Strong Genetic Influence Research Articles

Nature and nurture in fussy eating from toddlerhood to early adolescence: findings from the Gemini twin cohort

BackgroundFood fussiness (FF) describes the tendency to eat a small range of foods, due to pickiness and/or reluctance to try new foods. A common behaviour during childhood, and a considerable cause of caregiver concern; its causes are poorly understood. This is the first twin study of genetic and environmental contributions to the developmental trajectory of FF from toddlerhood to early adolescence, and stability and change over time.MethodsParticipants were from Gemini, a population‐based British cohort of n = 4,804 twins born in 2007. Parents reported on FF using the Child Eating Behaviour Questionnaire ‘FF’ scale when children were 16 months (n = 3,854), 3 (n = 2,666), 5 (n = 2,098), 7 (n = 703), and 13 years old (n = 970). A mixed linear model examined the trajectory of FF, and a correlated factors twin model quantified genetic and environmental contributions to variation in and covariation between trajectory parameters. A longitudinal Cholesky twin model examined genetic and environmental influences on FF at each discrete age.ResultsWe modelled a single FF trajectory for all children, which was characterised by increases from 16 months to 7 years, followed by a slight decline from 7 to 13 years. All trajectory parameters were under strong genetic influence (>70%) that was largely shared, indicated by high genetic correlations. Discrete age analyses showed that genetic influence on FF increased significantly after toddlerhood (16 months: 60%, 95% CI: 53%–67%; 3 years: 83%; 81%–86%), with continuing genetic influence as indicated by significant genetic overlap across every age. Shared environmental influences were only significant during toddlerhood. Unique environmental influences explained 15%–26% of the variance over time, with some enduring influence from 5 years onwards.ConclusionsIndividual differences in FF were largely explained by genetic factors at all ages. Fussy eating also shows a significant proportion of environmental influence, especially in toddlerhood, and may, therefore, benefit from early interventions throughout childhood. Future work needs to refine the FF trajectory and explore specific trajectory classes.

A Baseline Model of PTSD From the ACES Cohort.

Post-traumatic stress disorder (PTSD) is a primary military psychiatric condition with complex etiology including strong genetic and/or environmental influences. Environmental influences and demographics can play a role in supporting underlying genetic traits for clinical utility evaluation as risk modifying factors. We are undertaking an IRB approved study to evaluate polygenic scores of PTSD risk in the adverse childhood experience and serotonin (ACES) transporter cohort. Baseline demographic characteristics and statistical modeling of 291 active duty service members from ACES cohort were used and excluded individuals with traumatic brain injury-induced loss of consciousness, pre-deployment PTSD or anxiety disorder, and pre-deployment prescription of antidepressants or psychoactive medications. Summary of categorical and numerical variables were evaluated using chi-square and t-test, respectively. We model PTSD risk and associated scores using linear and logistic regressions. The ACES subset was 79.1% males, multi-ancestry, and mean age of 38.3 years. Most PTSD individuals received behavioral therapy (89.6%) and/or prescribed antidepressants (67%) had higher scores in ACES, combat exposure scales, PTSD checklist military version, neurobehavioral symptom inventory, Pittsburg sleep quality index, insomnia severity index, and composite autonomic symptom score surveys and were less likely to expect future deployment. A positive correlation between age, total months deployed, ACES, CES, PCL-M, and positive-PTSD diagnosis were consistent but not in older individuals, who were more likely and frequently deployed although increasing risk for combat exposure. Demographic characteristics of the ACES cohort fit a coherent model of risk for PTSD to evaluate polygenic scores. Additional research is merited to understand PTSD effects on these confounding factors.

The regulatory basis of migratory behaviour in birds: different paths to similar outcomes

