Common Variants Research Articles

EXTH-06. DEVELOPMENT OF ANTISENSE OLIGONUCLEOTIDE THERAPY AGAINST ZFTA-RELA EPENDYMOMA

Abstract Treatment for ependymoma (EPN), the third most common pediatric brain tumor, has not changed in the last 30 years, consisting of surgery and radiotherapy. When EPNs relapse, there are very limited therapeutic options, thus highlighting a dire need for more effective treatment for these tumors. Over 95% of supratentorial EPN are driven by ZFTA fusion oncoproteins, the most common variant being ZFTA-RELA. ZFTA fusion oncoproteins (FO) alone are sufficient to drive tumors in murine models. We hypothesize that: these tumors continue to depend on ZFTA-RELA expression, and that the FO represents a lead target for therapeutic development. RESULTS To assess this dependency, we utilized CRISPR-Cas9 mediated knockout (KO) of ZFTA-RELA oncoproteins from a series of patient derived cell lines as compared to control cells. We found that ZFTA FO driven patient models were dependent upon ZFTA FO expression, and KO led to impaired cellular proliferation. To determine whether a reduction in FO protein levels would also be sufficient to reduce tumor growth, we screened a series of antisense oligonucleotides (ASOs) for ZFTA FO knockdown efficiency in patient-derived cell lines. We quantified knockdown efficiency by western blot and selected the top-performing ASOs targeting a functionally important zinc finger domain of ZFTA. Top-performing ASOs reduced tumor cell proliferation in single dose experiments by 50%, while a non-targeting ASO treated population was unaffected. Repeated ASO doses over 96 hours saw a 75% reduction compared to a 10% reduction in the non-targeting group. CONCLUSION Our findings suggest that ZFTA-RELA drives tumor initiation and continued maintenance and proliferation of EPN. Tumor proliferation can be slowed by reducing FO levels below a required threshold. ASO therapy, potentially in combination with translation inhibitors, is one promising route for targeted treatments in this aggressive EPN subtype and could be expanded against other EPN driver proteins such as EZHIP.

A deep learning model for prediction of autism status using whole-exome sequencing data.

Autism is a developmental disability. Research demonstrated that children with autism benefit from early diagnosis and early intervention. Genetic factors are considered major contributors to the development of autism. Machine learning (ML), including deep learning (DL), has been evaluated in phenotype prediction, but this method has been limited in its application to autism. We developed a DL model, the Separate Translated Autism Research Neural Network (STAR-NN) model to predict autism status. The model was trained and tested using whole exome sequencing data from 43,203 individuals (16,809 individuals with autism and 26,394 non-autistic controls). Polygenic scores from common variants and the aggregated count of rare variants on genes were used as input. In STAR-NN, protein truncating variants, possibly damaging missense variants and mild effect missense variants on the same gene were separated at the input level and merged to one gene node. In this way, rare variants with different level of pathogenic effects were treated separately. We further validated the performance of STAR-NN using an independent dataset, including 13,827 individuals with autism and 14,052 non-autistic controls. STAR-NN achieved a modest ROC-AUC of 0.7319 on the testing dataset and 0.7302 on the independent dataset. STAR-NN outperformed other traditional ML models. Gene Ontology analysis on the selected gene features showed an enrichment for potentially informative pathways including potassium ion transport.

THE PROGINS VARIANT OF THE PGR GENE AND PLACENTAL ENDOCRINE FUNCTION AT RISK OF PRETERM LABOR: A PILOT STUDY

Progesterone receptors, which are encoded by the PGR gene, mediate the main physiological effects of progesterone – the hormone that is required for a successful pregnancy. The PROGINS variant is one of the most common variants of the PGR gene. Due to genetic heterogeneity, the presence of inferior forms of progesterone receptors in women can be a clinical problem. In addition to fertility problems, such women may theoretically respond differently to progesterone replacement therapy.Aim of the study to determine the effect of the PROGINS variant of the PGR gene on the hormonal status and results of progesterone deficiency treatment in pregnant women at risk of preterm labor.Material and methods. The main group included 30 pregnant women with progesterone deficiency and the threat of preterm labor, and the comparison group included 30 pregnant women with a normal course of pregnancy. The concentrations of progesterone, estradiol, and placental lactogen were measured in the pregnant women of both groups. Genotyping was assayed by PCR.Results. The genotypic frequencies of the PROGINS variant were not significantlydifferent between the main and comparison groups. Pregnant patients in the main group with the T2T2 genotype after treatment had significantly lower progesterone levels compared to patients with the T1T1 and T1T2 genotypes. Pregnant women in the main group with the T2T2 genotype delivered at a shorter gestational age.Conclusion. The results of our study showed the associations between the PROGINS variant of the PGR gene and the inefficacy of progesterone deficiency treatment in pregnant women at risk of preterm birth and shortened gestation.

