Association Of Variants Research Articles

Rare and common genetic variants underlying the risk of Hirschsprung’s disease

Abstract Hirschsprung’s disease (HSCR) is a congenital enteric neuropathic disorder characterized by high heritability (>80%) and polygenic inheritance (>20 genes). The previous genome-wide association studies (GWAS) identified several common variants associated with HSCR and demonstrated increased predictive performance for HSCR risk in Europeans using a genetic risk score, there remains a notable gap in knowledge regarding Chinese populations. We conducted whole exome sequencing in a HSCR case cohort in Chinese. By using the common controls (505 controls from 1KG EAS and 10 588 controls from ChinaMAP), we conducted GWAS for the common variants in the exome and gene-based association for rare variants. We further validated the associated variants and genes in replicated samples and in vitro and vivo experiments. We identified one novel gene PLK5 by GWAS and suggested 45 novel putative genes based the gene-based test. By using genetic variant at RET and PLK5, we constructed a genetic risk score that could identify the individuals with very high genetic risk for HSCR. Compared with patients with zero or one risk allele from the three variants, the risk for HSCR was 36.61 times higher with six alleles. In addition, we delineated a HSCR risk gene landscape that encompasses 57 genes, which explains 88.5% and 54.5% of HSCR in Chinese and European, respectively. In summary, this study improved the understanding of genetic architecture of HSCR and provided a risk prediction approach for HSCR in the Chinese.

Multi-omics analysis in inclusion body myositis identifies mir-16 responsible for HLA overexpression

BackgroundInclusion Body Myositis is an acquired muscle disease. Its pathogenesis is unclear due to the co-existence of inflammation, muscle degeneration and mitochondrial dysfunction. We aimed to provide a more advanced understanding of the disease by combining multi-omics analysis with prior knowledge. We applied molecular subnetwork identification to find highly interconnected subnetworks with a high degree of change in Inclusion Body Myositis. These could be used as hypotheses for potential pathomechanisms and biomarkers that are implicated in this disease.ResultsOur multi-omics analysis resulted in five subnetworks that exhibit changes in multiple omics layers. These subnetworks are related to antigen processing and presentation, chemokine-mediated signaling, immune response-signal transduction, rRNA processing, and mRNA splicing. An interesting finding is that the antigen processing and presentation subnetwork links the underexpressed miR-16-5p to overexpressed HLA genes by negative expression correlation. In addition, the rRNA processing subnetwork contains the RPS18 gene, which is not differentially expressed, but has significant variant association. The RPS18 gene could potentially play a role in the underexpression of the genes involved in 18 S ribosomal RNA processing, which it is highly connected to.ConclusionsOur analysis highlights the importance of interrogating multiple omics to enhance knowledge discovery in rare diseases. We report five subnetworks that can provide additional insights into the molecular pathogenesis of Inclusion Body Myositis. Our analytical workflow can be reused as a method to study disease mechanisms involved in other diseases when multiple omics datasets are available.

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests. We identify 9 genes; 5 with fetal-only effects on birth weight, 1 with maternal-only effects, 3 with both, and observe directionally concordant associations in an independent sample. Four of the genes were previously implicated by GWAS of birth weight. IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (fetal-acting) are involved in adipose tissue regulation, and the latter two also show associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG (fetal-acting) in adipocyte differentiation and placental angiogenesis. NOS3 (fetal and maternal-acting), NRK (fetal), and ADAMTS8 (maternal-acting) have been implicated in placental function and hypertension. To conclude, our analysis of rare coding variants identifies regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, and further evidence for the role of insulin-like growth factors.

PAK3 pathogenic variant associated with sleep-related hypermotor epilepsy in a family with parental mosaicism.