Animal migration is a fascinating phenomenon that has puzzled mankind since the time of ancient Greece. It is a process widespread across a varied range of taxa and it shines especially in birds which, because of their mobility, display an amazing diversity of routes and strategies. With the advances in tracking devices and improvements of sequencing technologies, recent work provides support for a strong genetic influence of several migratory traits across different species. However, there is little to no evidence of any common sequence‐based mechanism behind this complex behaviour, nor any unifying principle explaining it. We review how the focus in understanding the genetic basis for migratory traits should be shifted towards studying regulatory mechanisms of gene expression instead of the traditional candidate gene approach. Importantly, a role for gene expression as the underlying driver of the migratory phenotype can resolve the opposing and often strong views that migration is mainly either under genetic or environmental influence. We emphasise that research should take new directions, reinforcing that there is probably not a common genetic basis for how migration is regulated in birds. Here, we support the notion that 1) migration can only evolve this fast if it is a quantitative trait with a large standing variation; 2) the main drivers for migration evolution seem to be diverse expression–regulation mechanisms rather than gene‐level polymorphisms; and 3) non‐coding sequences of the genome, epigenetics and structural variation might be more important in shaping complex traits than previously thought. Further, we present several hypotheses outlining how these regulatory mechanisms might work across different bird species defining certain migratory traits.

Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes.

Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5'-cytosine-phosphate-guanine-3' loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at P = 6.62 × 10-14. In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.

Genetic Architectures of Adolescent Depression Trajectories in 2 Longitudinal Population Cohorts

Adolescent depression is characterized by diverse symptom trajectories over time and has a strong genetic influence. Research has determined genetic overlap between depression and other psychiatric conditions; investigating the shared genetic architecture of heterogeneous depression trajectories is crucial for understanding disease etiology, prediction, and early intervention. To investigate univariate and multivariate genetic risk for adolescent depression trajectories and assess generalizability across ancestries. This cohort study entailed longitudinal growth modeling followed by polygenic risk score (PRS) association testing for individual and multitrait genetic models. Two longitudinal cohorts from the US and UK were used: the Adolescent Brain and Cognitive Development (ABCD; N = 11 876) study and the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 8787) study. Included were adolescents with genetic information and depression measures at up to 8 and 4 occasions, respectively. Study data were analyzed January to July 2023. Trajectories were derived from growth mixture modeling of longitudinal depression symptoms. PRSs were computed for depression, anxiety, neuroticism, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, and autism in European ancestry. Genomic structural equation modeling was used to build multitrait genetic models of psychopathology followed by multitrait PRS. Depression PRSs were computed in African, East Asian, and Hispanic ancestries in the ABCD cohort only. Association testing was performed between all PRSs and trajectories for both cohorts. A total sample size of 14 112 adolescents (at baseline: mean [SD] age, 10.5 [0.5] years; 7269 male sex [52%]) from both cohorts were included in this analysis. Distinct depression trajectories (stable low, adolescent persistent, increasing, and decreasing) were replicated in the ALSPAC cohort (6096 participants; 3091 female [51%]) and ABCD cohort (8016 participants; 4274 male [53%]) between ages 10 and 17 years. Most univariate PRSs showed significant uniform associations with persistent trajectories, but fewer were significantly associated with intermediate (increasing and decreasing) trajectories. Multitrait PRSs-derived from a hierarchical factor model-showed the strongest associations for persistent trajectories (ABCD cohort: OR, 1.46; 95% CI, 1.26-1.68; ALSPAC cohort: OR, 1.34; 95% CI, 1.20-1.49), surpassing the effect size of univariate PRS in both cohorts. Multitrait PRSs were associated with intermediate trajectories but to a lesser extent (ABCD cohort: hierarchical increasing, OR, 1.27; 95% CI, 1.13-1.43; decreasing, OR, 1.23; 95% CI, 1.09-1.40; ALSPAC cohort: hierarchical increasing, OR, 1.16; 95% CI, 1.04-1.28; decreasing, OR, 1.32; 95% CI, 1.18-1.47). Transancestral genetic risk for depression showed no evidence for association with trajectories. Results of this cohort study revealed a high multitrait genetic loading of persistent symptom trajectories, consistent across traits and cohorts. Variability in univariate genetic association with intermediate trajectories may stem from environmental factors. Multitrait genetics may strengthen depression prediction models, but more diverse data are needed for generalizability.