Large-scale exome sequencing identified 18 novel genes for neuroticism in 394,005 UK-based individuals.

Existing genetic studies of neuroticism have been largely limited to common variants. Here we performed a large-scale exome analysis of white British individuals from UK Biobank, revealing the role of coding variants in neuroticism. For rare variants, collapsing analysis uncovered 14 neuroticism-associated genes. Among these, 12 (PTPRE, BCL10, TRIM32, ANKRD12, ADGRB2, MON2, HIF1A, ITGB2, STK39, CAPNS2, OGFOD1 and KDM4B) were novel, and the remaining (MADD and TRPC4AP) showed convergent evidence with common variants. Heritability of rare coding variants was estimated to be up to 7.3% for neuroticism. For common variants, we identified 78 significant associations, implicating 6 unreported genes. We subsequently replicated these variants using meta-analysis across other four ancestries from UK Biobank and summary data from 23andMe sample. Furthermore, these variants had widespread impacts on neuropsychiatric disorders, cognitive abilities and brain structure. Our findings deepen the understanding of neuroticism's genetic architecture and provide potential targets for future mechanistic research.

Clinical and laboratory-instrumental characteristics of patients with dyspepsia syndrome not associated with <i>Нelicobacter pylori</i> infection

BACKGROUND: The significant prevalence of dyspepsia in patients without Нelicobacter pylori infection, difficulties in differential diagnosis necessitate the identification of the most common nosological variants, optimization of the diagnosis algorithm. AIM: To study clinical, laboratory and instrumental characteristics of patients with dyspepsia syndrome unrelated to Нelicobacter pylori infection. MATERIALS AND METHODS: A 13C-Urea Breath test was performed to 856 patients with uninvestigated dyspepsia. According to its results, 342 patients with Нelicobacter pylori infection were excluded from the study. The remaining patients (n = 514) with negative Нelicobacter pylori status underwent esophagogastroduodenoscopy and ultrasound examination of the abdominal organs. The patients with an identified organic pathology (n = 129) explaining dyspeptic complaints were excluded from the study. 208 out of the 385 patients without organic pathology agreed to undergo laboratory and instrumental examination in accordance with the study protocol. To assess dyspeptic complaints, 208 patients filled out a “Dyspepsia Questionnaire” developed by the authors. Demographic, anthropometric data, and complaints were recorded in all the study participants; experimental psychological testing was performed (Beck’s questionnaires, generalized anxiety disorder questionnaire-7, Short Form-36) and laboratory and instrumental examination (the level of pepsinogen I, pepsinogen II, immunoglobulin class G to Нelicobacter pylori and gastrin-17 in serum), esophagogastrogastroduodenoscopy with biopsy and pathomorphological assessment according to the Operative Link for Gastritis Assessment (OLGA) system, 24-hour esophageal impedance–pH monitoring, radiography of the esophagus and stomach. RESULTS: The majority of the patients with dyspepsia syndrome were not infected at the time of Нelicobacter pylori complaints — 514 (60.1%) patients. An in-depth examination of 208 people with a negative helicobacter status and the absence of an organic pathology explaining the symptoms revealed the heterogeneity of the final diagnoses. The results of the study demonstrate positive correlations between the level of depression, anxiety and the AET (acid exposure time) index, the number of acid reflux. A decrease in the level of pepsinogen I, gastrin-17, and the ratio of pepsinogen I/II was revealed with an increase in the degree and stage of atrophy according to the results of an Operative Link for Gastritis Assessment biopsy. CONCLUSIONS: The revealed variability of diagnoses and comorbidity in patients with similar complaints deepens the understanding of dyspepsia syndrome and explains the possible ineffectiveness of standard therapy regimens.

