Identification of Differentially Expressed MicroRNAs in the Rat Hippocampus during Adolescence through an Epigenome-Wide Analysis

This study was funded by the research projects PID2020-114269GB-I00 (MCIN/AEI/10.13039/501100011033), BSEJ.514.UGR20 (FEDER, Junta de Andalucía, Spain), “Instituto de Salud Carlos III,” project PI18/00467 (co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”), and a predoctoral fellowship to AV-Á (FPU18/05012, MIU, Spain).Introduction: Epigenetic mechanisms involving microRNAs (miRNAs) play a fundamental role in many biological processes, particularly during prenatal and early postnatal development. Their role in adolescent brain development, however, has been poorly described. The present study aimed to explore miRNA expression in the hippocampus during adolescence compared to adulthood in rats. Method: The brains of female and male Wistar rats were extracted, and the hippocampus was freshly dissected at postnatal day 41 (adolescence) and postnatal day 98 (adulthood). An epigenome-wide analysis was conducted to identify the miRNAs significantly expressed in adolescence compared to adulthood. Additionally, target genes of such miRNAs were considered to perform an exploratory Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results: We identified 16 differentially expressed miRNAs in adolescent male rats compared with adult male rats and 4 differentially expressed miRNAs in adolescent females compared with adult females. Enrichment analysis reinforced that the target genes found are related to neurodevelopmental processes such as cell proliferation, cell migration, and nervous system development. Conclusion: Our findings suggest a complex pattern of miRNA expression during adolescence, which differs from that in adulthood. The differential expression of miRNA in the hippocampus during adolescence may be associated with the late developmental changes occurring in this brain region. Furthermore, the observed sex differences in miRNA expression patterns indicate potential sexual differentiation in hippocampal development. Further comprehensive investigations are needed to elucidate the roles of miRNA in normal brain development.MCIN/AEI/10.13039/501100011033 PID2020-114269GB-I00FEDER BSEJ.514.UGR20Junta de Andalucía, SpainEuropean Regional Development Fund “Instituto de Salud Carlos III” PI18/00467FPU18/05012, MIU, SpainUniversity of Granad

Structural brain imaging studies offer clues about the effects of the shared genetic etiology among neuropsychiatric disorders

Malalties; GenèticaEnfermedades; GenéticaDiseases; GeneticsGenomewide association studies have found significant genetic correlations among many neuropsychiatric disorders. In contrast, we know much less about the degree to which structural brain alterations are similar among disorders and, if so, the degree to which such similarities have a genetic etiology. From the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, we acquired standardized mean differences (SMDs) in regional brain volume and cortical thickness between cases and controls. We had data on 41 brain regions for: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), epilepsy, major depressive disorder (MDD), obsessive compulsive disorder (OCD), and schizophrenia (SCZ). These data had been derived from 24,360 patients and 37,425 controls. The SMDs were significantly correlated between SCZ and BD, OCD, MDD, and ASD. MDD was positively correlated with BD and OCD. BD was positively correlated with OCD and negatively correlated with ADHD. These pairwise correlations among disorders were correlated with the corresponding pairwise correlations among disorders derived from genomewide association studies (r = 0.494). Our results show substantial similarities in sMRI phenotypes among neuropsychiatric disorders and suggest that these similarities are accounted for, in part, by corresponding similarities in common genetic variant architectures

Occurrence of arsenic species in algae and freshwater plants of an extreme arid region in northern Chile, the Loa River Basin

This study reports data on arsenic speciation in two green algae species (Cladophora sp. and Chara sp.) and in five aquatic plants (Azolla sp., Myriophyllum aquaticum, Phylloscirpus cf. desserticola, Potamogeton pectinatus, Ruppia filifolia and Zannichellia palustris) from the Loa River Basin in the Atacama Desert (northern Chile). Arsenic content was measured by Mass Spectrometry coupled with Inductively Coupled Plasma (ICP-MS), after acidic digestion. Liquid Chromatography coupled to ICP-MS was used for arsenic speciation, using both anionic and cationic chromatographic exchange systems. Inorganic arsenic compounds were the main arsenic species measured in all samples. The main arsenic species in the extracts of freshwater algae and plants were arsenite and arsenate, whereas glycerol-arsenosugar (gly-sug), dimethylarsinic acid (DMA) and methylarsonic acid (MA) were present only as minor constituents. Of the samples studied, algae species accumulated more arsenic than aquatic plants. Total arsenic content ranged from 182 to 11,100 and from 20 to 248 mg As kg-1 (d.w.) in algae and freshwater plants, respectively. In comparison with As concentration in water samples, there was hyper-accumulation (>0.1% d.w.) in Cladophora sp