Protein-activated kinases mediate spine morphogenesis and synaptic plasticity. PAK3 is part of the p21-activated kinases (PAKs) family of Ras-signaling serine/threonine kinases. Pathogenic variants in the X-linked gene PAK3 have been described in patients with neurodevelopmental syndromes. We analyzed an Italian family with sleep-related hypermotor epilepsy, intellectual disability, psychiatric and behavioral problems, and dysmorphic facial features. A novel PAK3 c.342_344del (p.Lys114del) inframe deletion was detected in the family. Protein structure analysis supported deleterious impact of p.Lys114 deletion through loss or partial loss of autoinhibition of PAK3 protein kinase activity. The male proband had drug-resistant hypermotor seizures and moderate intellectual disability. His brother had drug-responsive hypermotor seizures and mild intellectual disability. Both brothers were hemizygous and had psychiatric and behavioral problems as well as dysmorphic facial features. Their mother had never had seizures but was shown to be mosaic for the PAK3 pathogenic variant. She had normal intellect but did have short stature and dysmorphic facial features similar to her sons. This is the first reported association of a PAK3 pathogenic variant with sleep-related hypermotor epilepsy. PAK3 testing should be considered in families with suspected X-linked sleep-related hypermotor epilepsy and intellectual disability, including for mosaicism in mildly affected females. PLAIN LANGUAGE SUMMARY: We studied an Italian family with sleep-related hypermotor epilepsy, intellectual disability, psychiatric and behavioral problems, and dysmorphic facial features. A novel PAK3 c.342_344del (p.Lys114del) inframe deletion was detected in the family. Protein structure analysis supported deleterious impact of p.Lys114 deletion through loss or partial loss of autoinhibition of PAK3 protein kinase activity. This is the first reported association of a PAK3 pathogenic variant with sleep-related hypermotor epilepsy. PAK3 testing should be considered in families with suspected X-linked sleep-related hypermotor epilepsy and intellectual disability, including for mosaicism in mildly affected females.

Biallelic variants in AGRN with recurrent pregnancy losses in a family with a fetal akinesia deformation sequence.

Agrin, encoded by AGRN, plays a vital role in the acetylcholine receptor clustering pathway, and any defects in this pathway are known to cause congenital myasthenic syndrome (CMS) 8 in early childhood with variable fatigable muscle weakness. The most severe or lethal form of CMS manifests as a fetal akinesia deformation sequence (FADS). To date, only one family has been reported with an association of null variants in AGRN and a lethal FADS. We identified a nonconsanguineous couple with recurrent pregnancy loss. Detailed phenotyping of fetuses was performed via perinatal autopsy. Genetic evaluation was performed along with split-read analysis to identify variants. Perinatal phenotyping revealed an FADS in the family, and genomic testing identified novel null variants in AGRN. First, whole-exome sequencing revealed the maternally inherited heterozygous variant c.952+1_952+3del in AGRN in fetuses. Split-read analysis of the exome led to the identification of the paternally inherited second variant, a heterozygous deletion of 41.33 kb, encompassing exons 1 and 2 of AGRN. This study highlights the importance of incorporating split-read analysis in clinical practice and emphasizes the association of null variants in AGRN with the FADS. To the best of our knowledge, this is the second report explaining FADS and null variants in AGRN.

Association of MTHFR C677T and A1298C variants with preeclampsia risk and angiogenic imbalance in Tunisian women.

Study cases comprised 675 Tunisian pregnant women, of whom 350 PE presented with PE, and the remaining 325 normotensive women served as controls. Genotyping of C677T and A1298C variants was performed by real-time PCR. There was no statistically significant difference in the minor allele frequencies of C677T and A1298C between preeclampsia cases and controls after adjusting for key covariates. In addition, the prevalence of MTHFR C677T and A1298C minor allele homozygote genotypes was significantly higher in PE cases. The association of 1298C/C, but not 677T/T, with PE persisted after adjusting for the main covariates. Carrying the (minor) 677T allele was associated with marginally higher BMI, significantly higher sFlt-1 serum levels, and median sFlt-1/PlGF ratio and sFlt-1/PlGF ratio≥85. Setting the major allele homozygotes (C677/A1298) as a reference, haplotype analysis demonstrated a higher prevalence of C677/C1298 and T677/C1298 haplotypes (P=0.03) in PE cases compared to controls, which persisted for C677/C1298, but not T677/C1298 after controlling for key covariates. Our results support an association between MTHFR polymorphisms and increased risk of PE, and an imbalance of PE-associated sFLT-1/PlGF.