The p.Gly2019Ser is a common LRRK2 pathogenic variant among Egyptians with familial and sporadic Parkinson’s disease

The p.Gly2019Ser is a common LRRK2 pathogenic variant among Egyptians with familial and sporadic Parkinson’s disease

Polygenic risk for psychotic disorders in relation to cardiac autonomic dysfunction in unmedicated patients with schizophrenia.

Cardiac autonomic dysfunction (CADF), mainly characterized by increased heart rate, decreased heart rate variability, and loss of vagal modulation, has been extensively described in patients with schizophrenia (SCZ) and their healthy first-degree relatives. As such, it represents an apparent physiological link that contributes to the increased cardiovascular mortality in these patients. Common genetic variation is a putative underlying mechanism, along with lifestyle factors and antipsychotic medications. However, the extent to which CADF is associated with genetic factors for SCZ is unknown. A sample of 83 drug-naive SCZ patients and 96 healthy controls, all of European origin, underwent a 30-minute autonomic assessment under resting conditions. We incorporated parameters from several domains into our model, including time and frequency domains (mean heart rate, low/high frequency ratio) and compression entropy, each of which provides different insights into the dynamics of cardiac autonomic function. These parameters were used as outcome variables in linear regression models with polygenic risk scores (PRS) for SCZ as predictors and age, sex, BMI, smoking status, principal components of ancestry and diagnosis as covariates. Of the three CADF parameters, SCZ PRS was significantly associated with mean heart rate in the combined case/control sample. However, this association was was no longer significant after including diagnosis as a covariate (p = 0.29). In contrast, diagnostic status is statistically significant for all three CADF parameters, accounting for a significantly greater proportion of the variance in mean heart rate compared to SCZ PRS (approximately 16% vs. 4%). Despite evidence for a common genetic basis of CADF and SCZ, we were unable to provide further support for an association between the polygenic burden of SCZ and cardiac autonomic function beyond the diagnostic state. This suggests that there are other important characteristics associated with SCZ that lead to CADF that are not captured by SCZ PRS.

Mutation spectrum and genotype-phenotype correlation of pediatric patients with methylmalonic acidemia.

MMA incidence is significantly greater in China than in the rest of the world, but the mutation spectrum of MMA in China has not yet been mapped. We summarized published MMA-related articles and conducted a systematic meta-analysis of the literature. We analyzed the gene variants information of 926 pediatric MMA patients in China; 517 were children with combined MMA, and 409 were children with isolated MMA. Almost all combined MMA cases were caused by MMACHC gene mutations (cblC-type). The c.609G>A variation was the most common in cblC-type children, accounting for 43.01%, followed by c.658_660delAAG, c.482G>A, c.80A>G, and c.394C>T variations. Mut-type MMA patients accounted for 98.8% (404/409) of all isolated MMA cases. The variant MMUT c.729_730insTT accounted for 10.30% (80/802) of all variants and was the most common variant in mut-type children, followed by c.323G>A and c.1106G>A. Our study summarized and characterized the mutation spectrum of Chinese pediatric patients with MMACHC and MMUT variants, and we also analyzed the relationships between common variants, onset time, and clinical phenotype. These findings will contribute to understanding the phenotypic characteristics and overall pathogenesis of MMA patients, supporting the goal of gene therapy. The incidence of methylmalonic academia (MMA) in China is significantly greater than that in the rest of the world, but the mutation spectrum of MMA in China has not yet been mapped. In this paper, for the first time, we investigated hot-spot gene variants in MMA patients in China and comprehensively described the MMA gene mutation spectrum of the Chinese population. We explored the relationship between MMA genotype and clinical phenotype in patients, providing a basis for family genetic counseling, prenatal diagnosis, and newborn screening.

Evaluating the Joint Effects of Recurrent Copy Number Variants and Polygenic Scores on the Risk of Psychiatric Disorders in the iPSYCH2015 Case-Cohort Sample.