Genetic association study of childhood aggression across raters, instruments, and age

Genòmica; Comportament humàGenómica; Comportamiento humanoGenomics; Human behaviourChildhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg|: 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.We very warmly thank all participants, their parents, and teachers for making this study possible. The project was supported by the “Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies” project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. Cohort-specific acknowledgements and funding information may be found in the Supplementary text

Genetic and epigenetic signatures of attention-deficit/hyperactivity disorder

[eng] Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental, complex and highly heritable disorder characterised by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that impair the daily functioning of patients. These symptoms typically initiate in childhood and persist over time in around two thirds of the diagnosed children. There is evidence that both common and rare genetic variants contribute to the risk for the disorder, with heritability estimates around 76% that seem to remain stable across the lifespan. However, the genetic variation associated with ADHD to date only explain a modest proportion of the phenotypic variance. In this context and taking into account that environmental factors also play a role into the disorder’s susceptibility, it has been proposed that epigenetic marks such as DNA methylation (DNAm) could be contributing as plausible mechanisms by which environmental influences lead to functional and/or structural brain alterations found in ADHD. Given this background and bearing in mind that the genetic and epigenetic investigations conducted on ADHD have been mainly focused on its childhood presentation, the objectives of the present doctoral thesis have been to explore the contribution of common genetic variants to the risk for ADHD across the lifespan and to examine whether there are DNAm patterns specifically associated with ADHD in adults. Firstly, to investigate the genetic basis of ADHD through a lifespan perspective, we have conducted the largest meta-analysis of genome-wide association studies (GWAS-MA) on persistent ADHD in adults to date, a GWAS-MA on ADHD in childhood, and a GWAS- MA on ADHD across the lifespan using data from children and adults in a total sample of 17,149 cases and 32,411 controls. Through this approach, we have identified nine new independent loci associated with ADHD across the lifespan and we have shown that the proportion of common genetic variation contributing to the disorder seems to be stable over time. Moreover, our results have revealed a high genetic overlap between ADHD in childhood and persistent ADHD in adults, driven by the whole group of children, and similar patterns of genetic correlation between ADHD and other ADHD-related phenotypes and different traits and disorders across the lifespan. Secondly, by conducting the largest epigenome-wide association study (EWAS) of ADHD in adults to date, comprising 103 clinical samples of adults with ADHD and 100 controls, we have identified DNAm patterns associated with ADHD in adults. Our results have shown that these patterns are not driven by the individuals’ smoking status or polygenic risk burden for ADHD, neither by exposure to stressful life events in the group of cases. Moreover, the localization of these DNAm patterns in or near genes previously involved in cancer, and the enrichment found for epigenetic signatures of smoking behaviour and maternal smoking among our findings, have reinforced that smoking behaviour is a key factor to account for in this type of analyses. In addition, our enrichment analyses results have supported that genome-wide DNAm is developmental- stage specific and point to an overlap between genetic and epigenetic signatures in ADHD that needs to be further studied in larger samples. In conclusion, the results of the present doctoral thesis provide new insights into the genetic basis of ADHD across the lifespan, support the hypothesis of the neurodevelopmental origin of persistent ADHD in adults, and shed light on the epigenetic signatures characterising ADHD in adults.[cat] El trastorn per dèficit d'atenció i hiperactivitat (TDAH) és un trastorn del neurodesenvolupament, complex i altament heretable caracteritzat per símptomes d’inatenció, impulsivitat i hiperactivitat inapropiats per l’edat que deterioren el funcionament diari dels pacients. Aquests símptomes normalment s’inicien a la infància i persisteixen en el temps en aproximadament dos terços dels nens diagnosticats. Hi ha evidències que recolzen que tant variants genètiques comunes com rares contribueixen al risc del trastorn, amb una heretabilitat estimada al voltant del 76% que sembla mantenir- se estable al llarg de la vida. Tanmateix, la variació genètica associada al TDAH fins ara només explica una modesta proporció de la variància fenotípica. En aquest context, i considerant que els factors ambientals també tenen un paper en la susceptibilitat al trastorn, s’ha proposat que les marques epigenètiques com la metilació de l’ADN (ADNm) podrien contribuir com a mecanismes mitjançant els quals les influències ambientals condueixen a alteracions funcionals i/o estructurals del cervell en el TDAH. Tenint en compte aquest context i donat que les investigacions genètiques i epigenètiques realitzades sobre el TDAH s’han centrat principalment en la seva presentació infantil, els objectius de la present tesi doctoral han sigut explorar la contribució de les variants genètiques comunes al risc de TDAH al llarg de la vida i examinar si hi ha patrons d’ADNm associats específicament amb el TDAH en adults. En primer lloc, per investigar les bases genètiques del TDAH al llarg de la vida, hem realitzat la meta-anàlisi més gran d’estudis d’associació de genoma complet (GWAS- MA) en TDAH persistent en adults fins al moment, una GWAS-MA en TDAH a la infància i una GWAS-MA en TDAH al llarg de la vida amb dades de nens i adults en una mostra total de 17,149 casos i 32,411 controls. Mitjançant aquesta aproximació, hem identificat nou nous loci independents associats amb el TDAH al llarg de la vida i hem mostrat que la proporció de variants genètiques comunes que contribueix al trastorn sembla ser estable al llarg del temps. A més, els nostres resultats han revelat un elevat solapament genètic entre el TDAH en la infància i el TDAH persistent en adults, degut a tot el grup de nens, i patrons de correlació genètica similars entre el TDAH i altres fenotips relacionats amb el TDAH i diferents trets i trastorns al llarg de la vida. En segon lloc, realitzant l’estudi d’associació d’epigenoma complet (EWAS) més gran realitzat en el TDAH en adults fins al moment, que comprèn 103 mostres clíniques d’adults amb TDAH i 100 controls, hem identificat patrons d’ADNm associats al TDAH en adults. Els nostres resultats han mostrat que aquests patrons no són deguts al tabaquisme, a la càrrega de risc poligènic per al TDAH, ni a l’exposició a situacions vitals estressants en el grup de casos. A més, la localització d’aquests patrons d’ADNm en gens prèviament implicats en el càncer i l’enriquiment que hem trobat en els nostres resultats per a patrons d’ADNm que caracteritzen el tabaquisme i el tabaquisme matern durant l’embaràs, han reforçat que el tabaquisme és un factor clau a tenir en compte en aquest tipus d’anàlisis. Addicionalment, els resultats de les nostres anàlisis d’enriquiment han recolzat que els patrons d’ADNm en tot el genoma són específics del període de desenvolupament de l’individu i assenyalen un solapament entre marques genètiques i epigenètiques en el TDAH que cal estudiar en més profunditat en mostres més grans. En conclusió, els resultats de la present tesi doctoral proporcionen nou coneixement sobre la base genètica del TDAH al llarg de la vida, donen suport a la hipòtesi de l’origen del TDAH persistent en adults en el neurodesenvolupament i posen de manifest marques epigenètiques que caracteritzen el TDAH en adults