Quality of Arabica coffee grown in Brazilian Savannah and impact of potassium sources

Located in Brazil’s Central Plateau, the Cerrado Savannah is an emerging coffee-growing region with significant potential for the national coffee market. This study investigated the impact of potassium fertilization on Arabica coffee quality in the Cerrado, using three potassium sources (K2SO4, KCl, and KNO3) and five cultivars (Arara, Aranãs, IPR103, Catiguá and Topázio) across two consecutive harvests. We focused on productivity, granulometry, chemical composition, and sensory characteristics. No significant difference in productivity across the cultivars studied or potassium sources as isolated factors were observed. Regarding chemical parameters, potassium sources only affected NO3− and SO42− levels in the grains. Cultivar-specific differences were noted in caffeine (CAF), citric acid (CA), and sucrose (SUC), highlighting a strong genetic influence. K2SO4 improved productivity in Arara (15 %) and IPR103 (11 %), while KNO3 reduced flat grain percentage to 70 % in Catiguá. Sensory evaluation showed that all potassium sources and cultivars produced specialty coffees, with the Arara cultivar treated with K2SO4 achieving the highest SCA score (83.3) while IPR 103 treated with KCl scored the lowest at 78. Only three treatments were below but very close to the threshold (80). Multivariate analysis indicated a trend where specific treatments correlated with higher productivity and quality. Despite the subtle differences in productivity and quality among potassium sources, a cost-benefit analysis may favor KCl due to its affordability, suggesting its viability as a potassium fertilization option in coffee cultivation. Future research is needed to confirm these trends and optimize potassium source selection to enhance coffee quality in the Cerrado.

Pancreatic Diseases: Genetics and Modeling Using Human Pluripotent Stem Cells.

Pancreas serves endocrine and exocrine functions in the body; thus, their pathology can cause a broad range of irreparable consequences. Endocrine functions include the production of hormones such as insulin and glucagon, while exocrine functions involve the secretion of digestive enzymes. Disruption of these functions can lead to conditions like diabetes mellitus and exocrine pancreatic insufficiency. Also, the symptoms and causality of pancreatic cancer very greatly depends on their origin: pancreatic ductal adenocarcinoma is one of the most fatal cancer; however, most of tumor derived from endocrine part of pancreas are benign. Pancreatitis, an inflammation of the pancreatic tissues, is caused by excessive alcohol consumption, the bile duct obstruction by gallstones, and the premature activation of digestive enzymes in the pancreas. Hereditary pancreatic diseases, such as maturity-onset diabetes of the young and hereditary pancreatitis, can be a candidate for disease modeling using human pluripotent stem cells (hPSCs), due to their strong genetic influence. hPSC-derived pancreatic differentiation has been established for cell replacement therapy for diabetic patients and is robustly used for disease modeling. The disease modeling platform that allows interactions between immune cells and pancreatic cells is necessary to perform in-depth investigation of disease pathogenesis.

“Examining the link between tooth agenesis and papillary thyroid cancer: is there a risk factor?” Observational study

BackgroundMutations in one or multiple genes can lead to hypodontia and its characteristic features. Numerous studies have shown a strong genetic influence on the occurrence of hypodontia, and identified several genes, including AXIN2, EDA, FGF3, FGFR2, FGFR10, WNT10A, MSX1, and PAX9, that are directly associated with dental agenesis and carcinogenesis. The objective of this study was to investigate the occurrence and pattern of tooth agenesis, microdontia, and palatally displaced canine (PDC) in women diagnosed with papillary thyroid cancer (PTC), compared to a control group of women without any malignancy or thyroid disease.Materials and methodsThis case–control study was carried at the Department of Orthodontics, School of Dental Medicine University of Zagreb, and Department of Oncology and Nuclear Medicine Sestre Milosrdnice University Hospital Centre. The study involved a clinical examination and evaluation of dental status, panoramic X-ray analysis, and assessment of medical and family history of 116 female patients aged 20–40 with PTC, as well as 424 females in the control group who were of similar age.ResultsThe prevalence of hypodontia, microdontia, and PDC was statistically higher in women with PTC than in the control group. The prevalence rate of hypodontia was 11.3% in the experimental group and 3.5% in the control group. The experimental group showed a higher occurrence of missing upper lateral incisors, lower left central incisors, and all the third molars (except the upper left) compared to the control group. Women with PTC showed the prevalence of PDC significantly higher than the control group (3.5%, 0.7%, p = 0.002). The probability of hypodontia as a clinical finding increases 2.6 times, and microdontia occurs 7.7 times more frequently in women with PTC.ConclusionOur study suggests a possible link between odontogenesis and PTC. The absence of permanent teeth may increase the likelihood of PTC in women. Leveraging the age-7 orthopantomogram to identify women at high risk for PTC within a critical early detection window could significantly improve oral health outcomes and PTC prognosis through proactive interventions.