The impact of rare recurrent copy number variants (rCNVs) and polygenic background attributed to common variants, on the risk of psychiatric disorders is well-established in separate studies. However, it remains unclear how polygenic background modulates the effect of rCNVs. Using the population-representative iPSYCH2015 case-cohort sample (N=96,599), we investigated the association between absolute risk of psychiatric disorders and carriage of rCNVs and polygenic scores (PGS), as well as the interaction effect between the two on disease risk. Carriers of rCNVs with higher gene constraint scores had an increased absolute risk for autism, ADHD, and schizophrenia, but not depression, whereas an increase in PGS for each respective disorder was associated with higher absolute risk across all four disorders. Similarly, elevated absolute risks were observed with the increase of both PGS and gene constraints of rCNVs except in the case of depression. In contrast to some previous case-control studies, our joint analysis of rCNV groups and PGS revealed no indication of significant interactive effect between these two factors on disease risk. Also, we found no significant interactions of PGS with any of the most common individual rCNVs, except in the case of 16p13.11 duplication, which was found to attenuate the effect of ADHD-PGS on the absolute risk of ADHD. This study advances our understanding of the interplay between rare and common important genetic risk factors for major psychiatric disorders and sheds light on the importance of population-based samples in implementing precision medicine.

Combination of macro-TSH and macroprolactinemia phenomena in a patient with autoimmune thyroiditis and vitiligo

Laboratory diagnostic methods are the main tools in the practice of a doctor of any specialty, including an endocrinologist. Factors were identified that could change the concentration of the biologically active fraction of the test substance, subsequently complicating the interpretation of laboratory results and making the right clinical decision. The literature describes a variety of circulating autoantibodies involved in binding to pituitary hormones (prolactin (PRL), thyroid-stimulating hormone (TSH), growth hormone, luteinizing, follicle-stimulating, and adrenocorticotropic hormones), hypothalamus (vasopressin and oxytocin), pancreas (insulin and glucagon) , parathyroid glands (parathyroid hormone), as well as with thyroid hormones. As a rule, the resulting macromolecules lead to an increase in laboratory parameters, in which the prevailing fraction of the hormone does not have biological activity, which determines the main problem of this phenomenon. The most common variants include immune complexes with PRL and TSH, causing the phenomena of macroprolactinemia and macrothyrotropinemia (macro-TSH-emia/macro-TSH), respectively. Most laboratory test systems used in clinical practice are capable of determining only the total amount of PRL and TSH. The presented clinical observation describes a combination of the phenomena of macro-TSH and macroprolactinemia in a patient with autoimmune thyroiditis (AIT) and vitiligo.

Model Predictive Control Used in Passenger Vehicles: An Overview

The following article presents a high-level overview of how Model Predictive Control (MPC) is leveraged in passenger vehicles and their subsystems for improved performance. This overview presents the fundamental concepts of MPC algorithms and their common variants. After building some understanding of MPC methods, the paper discusses state-of-the-art examples of how MPC methods are leveraged to perform low- to high-level tasks within a typical passenger vehicle. This review also aims to provide the reader with intuition in formulating MPC systems based on the strengths and weaknesses of the different formulations of MPC. The paper also highlights active areas of research and development.

Thousands of trait-specific KASP markers designed for diverse breeding applications in rice (Oryza sativa).

This study aimed to broaden applicability of KASP for Oryza sativa across diverse genotypes through incorporation of ambiguous (degenerate) bases into their primer designs and to validate 4000 of them for genotyping applications. A bioinformatics pipeline was used to compare 129 rice genomes from 89 countries with the indica reference genome R498 and generate ∼1.6 million KASP designs for the more common variants between R498 and the other genomes. Of the designs, 98,238 were for predicted functional markers. Up to five KASP each for 1024 breeder-selected loci were assayed in a panel of 178 diverse rice varieties, generating 3366 validated KASP. The 84% success rate was within the normal range for KASP demonstrating that the ambiguous bases do not compromise efficacy. The 3366-trait-specific marker panel was applied for population structure analysis in the diversity panel and resolved them into four expected groups. Target variations in thirteen of the genome sequences used for designs were compared with the corresponding KASP genotypes of other accessions of the same thirteen varieties in the diversity panel. There was agreement across 12 varieties for 79% of markers. Ten varieties had high agreement (>88%) but a variety selected from a landrace had only 46.5% agreement. Breeders can now search for the validated KASP and >1 million so-far untested designs across three alternative reference genomes (including Niponbare MSU7), search for designs proximal to previously published SSR markers and retrieve the target variations in 129 rice genomes plus their genomic locations with +/-25 bp flanking sequences.