Genetic variants in PD-1 and its ligands, gene-gene and gene-environment interactions in allergic rhinitis.

The etiology of allergic rhinitis (AR), in which genetic and environmental factors are closely intertwined, has not yet been completely clarified. Programmed cell death 1 (PD-1) and its ligands (PD-L1 and PD-L2) regulate the immune and inflammatory responses during the development of immune-related and atopic diseases. To clarify the associations of genetic variants in PD-1, PD-L1 and PD-L2 with susceptibility to AR, gene-gene and gene-environment interactions were investigated. A total of 452 AR patients and 495 controls were enrolled in this hospital-based case-control study. Eight single nucleotide polymorphisms (SNPs) in the PDCD1, PDCD1LG1 and PDCD1LG2 genes were genotyped. The correlations between SNPs and AR incidence, as well as gene-gene and gene-environment interactions were explored. Differentially expressed genes were screened by the Limma package in two Gene Expression Omnibus (GEO) datasets of AR patients. Expression qualitative trait locus (eQTL) analysis was performed via the Genotype-Tissue Expression (GTEx) database. The rs2297136 (A/G) in PDCD1LG1 was associated with a significantly increased risk of AR, whereas the PDCD1LG2 rs16923189 G allele was associated with a reduced risk of AR. In the subgroups according to AR-related phenotypes, the rs2297136 G allele increased, while the rs16923189 G allele reduced AR risk. Gene-gene interactions and gene-environment interactions (e.g., PDCD1LG1 polymorphisms with factors such as smoke, main road and cooking fumes) were verified in AR patients, but they were not significant after Bonferroni correction. PDCD1LG1 rs2297136 and PDCD1LG2 rs16923189 are associated with susceptibility to AR in this Chinese population. The PD-1/PD-L1 and PD-1/PD-L2 signaling pathways may regulate gene-gene and gene-environment interactions in the pathogenesis of AR.

Whole-genome sequencing identifies novel loci for keratoconus and facilitates risk stratification in a Han Chinese population.

Keratoconus (KC) is a prevalent corneal condition with a modest genetic basis. Recent studies have reported significant genetic associations in multi-ethnic cohorts. However, the situation in the Chinese population remains unknown. This study was conducted to identify novel genetic variants linked to KC and to evaluate the potential applicability of a polygenic risk model in the Han Chinese population. A total of 830 individuals diagnosed with KC and 779 controls from a Chinese cohort were enrolled and genotyped by whole-genome sequencing(WGS). Common and rare variants were respectively subjected to single variant association analysis and gene-based burden analysis. Polygenic risk score (PRS) models were developed using top single-nucleotide polymorphisms (SNPs) identified from a multi-ethnic meta-analysis and then evaluated in the Chinese cohort. The characterization of germline variants entailed correction for population stratification and validation of the East Asian ancestry of the included samples via principal component analysis. For rare protein-truncating variants (PTVs) with minor allele frequency (MAF) < 5%, ZC3H11B emerged as the top prioritized gene, albeit failing to reach the significance threshold. We detected three common variants reaching genome-wide significance (P ≤ 5 × 10-8), all of which are novel to KC. Our study validated three well known predisposition loci, COL5A1, EIF3A and FNDC3B. Additionally, a significant correlation of allelic effects was observed for suggestive SNPs between the largest multi-ethnic meta-genome-wide association study (GWAS) and our study. The PRS model, generated using top SNPs from the meta-GWAS, stratified individuals in the upper quartile, revealing up to a 2.16-fold increased risk for KC. Our comprehensive WGS-based GWAS in a large Chinese cohort enhances the efficiency of array-based genetic studies, revealing novel genetic associations for KC and highlighting the potential for refining clinical decision-making and early prevention strategies.

