Dynamics of the personalities of PCSK9 on missense variants (rs505151 and rs562556) from elderly cohort studies in Brazil.

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptors (LDLR). Gain-of-function (GOF) variants of PCSK9 significantly affects lipid metabolism leading to coronary artery disease (CAD), owing to the raising the plasma low-density lipoprotein (LDL). Considering the public health matter, large-scale genomic studies have been conducted worldwide to provide the genetic architecture of populations for the implementation of precision medicine actions. Nevertheless, despite the advances in genomic studies, non-European populations are still underrepresented in public genomic data banks. Despite this, we found two high-frequency variants (rs505151 and rs562556) in the ABraOM databank (Brazilian genomic variants) from a cohort SABE study conducted in the largest city of Brazil, São Paulo. Here, we assessed the structural and dynamical features of these variants against WT through a molecular dynamics study. We sought fundamental dynamical interdomain relations through Perturb Response Scanning (PRS) and we found an interesting change of dynamical relation between prodomain and Cysteine-Histidine-Rich-Domain (CHRD) in the variants. The results highlight the pivotal role of prodomain in the PCSK9 dynamic and the implications for the development of new drugs depending on patient group genotype.

The course of attention-deficit/hyperactivity disorder through midlife.

The course of ADHD from childhood up to young adulthood has been characterized in several studies. However, little is known about the course of symptoms into middle age and beyond. This study aims to evaluate predictors of ADHD trajectories in midlife based on three assessments. The follow-up sample comprised 323 adults with ADHD, evaluated at baseline and seven and thirteen years later, from the average ages of 34 up to 47 years old. ADHD status at reassessments was used to characterize trajectories. Demographics, ADHD features, comorbidities, and polygenic scores for ADHD and genetically correlated psychiatric disorders were evaluated to predict ADHD trajectories. Study retention rate was 67% at T2 (n = 216) and 62% at T3 (n = 199). Data from patients evaluated three times showed that 68.8% coursed stable, 25.5% unstable, and 5.7% remission trajectory of ADHD. Women, individuals with more severe syndromes, higher frequency of comorbidities at reassessments, and genetic liability to depression present a higher probability of a stable trajectory. Our findings shed light on midlife ADHD trajectories and their gender, genomic and clinical correlates.

Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank.

PURPOSE: Genome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites. METHODS: PRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry. RESULTS: Among the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by <1% with the inclusion of PRS for most cancers. CONCLUSION: PRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.

Obsessive-Compulsive Symptoms, Polygenic Risk Score, and Thalamic Development in Children From the Brazilian High-Risk Cohort for Mental Conditions (BHRCS).

Background: Thalamic volume measures have been linked to obsessive-compulsive disorder (OCD) in children and adolescents. However, it is unclear if alterations in thalamic volumes occur before or after symptom onset and if there is a relation to the presence of sub-clinical obsessive-compulsive symptoms (OCS). Here, we explore the relationship between OCS and the rate of thalamic volume change in a cohort of children and youth at high risk to develop a mental disorder. A secondary aim was to determine if there is a relationship between OCS and the individual's OCD polygenic risk score (OCD-PRS) and between the rate of thalamic volume change and the OCD-PRS. Methods: The sample included 378 children enrolled in the longitudinal Brazilian High-Risk Cohort for Mental Conditions. Participants were assessed for OCS and the symmetrized percent change (SPC) of thalamic volume across two time-points separated by 3 years, along with the OCD-PRS. Zero-altered negative binomial models were used to analyze the relationship between OCS and thalamic SPC. Multiple linear regressions were used to examine the relationship between thalamic SPC and OCD-PRS. Results: A significant relationship between OCS and the right thalamus SPC (p = 0.042) was found. There was no significant relationship between changes in thalamic volume SPC and OCD-PRS. Conclusions: The findings suggest that changes in the right thalamic volume over the course of 3 years in children may be associated to OCS. Future studies are needed to confirm these results and further characterize the specific nature of OCS symptoms associated with thalamic volumes.

Ancestry effects on type 2 diabetes genetic risk inference in Hispanic/Latino populations.

BACKGROUND: Hispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations. METHODS: Whole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here. RESULTS: T2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences. CONCLUSIONS: T2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.

High polygenic burden is associated with blood DNA methylation changes in individuals with suicidal behavior.