A phenotypic comparison of the Romanian and French ATTRv cohorts: Glu54Gln founder pathogenic variant vs the most common variants in Western Europe

Aim and methodsWe conducted a retrospective observational study of the ATTRv heterozygous mutation frequency, phenotype, and all-cause mortality at two cardiac amyloidosis centers in Romania and France. Results291 patients were included: 26 Glu54Gln (all Romanian), 200 Val122Ile, 47 Val30Met and 18 Ser77Tyr. On diagnosis, Gu54Gln patients were younger than Val122Ile or late-onset Val30Met (median age: 46 [42–50], 76 [71–80] and 70 [61–76], respectively; p < 0.001) and had more autonomic dysfunction (50 %, 6.3 %, and 7.7 %, respectively; p < 0.001) and similar cardiac symptom profiles. They had fewer conduction disorders (11.5 %) than early-onset Val30Met (76.9 %, p < 0.001) and Ser77Tyr group, notably less cardiac pacemaker present on diagnosis: 3.8 % for Glu54Gln vs. 23.5 % for Ser77Tyr; p = 0.014. Glu54Gln, Val122Ile, late-onset Val30Met and Ser77Tyr patients had similar left ventricular mass and systolic function values. Median survival for Glu54Gln patients was 58.7 years (95 %CI 55.9 – upper bound indeterminable), significantly lower than that of Val122Ile (83.6 years 95 %CI 81.6–85.5, log-rank test p < 0.001), late-onset Val30Met (83.4 years 95 %CI 81.9–84.9, log-rank test p < 0.001) and Ser77Tyr (74.8 years 95 %CI 68.7–80.9, log-rank test p = 0.022). Median survival after diagnosis was 5.7 years for Glu54Gln patients (95 %CI 4.7–6.4). ConclusionWe established that the Glu54Gln variant has an aggressive, mixed phenotype, with an early onset of autonomic dysfunction and heart failure symptoms. We emphasize the need for systematic genetic testing in patients with ATTR as understanding genotype-phenotype correlations is key for the management and the counseling of patients and their family members.

Opportunistic genomic screening has clinical utility: An interventional cohort study

Practice is shifting toward genome-first approaches, such as opportunistic screening for secondary findings (SFs). Analysis of SFs could be extended beyond medically actionable results to include non-medically actionable monogenic disease risks, carrier status, pharmacogenomic variants, and risk variants for common complex disease. However, evidence on the clinical utility of returning these results is lacking. We assessed the outcomes of opportunistic screening for a broad spectrum of SFs by evaluating the yield, impact on clinical management, and consistency between SFs and participants' clinical features and family history. Adult cancer patients had GS with the option to learn multiple categories of SFs. Outcomes data were collected through chart review and participant-reported measures up to one year after return of results. All participants (n=139, 85.6% female, average 54.6 years old) who elected to learn SFs had ≥1 variant reported (100% [139/139]). The yield of reportable findings was highest for pharmacogenomic variants (97.8% [135/138] of participants), followed by common disease risk variants (89.4% [118/132]), carrier status (89.3% [117/131]), and variants related to Mendelian (27.2% [34/125]), medically actionable (15.2% [21/138]), and early-onset neurodegenerative (2.6% [3/117]) disease risks. SFs from the ACMG list (v3.2, non-cancer genes) were reported in 1.4% (2/138) of participants. SFs across all categories demonstrated clinical utility by prompting management changes in 28.1% (39/139) of participants. Moreover, a considerable proportion of participants had suggestive clinical features (49.0% (24/49)]) or family history (21.8% (27/124)) potentially related to their SFs. Our findings indicate there are potential benefits from opportunistic screening for a broad range of SFs.

Straw return can increase maize yield by regulating soil bacteria and improving soil properties in arid and semi-arid areas