Association of Novel Pathogenic Variant (p. Ile366Asn) in PLA2G6 Gene with Infantile Neuroaxonal Dystrophy.

A couple presented to the office with an apparently healthy infant for a thorough clinical assessment, as they had previously lost two male children to a neurodegenerative disorder. They also reported the death of a male cousin abroad with a comparable condition. We aimed to evaluate a novel coding pathogenic variant c.1097T>A, PLA2G6, within the affected family, previously identified in a deceased cousin, but its clinical significance remained undetermined. A 200 bp PCR product of target genome (including codon 366 of PLA2G6) was amplified followed by enzymatic digestion (MboI) and sequencing. Structural pathogenic variant analysis was performed using PyMOL 2.5.4. In RFLP analysis, the mutant-type allele produced a single band of 200 bp, and the wild-type allele manifested as two bands of 112 bp and 88 bp. The pathogenic variant was identified in nine family members, including two heterozygous couples with consanguineous marriages resulting in affected children. It was predicted to be deleterious by multiple bioinformatic tools. The substitution of nonpolar isoleucine with polar asparagine of iPLA2 (Ile366Asn) resulted in a eense pathogenic variant (ATC>AAC). A missense variant (p. Ile366Asn) in the PLA2G6 gene is associated with clinically evident infantile neuroaxonal dystrophy, which is transmitted in an autosomal recessive pattern, and is also predicted to be dysfunctional by bioinformatic analyses.

Investigating the association of VHL gene variants with disease risk and clinicopathological outcomes in ccRCC patients from West Bengal, India.

Clear cell renal cell carcinoma (ccRCC) is a prevalent and aggressive malignancy, with the von Hippel-Lindau (VHL) gene playing a critical role in its pathogenesis. However, the association between VHL gene variants and sporadic ccRCC risk remains unexplored in the Indian population. This study aimed to investigate the somatic and germline variants of the VHL gene in sporadic ccRCC patients from West Bengal, India, and their association with disease risk and clinicopathological parameters. A total of 210 ccRCC patients and 255 ethnicity-matched healthy controls were enrolled. Genomic DNA from blood and tissue samples was analyzed using PCR-based Sanger sequencing. The association of VHL variants with ccRCC risk was assessed using Chi-square tests. The impact of genetic variants on patient clinicopathological features and overall survival was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models. We identified twenty-three single nucleotide variants (SNVs) in the VHL gene, including 3 novel variants, OR250433 T > G, OR125589 C > T and OQ627404 G > C. The intronic variant rs61758376 G > C and 3'UTR variant rs1642742 A > G were significantly associated with an increased risk of ccRCC (OR = 1.676, P = 0.0074; OR = 1.735, P = 0.0171, respectively). The rs1642742 GG genotype was also significantly associated with larger tumor size (P < 0.05) and advanced tumor stage (pT4). Kaplan-Meier analysis indicated poorer overall survival for patients with the rs1642742 GG genotype (log-rank P = 0.029). Our study is the first to document the association of VHL gene variants with sporadic ccRCC risk and clinical outcomes in the Indian population. The identified variants, particularly rs61758376 and rs1642742, could serve as potential biomarkers for ccRCC susceptibility and prognosis.