Clinical features, polysomnography, and genetics association study of restless legs syndrome in clinic based Chinese patients: A multicenter observational study

Study objectivesTo systemically describe the clinical features, polysomnography (PSG) finding, laboratory tests and single-nucleotide polymorphisms (SNPs) in a clinic based Chinese primary restless legs syndrome (RLS) population. MethodsThis observational study, conducted from January 2020 to October 2021 across 22 sleep labs in China, recruited 771 patients diagnosed with RLS following the 2014 RLSSG criteria. Clinical data, PSG testing, and laboratory examination and SNPs of patients with RLS were collected. A total of 32 SNPs in 24 loci were replicated using the Asian Screening Array chip, employing data from the Han Chinese Genomes Initiative as controls. ResultsIn this study with 771 RLS patients, 645 had primary RLS, and 617 has DNA available for SNP study. Among the 645 primary RLS, 59.7% were women. 33% had a family history of RLS, with stronger familial influence in early-onset cases. Clinical evaluations showed 10.4% had discomfort in body parts other than legs. PSG showed that 57.1% of RLS patients had periodic leg movement index (PLMI) of >5/h and 39.1% had PLMI >15/h, respectively; 73.8% of RLS patients had an Apnea-Hypopnea Index (AHI) > 5/h, and 45.3% had an AHI >15/h. The laboratory examinations revealed serum ferritin levels <75 ng/ml in 31.6%, and transferrin saturation (TSAT) of <45% in 88.7% of RLS patients. Seven new SNPs in 5 genes showed a significant allelic association with Chinese primary RLS, with one previously reported (BTBD9) and four new findings (TOX3, PRMT6, DCDC2C, NOS1). ConclusionsChinese RLS patients has specific characters in many aspects. A high family history with RLS not only indicates strong genetic influence, but also reminds us to consider the familial effect in the epidemiological study. Newly developed sequencing technique with large samples remains to be done.

Prevalence and heritability of parental-reported speech and/or language difficulties in a Swedish population-based twin sample.

Research on genetic and environmental influences on speech and/or language difficulties (SaLD) is sparse, with inconsistent heritability estimates. We aimed to estimate the prevalence of parental reported SaLD and the relative contributions of genetic and environmental factors for the phenotype using a Swedish population-based twin sample. We hypothesized that there would be a stronger genetic than environmental effect on SaLD. Data were collected from The Child and Adolescent Twin Study in Sweden. The study sample included 16,774 twin pairs (16,946 males, 16,602 females), of which 5141 were monozygotic, 5861 dizygotic (DZ), and 5772 opposite-sex DZ pairs. The language items in the Autism-Tics, Attention-Deficit Hyperactivity Disorder, and other Comorbidities inventory were used to categorize individuals as having parental-reported SaLD. A classical twin design was used to estimate the relative contribution of genetic and environmental factors to the liability of SaLD. The prevalence of SaLD was 7.85% (95% confidence interval (CI) [7.57%-8.15%]) and 7.27% (95% CI [6.99%-7.55%]) when excluding individuals with autism and intellectual disability (ID). We also found that SaLD were significantly more prevalent in males than females with a ratio of 2:1. The heritability was estimated to be 75% (95% CI [67%-83%]) for SaLD. Shared environment played a significant role with an estimated contribution of 22% (95% CI [14%-30%]). The heritability estimate was reduced to 70% but with overlapping CI when excluding individuals with autism and ID. We provide evidence that SaLD is common in the population and under strong genetic influence. Future studies should focus on mapping the genetic architecture of SaLD and related disorders.

Variation in personality shaped by evolutionary history, genotype and developmental plasticity in response to feeding modalities in the Arctic charr

Animal personality has been shown to be influenced by both genetic and environmental factors and shaped by natural selection. Currently, little is known about mechanisms influencing the development of personality traits. This study examines the extent to which personality development is genetically influenced and/or environmentally responsive (plastic). We also investigated the role of evolutionary history, assessing whether personality traits could be canalized along a genetic and ecological divergence gradient. We tested the plastic potential of boldness in juveniles of five Icelandic Arctic charr morphs ( Salvelinus alpinus ), including two pairs of sympatric morphs, displaying various degrees of genetic and ecological divergence from the ancestral anadromous charr, split between treatments mimicking benthic versus pelagic feeding modalities. We show that differences in mean boldness are mostly affected by genetics. While the benthic treatment led to bolder individuals overall, the environmental effect was rather weak, suggesting that boldness lies under strong genetic influence with reduced plastic potential. Finally, we found hints of differences by morphs in boldness canalization through reduced variance and plasticity, and higher consistency in boldness within morphs. These findings provide new insights on how behavioural development may impact adaptive diversification.