Straw return has been found to benefit soil fertility and crop yield, however, by which it affects microbial communities to mediate soil factors driving crop yields under maize continuous cropping systems in dryland areas is still unclear. To fill this gap, a 6-year field experiment was established with five straw return amounts (T0, T1, T2, T3, and T4, representing 0, 3,000, 6,000, 9,000, and 12,000kgha-1 of straw, respectively), and investigated the effects of on soil properties, enzymes, bacterial community composition and diversity, and crop yields. Our analysis showed that soil organic carbon (SOC), total nitrogen (TN), and total phosphorus (TP) contents significantly increased by 1-8%, 5-25%, and 2-9% under straw return treatments, respectively, compared to the T0, and soil catalase, urease, and alkaline phosphatase activities increased by at least 34.00%. Additionally, crop yield significantly increased by 4.23-12.00% under T1-T4 treatments, and showed highly significant relationships with SOC, TN, and TP. Importantly, we found straw return significantly altered the community of bacteria involved in the carbon and nitrogen cycle, and their abundance of strong responses depending on the amounts of straw return. For example, straw input increased the abundance of Proteobacteria (+2.64–5.57%), Acidobacteria (+3.82–13.83%), and Bacteroidetes (+15.37–30.49%). Similarly, the amount of straw application increased the bacterial diversity indexes (Shannon, 2.65–10.93%; Chao1, 13.47–18.50%), and had significant positive correlations with SOC, TN, and TP contents. Structural equation models (SEM) revealed that straw return management practice had positive and indirect effects on crop yields by influencing soil properties or the bacteria community. In conclusion, our findings revealed common associations and variations of bacterial community diversity with soil factors and crop yields at different straw return rates, and these findings provide insights and options for the development of better straw return strategies and sustainable agriculture in semi-arid regions.

CYP2C19 Genetic Variants and Major Depressive Disorder: A Systematic Review

Major depressive disorder (MDD) affects over 300 million people globally and has a multifactorial etiology. The CYP2C19 enzyme, involved in metabolizing certain antidepressants, can influence treatment response. Following the PRISMA protocol and PECOS strategy, this systematic review assessed the variation in common CYP2C19 gene variants’ frequencies across populations with MDD, evaluating their impact on clinical characteristics and treatment response. We comprehensively searched five databases, identifying 240 articles, of which only nine within the last decade met our inclusion criteria. Except for one study that achieved 74.28% of STROPS items, the rest met at least 75% of GRIPS and STROPS guidelines for quality and bias risk assessment. The CYP2C19’s *1 allele, the *1/*1 genotype, and the NM phenotype, considered as references, were generally more frequent. Other CYP2C19 polymorphism frequencies exhibit significant variability across different populations. Some studies associated variants with MDD development, a more extended history of depression, prolonged depressive episodes, and symptom severity, while others reported no such association. Some studies confirmed variants’ effects on escitalopram and citalopram metabolism but not that of other drugs, such as sertraline, venlafaxine, and bupropion. Treatment tolerability and symptom improvement also varied between studies. Despite some common findings, inconsistencies highlight the need for further research to clarify the role of these polymorphisms in MDD and optimize treatment strategies.

Lichen Planus: Health Related Quality of Life, Dermoscopic Features and Clinical Variants in Uganda

Background: Lichen planus is a chronic, lichenoid inflammatory disorder affecting skin, mucous and appendages that can negatively impact patients’ quality of life. The clinical variants and dermoscopic feature vary based on skin type and race. Such an understanding can ease the diagnosis of lichen planus among dark skinned people. Aims and Objective: The goal of this study was to assess the quality of life and to describe the clinical variants and dermoscopic features among adult patients with lichen planus attending a Regional Referral Hospital skin clinic. Methods: A cross-sectional study was conducted from January to June 2024. A questionnaire was used to collect patients’ data, a standardized tool (DLQI) to assess the quality of life, dermoscopy for describing dermoscopic features and data analyzed using Stata version 17.0. Results: We enrolled 52 adult patients, the median age was 34.5 IQR= 25 – 47. There was a significant relationship between itch X2(1, n = 52) =17.5102, p&lt;.001), embarrassment X2(1, n = 52) =9.5510, p&lt;.002) with patients’ impaired quality of life. More patients had a very large effect on their quality of life (36.54%). The most common variants were classical (50%) and hypertrophic (23.08%). On dermoscopy 104 lesions were examined, (25.96%) of lesions had a violet, (22.11%) gray, (15.38%) gray-blue and (15.38%) gray-violet background. The pigmentary changes seen were mostly brown (69.23%). Wickham’s striae patterns were reticulate (21.15%) and diffuse (14.42%). Limitation: A single study site. Conclusions: lichen planus exerts a very large effect on patient’s quality of life. Itchy skin and a feeling of embarrassment significantly affected the quality of life. Classical and hypertrophic were the most common forms of lichen planus. The most lesions had violaceous or a grayish background, and had brown pigments with a reticulate and diffuse wickham’s striae patterns. Routine screening of quality of life should be practiced on patients with lichen planus.