Exploring the relationship between melanopsin gene variants, sleep, and markers of brain health

AbstractINTRODUCTIONMelanopsin is a photopigment with roles in mediating sleep and circadian‐related processes, which are often disrupted in Alzheimer's disease (AD). Melanopsin also impacts cognition and synaptogenesis. This study investigated the associations between melanopsin genetic variants, sleep, and markers of brain health.METHODSLinear regression analyses examined the relationship of single‐nucleotide polymorphisms (SNPs) within the melanopsin gene (OPN4), with cortical amyloid beta (Aβ), cognition, brain volumes, and self‐reported sleep traits in cognitively unimpaired older adults. Further analyses assessed whether sleep traits x OPN4 SNP interactions were associated with markers of brain health.RESULTSOPN4 SNPs rs2355009 and rs3740334 were associated with attention and processing speed and ventricular volume and language, respectively. Furthermore, rs3740334 and rs1079610 showed significant interactions with sleep traits in association with language.DISCUSSIONThis study shows associations of OPN4 genetic variants with markers of brain health, and suggests that these variants interact with sleep to exacerbate cognitive effects.Highlights The relationships between melanopsin gene (OPN4) variants and markers of brain health were examined cross‐sectionally in cognitively unimpaired older individuals. Variation within OPN4is associated with differences in cognition and ventricular volume. rs2355009 and rs3740334 show small–moderate associations with differences in attention and processing speed. Further to this, rs2355009 and rs3740334 were associated with ventricular volumes and language performance, respectively. The interactions between rs3740334 and rs1079610 and sleep traits also showed small–moderate associations with differences in language performance.

The impact of common and rare genetic variants on bradyarrhythmia development

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (rg = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.

BEST1 VARIANT ASSOCIATED WITH AN ATYPICAL MACULAR AND PERIPHERAL RETINAL PHENOTYPE.

Best vitelliform macular dystrophy is an inherited macular dystrophy associated with over 250 pathogenic variants of the Bestrophin-1 ( BEST1 ) gene. Although several types of lesions of best vitelliform macular dystrophy are well-described, reports of phenotypic variations associated with rare genetic variants are limited. This was a retrospective case series performed in 2021 at a tertiary eye care center. Three members of one family referred to a tertiary eye care clinic for evaluation of their autosomal dominant macular dystrophy. Study subjects presented with atypical findings of peripheral schisis-like lesions and atrophy with abnormal electroretinogram in addition to typical macular lesions found in best vitelliform macular dystrophy. Genetic analyses identified a heterozygous BEST1 c.227T>A, p.(Ile76Asn) pathogenic variant in all three subjects. This study represents the first report of the phenotype associated with the c.227T>A, p.(Ile76Asn) BEST1 variant, which-while mentioned twice in the literature-has not been previously described. The phenotype is unique, comprising features of typical best vitelliform macular dystrophy with electroretinogram and peripheral findings, suggestive of a panretinal dysfunction.

Breast Cancer Susceptibility Gene Sequence Variations and Development of Contralateral Breast Cancer

Heterogeneity in development of estrogen receptor (ER)-specific first primary breast cancer exists due to deleterious germline variants in moderate- to high-penetrance breast cancer susceptibility genes, but it is unknown if these associations occur in ER-specific CBC. To determine the association of deleterious germline variants in breast cancer susceptibility genes with ER-specific CBC development and whether ER status of the first primary breast cancer modifies these associations. This case-control study included CBC cases and matched unilateral breast cancer controls from The Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based case-control study. Eligible women were diagnosed between 1985 and 2000 with data and biospecimens collected from 2001 to 2004. Eligible participants were women younger than 55 years at first invasive breast cancer diagnosis. Participants were matched on age, diagnosis year, cancer registry region, and race and ethnicity, and countermatched on radiation treatment. For cases, CBC occurred 1 year or more following first breast cancer diagnosis. Analyses were performed from May to October 2024. CHEK2 1100delC and deleterious variants in ATM, BRCA1, and BRCA2. Development of CBC, measured as a rate ratio (RR). A total of 1290 women were included in analysis (median [IQR] age at first diagnosis, 47 [42-51] years). The ER-positive CBC rate for women with deleterious ATM variants was 4 times higher than for women without deleterious ATM variants (RR, 4.84; 95% CI, 1.11-21.08; P = .04); no women with ER-negative CBC carried deleterious ATM variants. The ER-positive CBC rates for women with deleterious variants in BRCA2 or CHEK2 1100delC were 5 to 6 times higher than for women without deleterious variants in BRCA2 or CHEK2 1100delC, respectively (BRCA2: RR, 5.88; 95% CI, 2.61-13.26, P < .001; CHEK2 1100delC: RR, 6.06; 95% CI, 1.26-29.04; P = .02). The ER-negative CBC rate for women with deleterious BRCA1 variants was 26 times higher than for women without deleterious BRCA1 variants (RR, 26.16; 95% CI, 8.01-85.44; P < .001). First primary breast cancer ER status did not modify associations between deleterious variants and ER-specific CBC development. In this case-control study of CBC, deleterious variants in breast cancer susceptibility genes were differentially associated with ER-specific CBC development. Germline variation profile may inform estimates of outcomes for ER-specific CBC subtypes.