Correlation and variability analysis for yield and related traits of sweet corn in backcross populations

The 14 biometrical traits of sweet corn were studied in BC2F2 and BC2F3 generations of SCM-Se-Y-1 x UMI 1230β+ to analyse the mean performance and frequency distribution patterns to select potential individuals with high yielding agronomic traits. The mean, GCV, PCV, heritability, and GAM were calculated for all the recorded traits. The Pearson correlation coefficient revealed the strong and positive association of cob weight with cob length, number of kernels in a row and number of kernel rows per cob. Similarly, single plant yield shows positive correlation with number of kernels per row, number of kernel rows per cob, cob length and cob weight. The populations exhibit high PCV than the GCV, which reflects the direct influence of environments on trait performance. The BC2F2 generation exhibits greater trait variability, while BC2F3 shows signs of stabilization. Both generations display high heritability, indicating strong genetic influences for yield related traits. Heritability and GAM for the trait cob weight and single plant yield were higher, which gives added advantage for isolating the superior individual. The results of this study suggest that the selection of agronomical traits to enhance yield in sweet corn is of utmost importance due to its far-reaching economic, nutritional, and environmental implications.

THU206 Constitutional Delay Of Puberty And Idiopathic Hypogonadotropic Hypogonadism: Differential Contributions Of Common Genetic Variants

Abstract Disclosure: M.F. Lippincott: None. E. Schafer: None. A.A. Hindman: None. R. Brauner: None. A. Delaney: None. K. McElreavey: None. J.E. Hall: None. J.N. Hirschhorn: None. M.R. Palmert: None. S.B. Seminara: None. R.M. Salem: None. Y. Chan: None. Introduction: Disorders of pubertal timing include self-limited constitutional delay of puberty (CDP) and longer lasting idiopathic hypogonadotropic hypogonadism (IHH). Both conditions have strong genetic influences. We sought to determine if common genetic variants that influence pubertal timing contribute to CDP and IHH. Hypothesis: IHH and CDP can sometimes be caused by the accumulation of common genetic variants that delay pubertal onset. Therefore, compared to controls, patients with CDP and IHH have higher polygenic risk scores (PRS) based on genome-wide association studies (GWAS) for pubertal timing. Methods: All research and data-sharing were conducted with participant/guardian consent and institutional ethical approval. We defined CDP as puberty starting between 12 and 18 y in girls and between 13.5 and 18 y in boys and IHH as low sex steroids and non-elevated gonadotropins at ≥18 y, both with no cause identified on standard clinical evaluation. We genotyped CDP cases (n=106) on the Illumina Infinium OmniExpress Exome 8-1v6 platform and retrieved array-matched control data from dbGaP (n=9,222). IHH cases (n=713) and controls from the Schizophrenia Psychiatric GWAS (n=1,868) were genotyped on the Infinium PsychArray. After data harmonization, quality control, and principal components analysis were performed on combined sets, genotype imputation was performed on all unrelated individuals of European ancestry using the Michigan Imputation Server. We downloaded summary statistics for: 1) GWAS meta-analysis for age at menarche (AAM), 2) multi-trait GWAS for male pubertal hallmarks, and 3) a negative control using GWAS for basal cell carcinoma (BCC). We calculated and compared PRS between cases and controls using PRS-CS and PRSice2, with the first 10 ancestral principal components and sex as covariates. We also performed sex-stratified analyses. Results: Both the CDP and the IHH cohorts had significantly higher PRS for male pubertal hallmarks compared to controls, but the difference was smaller for IHH (CDP Cohen’s d=0.59, p=2×10-10; IHH d=0.13, p=0.007). The CDP cohort also had a significantly higher PRS for AAM compared to controls (d=0.83, p=8×10-20), but the IHH cohort did not (d=0.08, p=0.06). Of note, sex-specific PRS provided greater discrimination between CDP cases and controls in stratified analyses of the corresponding sex (AAM in females: d=1.1, p=4×10-11; AAM in males d=0.72, p=8×10-11; male hallmarks in females: d=0.52, p=0.001; male hallmarks in males: d=0.63, p=2×10-8). No significant differences were observed between cases and controls for BCC PRS. Conclusions: Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, with some sex-specificity, but only weakly to IHH. These findings support the hypothesis that the common-variant genetics of CDP and IHH are largely distinct. Presentation: Thursday, June 15, 2023

