found a significant association between rs2230912 and combined mood disorders (major depressive disorder (MDD) or bipolar disorder (BD)) for the allelic, dominant and heterozygous-disadvantage model, all withstanding the threshold of correction for multiple testing. Stratifying by disorder revealed significant findings for the MDD-subgroup (OR of 1.12 for the allelic model), while the BD-subgroup presented with a lower effect size (OR of 1.05) and no significance. P2RX7 encodes a purinergic receptor which is expressed in the brain and also localized in immune cells. Animal studies and functional studies will be necessary to enlighten its involvement in the etiology of mood disorders and its applicability for pharmacological purposes.
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Trastorno Bipolar/genética , Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Receptores Purinérgicos P2X7/genética , Depresión/genética , HumanosRESUMEN
Matrix metalloproteinase 9 (MMP9) plays an important role in the pathogenesis of multiple sclerosis (MS). However, the impact of genetic variants affecting MMP9 on MS susceptibility is still in debate. We could not detect an association of MMP9 SNPs with MS on a genome-wide significance level by SNP genotyping, followed by imputation of SNPs within a region stretching 2Mbp up- and down-stream of MMP9. Rs6073751, located within WFDC2, was found associated with MS most strongly. Rs3918242, associated with MS according to previous reports, showed nominal significance only. Meta-analysis of our own and published data did not confirm this effect.
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Predisposición Genética a la Enfermedad , Metaloproteinasa 9 de la Matriz/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Alemania , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Adulto JovenRESUMEN
Response to antidepressant treatment is highly variable with some patients responding within a few weeks, whereas others have to wait for months until the onset of clinical effects. Gene expression profiling may be a tool to identify markers of antidepressant treatment response and new potential drug targets. In a first step, we selected 12 male, age- and severity-matched pairs of remitters and nonresponders, and analyzed expression profiles in peripheral blood at admission and after 2 and 5 weeks of treatment using Illumina expression arrays. We identified 127 transcripts significantly associated with treatment response with a minimal P-value of 9.41 × 10(-)(4) (false discovery rate-corrected). Analysis of selected transcripts in an independent replication sample of 142 depressed inpatients confirmed that lower expression of retinoid-related orphan receptor alpha (RORa, P=6.23 × 10(-4)), germinal center expressed transcript 2 (GCET2, P=2.08 × 10(-2)) and chitinase 3-like protein 2 (CHI3L2, P=4.45 × 10(-2)) on admission were associated with beneficial treatment response. In addition, leukocyte-specific protein 1 (LSP1) significantly decreased after 5 weeks of treatment in responders (P=2.91 × 10(-2)). Additional genetic, in vivo stress responsitivity data and murine gene expression findings corroborate our finding of RORa as a transcriptional marker of antidepressant response. In summary, using a genome-wide transcriptomics approach and subsequent validation studies, we identified several transcripts including the circadian gene transcript RORa that may serve as biomarkers indicating antidepressant treatment response.
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Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/genética , Perfilación de la Expresión Génica/métodos , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , ARN/genética , Adulto , Animales , Modelos Animales de Enfermedad , Estudios de Seguimiento , Marcadores Genéticos/genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical abilities (P(comb) = 7.71 × 10(-10), n = 699), with an effect size of 4.87%. This association was also found in a sample from the general population (P = 0.048, n = 1080), albeit with a lower effect size. The identified variant encodes an amino-acid substitution in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between rs133885 and mathematical disability at the level of a specific intermediate phenotype.
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Discalculia/genética , Dislexia/genética , Variación Genética , Miosinas/genética , Lóbulo Parietal/anatomía & histología , Proteínas Supresoras de Tumor/genética , Adulto , Envejecimiento/genética , Niño , Discalculia/fisiopatología , Dislexia/fisiopatología , Femenino , Marcadores Genéticos , Alemania , Humanos , Masculino , Pruebas Neuropsicológicas , Lóbulo Parietal/fisiopatología , RiesgoRESUMEN
Previous studies have shown that individuals with schizophrenia and dyslexia display common neurocognitive abnormalities. The aim of the present study was to determine whether known schizophrenia-risk genes contribute to dyslexia risk or to disease-relevant cognitive functions. For this purpose, we genotyped the schizophrenia-associated risk variants within zinc-finger protein 804A (ZNF804A), transcription-factor 4 and neurogranin in a large dyslexia case-control sample. We tested all variants for association with dyslexia (927 cases, 1096 controls), and with eight language-relevant cognitive processes (1552 individuals). We observed six significant associations between language-relevant traits and the ZNF804A-variant rs1344706. Interestingly, the ZNF804A schizophrenia risk variant was associated with a better cognitive performance in our data set. This finding might be consistent with a previously reported ZNF804A association in schizophrenia, in which patients carrying the schizophrenia-risk allele at rs1344706 showed a better performance in two memory tests. In conclusion, the present study provides evidence that ZNF804A might have a role in cognitive traits of relevance to reading and spelling, and underlines the phenotypic complexity that might be associated with ZNF804A.
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Dislexia/genética , Variación Genética/fisiología , Factores de Transcripción de Tipo Kruppel/genética , Lenguaje , Neurogranina/genética , Esquizofrenia/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Pruebas Neuropsicológicas , LecturaRESUMEN
A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.