Disentangling the genetic overlap between ischemic stroke and obesity

ObjectiveObesity has been recognized as a risk factor for cerebrovascular diseases, with observational studies suggesting a heightened incidence of stroke. However, the genetic epidemiology field has yet to reach a consensus on the causal relationship and genetic overlap between ischemic stroke (IS) and obesity.MethodsWe utilized linkage disequilibrium score regression, high-definition likelihood, and local analysis of variant associations to assess the genetic correlation between body mass index (BMI) and IS. Bidirectional Mendelian randomization was employed to infer causality. We identified shared risk single nucleotide polymorphisms (SNPs) through cross-trait meta-analyses and estimated heritability using summary statistics. Summary-data-based Mendelian randomization (SMR) was applied to explore potential functional genes.ResultsOur analysis revealed a significant positive genetic correlation between BMI and IS, supporting a causal link from BMI to IS. Cross-trait analysis yielded 9 and 16 shared risk SNPs for IS and small vessel stroke (SVS), respectively. We observed a notable enrichment of SNP heritability for IS and BMI in brain tissues, suggesting tissue-specific influences. The genes shared between the traits were predominantly involved in brain development, synaptic electrical activity, and immunoregulation. Notably, our SMR analysis identified the risk genes CHAF1A, CEP192, ULK4, CYP2D6, AS3MT, and WARS2 across the majority of the 14 enriched tissues shared by both traits.ConclusionOur study uncovered a significant genetic correlation and identified shared risk SNPs between BMI and IS. The identification of CHAF1A, CEP192, ULK4, CYP2D6, AS3MT, and WARS2 as potential functional genes common to both obesity and IS enriched our understanding of their genetic interplay, potentially advanced our grasp of their pathogenesis and therapeutic targets.

Lack of association between common polymorphisms associated with successful aging and longevity in the population of Sardinian Blue Zone

More than two decades ago, in the central-eastern region of the Mediterranean island of Sardinia, a mountain area was identified where the population displays exceptional longevity, especially among men (the Longevity Blue Zone, LBZ). This community was thoroughly investigated to understand the underlying causes of the phenomenon. The present study analyzed 11 genetic markers previously associated with increased survival in several long-lived populations. APOE (rs429358 and rs7412), APOE promoter (rs449647, rs769446, and rs405509), ACE1 (rs1799752), IL6 ‒174G/C (rs1800795), TNFα ‒308G/A (rs1800629), FOXO3A (rs2802292), KLOTHO (rs9536314) and G6PD (rs5030868) polymorphisms were investigated. PCR-based genotyping was performed following genomic DNA extraction from 150 nonagenarians living in the LBZ and 150 controls from a nearby area. No significant deviation in the frequency of the analyzed markers was detected between the two subgroups except for a weak association with the − 174G > C gene variant in the IL-6 gene (p = 0.040), which codes for a major modulator of the inflammatory response. Overall, the findings of this study do not support a significant association of known genetic variants on survival in the population of the Sardinian LBZ, suggesting that other genetic or epigenetic traits not yet identified might play a role.