The Impact of Orthodontic Treatment on Facial Appearance in Angle Class III Patients: A Mini Review

Angle Class III malocclusion has a strong genetic influence that can occur in several generations of the same family group. This dentofacial deformity can be identified from an early age, even in childhood. The perception of beauty in the transition phase to adolescence has a greater weight, because in this phase there are immense physiological changes. The need for attention through aesthetic enhancement generates vanity, which can have both beneficial and harmful influences. Nowadays, the young generation craves prominence and subsequently values the exaggerated importance of beauty and the quest for aesthetic perfection. A young patient with a dentofacial deformity caused by Angle Class III malocclusion has a major facial impact. They are usually the victims of teasing, nicknames and psychological pressure and bullying. They become embarrassed, irritable and their self-esteem and social integration suffer. From this perspective, early treatment in children can be beneficial, reducing the psychological burden of facial and dental alterations in the future. The purpose of this article is to review the literature on the facial aspects resulting from orthodontic treatment in Angle Class III patients.

The Dysfunctional Mechanisms Throwing Tics: Structural and Functional Changes in Tourette Syndrome.

Tourette Syndrome (TS) is a high-incidence multifactorial neuropsychiatric disorder characterized by motor and vocal tics co-occurring with several diverse comorbidities, including obsessive-compulsive disorder and attention-deficit hyperactivity disorder. The origin of TS is multifactorial, with strong genetic, perinatal, and immunological influences. Although almost all neurotransmettitorial systems have been implicated in TS pathophysiology, a comprehensive neurophysiological model explaining the dynamics of expression and inhibition of tics is still lacking. The genesis and maintenance of motor and non-motor aspects of TS are thought to arise from functional and/or structural modifications of the basal ganglia and related circuitry. This complex wiring involves several cortical and subcortical structures whose concerted activity controls the selection of the most appropriate reflexive and habitual motor, cognitive and emotional actions. Importantly, striatal circuits exhibit bidirectional forms of synaptic plasticity that differ in many respects from hippocampal and neocortical plasticity, including sensitivity to metaplastic molecules such as dopamine. Here, we review the available evidence about structural and functional anomalies in neural circuits which have been found in TS patients. Finally, considering what is known in the field of striatal plasticity, we discuss the role of exuberant plasticity in TS, including the prospect of future pharmacological and neuromodulation avenues.

Water deficit influence upon pollen grain production in cacao genotypes (Theobroma cacao)

Genetic improvement programs in cacao (Theobroma cacao L) have focused on obtaining new varieties with high yield and resistance to diseases. However, drought tolerance response has not been considered enough in order to face the climate change emergency. Events such as prolonged droughts or excessive rainfall can affect the pollen production of cacao flowers and others reproductive characteristics. Hence, this study was proposed to learn about the hydric deficit influence on pollen production of four Ecuadorian cacao genotypes. The results indicated statistical differences between CCN-51 and the "National" clones (P≤0.05). CCN-51 reached the highest pollen production values in the wettest treatment (26,546 ±100) compared to the “National” clones, which had no differences among them. There was a positive correlation between pollen production and the highest irrigation treatments (r=0.78), observing that while the water level was the highest, the pollen grain formation (PGF) increased, and the opposite when the water level diminished. It is concluded that the adequate water amount in the soil can increase pollen production. However, it is essential to emphasize the strong genetic influence on drought tolerance traits that could be severely affected by climatic changes. The CCN-51 and EET-575 clones should be considered when planning to develop drought-tolerant hybrids of cacao.

Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins

Emerging evidence implicate the gut microbiota as a potential susceptibility factor in attention-deficit hyperactivity disorder (ADHD), a common multifactorial neurodevelopmental condition. However, little is known about the biochemical signature of ADHD, including the metabolic contribution of the microbiota via the gut-brain axis, and the relative contribution of genetics and environmental factors. Here, we perform unbiased metabolomic profiling of urine and fecal samples collected from a well-characterized Swedish twin cohort enriched for ADHD (33 ADHD, 79 non-ADHD), using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. Our results highlight sex-specific patterns in the metabolic phenotype of individuals with ADHD. Specifically, the urine profile of males, but not females, with ADHD was characterized by greater excretion of hippurate, a product of microbial-host co-metabolism that can cross the blood-brain-barrier with bioactivity of potential relevance to ADHD. This trans-genomic metabolite was also negatively correlated with IQ in males and was significantly correlated with fecal metabolites associated with gut microbial metabolism. The fecal profile of ADHD individuals was characterized by increased excretion of stearoyl-linoleoyl-glycerol, 3,7-dimethylurate, and FAD and lower amounts of glycerol 3-phosphate, thymine, 2(1H)-quinolinone, aspartate, xanthine, hypoxanthine, and orotate. These changes were independent of ADHD medication, age, and BMI. Furthermore, our specific twins’ models revealed that many of these gut metabolites had a stronger genetic influence than environmental. These findings suggest that metabolic disturbances in ADHD, involving combined gut microbial and host metabolic processes, may largely derive from gene variants previously linked to behavioral symptoms in this disorder.This article is part of the Special Issue on “Microbiome & the Brain: Mechanisms & Maladies”.

Using epigenomics to understand cellular responses to environmental influences in diseases.

It is a generally accepted model that environmental influences can exert their effects, at least in part, by changing the molecular regulators of transcription that are described as epigenetic. As there is biochemical evidence that some epigenetic regulators of transcription can maintain their states long term and through cell division, an epigenetic model encompasses the idea of maintenance of the effect of an exposure long after it is no longer present. The evidence supporting this model is mostly from the observation of alterations of molecular regulators of transcription following exposures. With the understanding that the interpretation of these associations is more complex than originally recognised, this model may be oversimplistic; therefore, adopting novel perspectives and experimental approaches when examining how environmental exposures are linked to phenotypes may prove worthwhile. In this review, we have chosen to use the example of nonalcoholic fatty liver disease (NAFLD), a common, complex human disease with strong environmental and genetic influences. We describe how epigenomic approaches combined with emerging functional genetic and single-cell genomic techniques are poised to generate new insights into the pathogenesis of environmentally influenced human disease phenotypes exemplified by NAFLD.

Current understanding of the immunological basis of rheumatoid arthritis: from post-translational modification of proteins to the use of disease-modifying antirheumatic drugs

Background. Rheumatoid arthritis (RA) is a multietiological chronic systemic autoimmune disease associated with inflammatory joint damage and extra-articular processes in internal organs. RA is recognized as the most common autoimmune inflammatory arthritis with an incidence of 0.4% to 1.3% of the population. Objective. Summarize current information on the immunopathogenesis of RA based on data from open sources of information. Methods. The selection of publications that covered information about the immunopathogenesis of rheumatoid arthritis was performed using the following keywords: systemic autoimmune diseases, RA, citrullination, carbamylation. Results. RA is considered an immune-mediated disease with a strong genetic influence. An important role in the initiation of the development of RA is played by genetic factors and damage to the mucous membranes in the lungs, oral cavity, and gastrointestinal tract.. In response to the appearance of post-translationally modified (citrullinated/carbamylated) proteins, B-cells induce the production of antibodies to cyclic citrullinated peptide (anti-citrullinated peptide antibodies – ACPA). Rheumatoid factor is another well-studied autoantibody involved in the development of RA. Given the complex role that dendritic cells play in the pathogenesis of RA, targeted therapies are being developed to block their immunogenic or enhance their tolerogenic functions. Dysfunction of fibroblast-like synoviocytes leads to synovial hyperplasia. Disease-modifying antirheumatic drugs (DMARDs) are used to target inflammation and prevent disease progression. Conclusions. Genetic predisposition and specific post-translational modifications of proteins play a significant role in the development of RA. The introduction of DMARDs and the prospects for the use of mesenchymal stem cells and their derivatives allows for the development of new effective treatment strategies to implement more effective control over this disease.

Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome.

Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohn's disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 × 10-15] and RPS6KA2 [6.43 × 10-13], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 × 10-15]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 × 10-16]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 × 10-7 vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 × 10-4). These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.