Occurrence of arsenic species in algae and freshwater plants of an extreme arid region in northern Chile, the Loa River Basin

This study reports data on arsenic speciation in two green algae species (Cladophora sp. and Chara sp.) and in five aquatic plants (Azolla sp., Myriophyllum aquaticum, Phylloscirpus cf. desserticola, Potamogeton pectinatus, Ruppia filifolia and Zannichellia palustris) from the Loa River Basin in the Atacama Desert (northern Chile). Arsenic content was measured by Mass Spectrometry coupled with Inductively Coupled Plasma (ICP-MS), after acidic digestion. Liquid Chromatography coupled to ICP-MS was used for arsenic speciation, using both anionic and cationic chromatographic exchange systems. Inorganic arsenic compounds were the main arsenic species measured in all samples. The main arsenic species in the extracts of freshwater algae and plants were arsenite and arsenate, whereas glycerol-arsenosugar (gly-sug), dimethylarsinic acid (DMA) and methylarsonic acid (MA) were present only as minor constituents. Of the samples studied, algae species accumulated more arsenic than aquatic plants. Total arsenic content ranged from 182 to 11,100 and from 20 to 248 mg As kg-1 (d.w.) in algae and freshwater plants, respectively. In comparison with As concentration in water samples, there was hyper-accumulation (>0.1% d.w.) in Cladophora sp