Transcriptomic and genetic profiling in a spontaneous non-human primate model of hypertrophic cardiomyopathy and sudden cardiac death

Hypertrophic cardiomyopathy (HCM) afflicts humans, cats, pigs, and rhesus macaques. Disease sequelae include congestive heart failure, thromboembolism, and sudden cardiac death (SCD). Sarcomeric mutations explain some human and cat cases, however, the molecular basis in rhesus macaques remains unknown. RNA-Seq of the LV tissues of five HCM-affected and seven healthy control rhesus macaques was employed for differential transcriptomic analyses. DNA from 15 severely HCM-affected and 21 healthy geriatric rhesus macaques were selected for whole-genome sequencing. A genome-wide association study (GWAS) of disease status and SCD outcome was performed. 614 down- and 1,065 upregulated differentially expressed genes (DEGs) were identified between groups. The top DEG (MAFF) was overexpressed in affected animals (log2FoldChange = 4.71; PAdjusted-value = 1.14E-133). Channelopathy-associated enriched terms were identified in ~ 57% of downregulated DEGs providing transcriptomic evidence of hypertrophic and arrhythmic disease processes. For GWAS, no putative variant withstood segregation. Polygenic modeling analysis resulted in poor prediction power and burden testing could not explain HCM by an association of multiple variants in any gene. Neither single nor compound genetic variant(s), or identified polygenic profile, suggest complex genotype–phenotype interactions in rhesus macaques. Brought forth is an established dataset of robustly phenotyped rhesus macaques as an open-access resource for future cardiovascular disease genetic studies.

Gene variability of natriuretic peptides in patients with rheumatic heart disease and atrial fibrillation

Introduction: Atrial fibrillation (AF) is one of the most common arrhythmias in rheumatic heart disease (RHD) patients. The pathophysiological mechanisms of AF development against the background of RHD are still understudied. Similarly to most cardiovascular pathologies, AF is a multifactorial disease with a significant genetic predeterminacy.Objective: The study was aimed at searching for associations of polymorphic gene variants of the natriuretic peptides (NPPA, NPPB and NPPC) with the AF risk in RHD patients. Methods: The study included 251 patients diagnosed with RHD, who were divided into 2 groups: patients with RHD and AF (n = 191) and patients with RHD without AF (n = 60). Genotyping of 7 allelic variants of genes encoding natriuretic peptides was performed using real-time polymerase chain reaction.Results: Polymorphic variants rs198388 and rs198389 of the NPPB gene were found to have a protective effect against the AF in RHD patients on the model of a codominant inheritance. The rs198358 allelic variant of the NPPA-AS1 gene was associated with the two-fold increased AF risk in RHD patients (OR 1.96, 95% CI 1.02-3.75, p = 0.037). Two models of gene-gene interactions characterized by the high efficacy and sensitivity have been identified in this study. The most significant combinations of genotypes associated with an increased AF risk in RHD patients were rs198388 C/T × rs198389 A/G × rs198358 T/C × rs5063 C/C × rs632793 A/G and rs198388 C/T × rs198358 T/ C × rs5063 C/C.Conclusion: Polymorphic gene variants of the natriuretic peptides (NPPB rs198388, rs198389 and NPPA-AS1 rs198358), associated with AF risk, were identified in RHD patients. Three-locus (NPPB rs198388, NPPA-AS1 rs198358 and NPPA rs5063) and five-locus (NPPB rs198388, NPPB rs198389, NPPA-AS1 rs198358, NPPA rs5063 and NPPA rs632793) models of gene-gene interactions were associated with the studied phenotype. Received 16 April 2024. Revised 10 October 2024. Accepted 2 November 2024. FundingThis research was supported by the Complex Program of Fundamental Research of the Siberian Branch of the Russian Academy of Sciences within the framework of the fundamental research project of the Research Institute for Complex Issues of Cardiovascular Diseases No. 0419-2022-0001. Conflict of interestThe authors declare no conflict of interest. Contribution of the authorsConception and study design: A.V. Sinitskaya, M.V. KhutornayaData collection and analysis: O.N. Hryachkova, A.O. Poddubnyak, M.V. Khutornaya, M.A. Asanov Statistical analysis: A.V. SinitskayaDrafting the article: A.V. SinitskayaCritical revision of the article: M.Yu. SinitskyFinal approval of the version to be published: A.V. Sinitskaya, M.V. Khutornaya, O.N. Hryachkova, A.O. Poddubnyak, M.A. Asanov, M.Yu. Sinitsky