Heritability and genetic contribution analysis of structural-functional coupling in human brain

Abstract The flow of functional connectivity (FC) is thought to be supported by white matter structural connectivity (SC). While research on the correlations between SC and FC (SC-FC coupling) has progressed, the genetic implications of SC-FC coupling have not been thoroughly examined. Traditionally, SC-FC coupling investigations utilize predefined atlases. Here, we adopted an atlas-free SC-FC coupling built on the high-resolution white surface (the interface of white matter and gray matter) to uncover common genetic variations. Leveraging data from the Human Connectome Project, we demonstrated considerable heritability in areas within the early and intermediate visual cortex and across dorsal-attention, language, and somatomotor functional networks. We detected 334 genetic loci (spanning 234 cytogenetic bands) linked to SC-FC coupling (P &amp;lt; 1.26 × 10−11), notably in cingulo-opercular, somatomotor, and default mode networks. Using an external dataset from the Adolescent Brain Cognitive Development study, we confirmed 187 cytogenetic bands associated with SC-FC coupling across 22 brain regions (P &amp;lt; 1 × 10-5). Genetic correlation analyses revealed high genetic interrelatedness for SC-FC coupling in neighboring regions. Furthermore, it showed genetic correlations with a spectrum of complex traits, encompassing various neurological and psychiatric conditions. In essence, our study paves the way towards deciphering the genetic interplay between structural and functional connectivity of the brain.

ΜicroRNA (miRNA) Variants in Male Infertility: Insights from Whole-Genome Sequencing

Background/Objectives: Male infertility is a complex condition with various underlying genetic factors. microRNAs (miRNAs) play a crucial role in gene regulation, and their disruption can significantly impact fertility. This study aimed to identify variants within miRNA genes and elucidate their impact on male infertility. Methods: Whole genome sequencing was performed on blood samples from men with asthenozoospermia, oligozoospermia, and teratozoospermia, compared to normozoospermic controls. The analysis revealed a significant number of unique variants in each infertile group. We subsequently focused on variants in miRNA regions, followed by an in silico analysis to investigate the role of the identified variants and miRNAs in male infertility. Results: Focused analysis on miRNA genes identified 19 exclusive variants in teratozoospermic men, 24 in asthenozoospermic, and 27 in oligozoospermic, all mapping to pre-miRNAs or mature miRNAs. Functional analyses using Gene Ontology (GO) and KEGG pathways highlighted key biological processes and pathways disrupted by these variants and miRNA–mRNA interactions, including transcription regulation, signaling, and cancer-related pathways. Furthermore, six variants (rs17797090, rs1844035, rs7210937, rs451887, rs12233076, and rs6787734) were common across the infertile groups, suggesting their importance in male infertility or their potential as biomarkers. Common variants were also validated in another clinically relevant group of men. Some miRNAs with identified variants, such as hsa-miR-449b and hsa-miR-296, have been previously implicated in male infertility and exhibit differential expression between fertile and infertile men, according to the literature, too. Conclusion: These results provide new insights into the genetic basis of male infertility and open avenues for future research and therapeutic interventions.

Whole exome sequencing identified six novel genes for depressive symptoms.

Previous genome-wide association studies of depression have primarily focused on common variants, limiting our comprehensive understanding of the genetic architecture. In contrast, whole-exome sequencing can capture rare coding variants, helping to explore the phenotypic consequences of altering protein-coding genes. Here, we conducted a large-scale exome-wide association study on 296,199 participants from the UK Biobank, assessing their depressive symptom scores through the Patient Health Questionnaire-4. We identified 22 genes associated with depressive symptoms, including 6 newly discovered genes (TRIM27, UBD, SVOP, ADGRB2, IRF2BPL, and ANKRD12). Both ontology enrichment analysis and plasma proteomics association analysis consistently revealed that the identified genes were associated with immune responses. Furthermore, we identified associations between these genes and brain regions related to depression, such as anterior cingulate cortex and orbitofrontal cortex. Additionally, phenome-wide association analysis demonstrated that TRIM27 and UBD were associated with neuropsychiatric, cognitive, biochemistry, and inflammatory traits. Our findings offer new insights into the potential mechanisms and genetic architecture of depressive symptoms.