Suicidal behavior is result of the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide). Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. We identified 153 differentially methylated sites between individuals with low and high-PRS. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment (CHD7, RFX4, KCNA1, PLCB1, PITX1, NUMBL) and ATP binding (KIF7, NUBP2, KIF6, ATP8B1, ATP11A, CLCN7, MYLK, MAP2K5). Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

Pesquisa inmuno-epidemiológica en niños con meningoencefalitis vírica vacunados contra la parotiditis, rubeola y sarampión / Immuno-epidemiological inquiry in children suffering viral meningoncephalitis vaccinate against mumps, rubella and measles

En las meningoencefalitis de etiología viral se encuentran implicados los paramixovirus (virus de la parotiditis, sarampión y rubeola). Las vacunas combinadas trivalentes han sido utilizadas durante años en muchos países. El objetivo del trabajo es determinar la respuesta poliespecífica de anticuerpos de tipo IgG anti parotiditis, rubeola y sarampión en pacientes pediátricos con meningoencefalitis víricas agudas. Se realizó un estudio retrospectivo en el año 2018 en muestras de pacientes pediátricos con meningoencefalitis viral aguda vacunados con la triple viral, donde se utilizó el índice de anticuerpos específicos anti-parotiditis, anti-rubeola y anti-sarampión para identificar el estado de respuesta inmunológica contra dichos virus en la muestra estudiada, procedentes de la serorraquioteca de LABCEL. Las determinaciones se hicieron por ELISA. Todos los pacientes presentaron respuesta poliespecífica intratecal, disminución significativa del índice de anticuerpos IgG anti-parotiditis con respecto a la edad y al tiempo de respuesta. Se evidencia un acortamiento del tiempo de respuesta de los anticuerpos de tipo IgG específicos anti-parotiditis en relación a la edad de vacunación(AU)

Paramixovirus like mumps, rubella and measles are involved in some viral meningoencephalitis. Triple combined vaccines have been employed for several years in many countries. The aim of this work is to determine the IgG anti mumps, rubella and measles polyspecific response in pediatric patients with acute viral meningoencephalitis. A 2018 retrospective study in pediatric patients with acute viral meningoencephalitis previously vaccinated with the triple viral vaccine MMR was performed to identify the immune response status against mumps, rubella and measles in samples from LABCEL serum and cerebrospinal fluid collection. Quantification of IgG specific antibody was performed by ELISA. Intrathecal polyspecific response was present in all patients. A significant decrement of anti IgG mumps specific antibody index was observed according to age and response time. A shortage of the response time of IgG mumps specific antibodies according to the age of vaccination was demonstrated(AU)

Development and functional morphology of the mouthparts and foregut in larvae and post-larvae of Macrobrachium jelskii (Decapoda: Palaemonidae).

The morphology of the mouthparts and foregut of the larvae and post-larvae of Macrobrachium jelskii was investigated to determine their functional roles in feeding, in order to understand the larval feeding behaviour and the changes that occur during its development. The mouthparts and foregut of the zoea I and II are morphologically similar, rudimentary and non-functional in feeding. Only in the final larval stage, zoea III, do the external mouthparts and foregut become structurally more complex and thus likely to play a potential role in feeding. Two behavioral trials (point of no return, point of reserve saturation) evaluated the resistance to starvation in zoea I, II, and III. The results indicate that they have sufficient nutritional reserves to permit them to complete metamorphosis without feeding. Overall, our results suggest that the zoea I and II of Macrobrachium jelskii engage in obligate lecithotrophy and zoea III in facultative lecithotrophy.

Evolutionary implications of infra- and interspecific molecular variability of pathogenesis-related proteins

We have examined phylogenetic relationships in seven pathogenesis-related (PR) protein families. Within-family comparisons involved 79 species, 166 amino acid sequences, and 1,791 sites. For 37 species, 124 different PR isoforms were identified (an average of 3.3 per species). Thirty-one of the 37 species investigated tended to cluster together (84%). Of the 17 clusters distinguished in the seven phylogenetic trees, 10 (59%) were in agreement with their taxonomic status, ascertained at the family level. The strong similarities among the intraspecific forms, as compared to interspecific differences, argue for some kind of gene conversion, but the rare occurrence of widely different isoforms also suggests diversifying selection. PRs 1, 6, and 4 seem to be less differentiated than PRs 3, 2, 10, and 5.

Foram analisadas as relações filogenéticas em sete famílias de proteínas relacionadas à patogênese. As comparações dentro das famílias envolveram 79 espécies, 166 seqüências de aminoácidos e 1.791 sítios nucleotídicos. Para 37 espécies, foram identificadas 124 isoformas diferentes de PRs (uma média de 3,3 por espécie). Trinta e uma (84%) das investigadas nas 37 espécies tenderam a se agrupar. Dos 17 agrupamentos diferenciados nas sete árvores filogenéticas, 10 (59%) estiveram de acordo com a classificação taxonômica, avaliada em nível de família. A forte similaridade entre as formas intraespecíficas, quando comparadas às diferenças interespecíficas, sugere algum tipo de conversão gênica, mas a ocorrência rara de isoformas muito diferentes pode também sugerir seleção diversificadora. As PRs 1, 6 e 4 parecem ser menos diferenciadas do que as PRs 3, 2, 10 e 5.