GeniePool 2.0: advancing variant analysis through CHM13-T2T, AlphaMissense, gnomAD V4 integration, and variant co-occurrence queries.

Originally developed to meet the challenges of genomic data deluge, GeniePool emerged as a pioneering platform, enabling efficient storage, accessibility, and analysis of vast genomic datasets, enabled due to its data lake architecture. Building on this foundation, GeniePool 2.0 advances genomic analysis through the integration of cutting-edge variant databases, such as CHM13-T2T, AlphaMissense, and gnomAD V4, coupled with the capability for variant co-occurrence queries. This evolution offers an unprecedented level of granularity and scope in genomic analyses, from enhancing our understanding of variant pathogenicity and phenotypic associations to facilitating research collaborations. The introduction of CHM13-T2T provides a more accurate reference for human genetic variation, AlphaMissense enriches the platform with protein-level impact predictions of missense mutations, and gnomAD V4 offers a comprehensive view of human genetic diversity. Additionally, the innovative feature for variant co-occurrence analysis is pivotal for exploring the combined effects of genetic variations, advancing our comprehension of compound heterozygosity, epistasis, and polygenic risk factors in disease pathogenesis. GeniePool 2.0 is a comprehensive and scalable platform, which aims to enhance genomic data analysis and contribute to genomic research, potentially supporting new discoveries and clinical innovations. Database URL: https://GeniePool.link.

Association and function analysis of genetic variants and the risk of gestational diabetes mellitus in a southern Chinese population.

Gestational diabetes mellitus (GDM) is a complex metabolic disease that has short-term and long-term adverse effects on mothers and infants. However, the specific pathogenic mechanism has not been elucidated. The aim of this study was to confirm the associations between candidate genetic variants (rs4134819, rs720918, rs2034410, rs11109509, and rs12524768) and GDM risk and prediction in a southern Chinese population. Candidate variants were genotyped in 538 GDM cases and 626 healthy controls. The odds ratio (OR) and its corresponding 95% confidence interval (CI) were calculated to assess the associations between genotypes and GDM risk. Then, the false-positive report probability (FPRP) analysis was adopted to confirm the significant associations, and bioinformatics tools were used to explore the potential biological function of studied variants. Finally, risk factors of genetic variants and clinical indicators identified by logistics regression were used to construct a nomogram model for GDM prediction. It was shown that the XAB2 gene rs4134819 was significantly associated with GDM susceptibility (CT vs. CC: adjusted OR = 1.38, 95% CI: 1.01-1.87, p = 0.044; CT/TT vs. CC: crude OR = 1.42, 95% CI: 1.08-1.86, p = 0.013). Functional analysis suggested that rs4134819 can alter the specific transcription factors (CPE bind and GATE-1) binding to the promoter of the XAB2 gene, regulating the transcription of XAB2. The nomogram established with factors such as age, FPG, HbA1c, 1hPG, 2hPG, TG, and rs4134819 showed a good discriminated and calibrated ability with an area under the curve (AUC) = 0.931 and a Hosmer-Lemeshow test p-value > 0.05. The variant rs4134819 can significantly alter the susceptibility of the Chinese population to GDM possibly by regulating the transcription of functional genes. The nomogram prediction model constructed with genetic variants and clinical factors can help distinguish high-risk GDM individuals.