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This study presents the findings of a newborn screening (NBS) pilot project for 5q-spinal muscular atrophy (5q-SMA) in multiple regions across Russia for during the year 2022. The aim was to assess the feasibility and reproducibility of NBS for SMA5q in diverse populations and estimate the real prevalence of 5q-SMA in Russia as well as the distribution of patients with different number of SMN2 copies. The pilot project of NBS here was based on data, involving the analysis of 202,908 newborns. SMA screening assay was performed using a commercially available real-time polymerase chain reaction kit, the Eonis SCID-SMA. In one year, 202,908 newborns were screened, identifying 26 infants with homozygous deletion of SMN1 exon 7, yielding an estimated 5q-SMA incidence of 1:7804 newborns. It was found that 38.46% had two SMN2 copies, 42.31% had three copies, 15.38% had four copies, and 3.85% had five copies of SMN2. Immediate treatment was proposed for patients with two or three SMN2 copies. Infants with four or more SMN2 copies warranted further investigation on management and treatment. Short-term monitoring after gene therapy showed motor function improvements. Delays in treatment initiation were observed, including the testing for adeno-associated virus 9 antibodies and nonmedical factors. The study emphasizes the need for a standardized algorithm for early diagnosis and management through NBS to benefit affected families. Overall, the NBS program for 5q-SMA in Russia demonstrated the potential to improve outcomes and transform SMA from a devastating disease to a chronic condition with evolving medical requirements. [ABSTRACT FROM AUTHOR]

La spondyloarthrite est une maladie à médiation immunitaire caractérisée par une forte héritabilité, comme en témoigne sa fréquente agrégation familiale. Les études familiales offrent donc un outil intéressant pour clarifier les bases génétiques de la spondyloarthrite. Elles ont notamment permis d'évaluer l'importance relative des facteurs génétiques et environnementaux, et d'établir le caractère polygénique de la maladie. Les analyses de liaison sont la méthode privilégiée dans les études familiales en vue d'identifier des facteurs génétiques de prédisposition. Dans la spondyloarthrite, trois études de liaison pangénomiques ont été publiées dans les années 1990, avec malheureusement des résultats peu reproductibles. Abandonnées pendant quelques années au profit des études d'association génome entier cas-témoin, les approches familiales suscitent actuellement un regain d'intérêt, notamment pour détecter des associations avec des variants rares. La présente revue récapitule la contribution des études familiales à la compréhension de la génétique des spondyloarthrites, depuis les études d'épidémiologie génétique jusqu'aux plus récentes analyses de variants rares. Elle met aussi en évidence l'intérêt potentiel de la présence d'antécédents familiaux de spondyloarthrite pour guider le diagnostic et l'identification de patients ayant un risque élevé de déclarer la maladie. Spondyloarthritis (SpA) is an immune-mediated disease characterized by a high heritability, reflected by strong familial aggregation. Therefore, family studies are a powerful tool for elucidating the genetic basis of SpA. First, they helped to assess the relative importance of genetic and environmental factors, and established the polygenic character of the disease. Family-based designs were also historically used to identify genetic factors of susceptibility through linkage analyses. In SpA, three whole genome linkage studies were published in the 1990s, unfortunately with few consistent results. After having been put aside for several years in favour of case-control GWAS, there is a renewed interest in family-based designs in particular to detect rare variant associations. This review aims at summarizing what family studies have brought to the field of SpA genetics, from genetic epidemiology studies to the most recent rare variant analyses. It also highlights the potential interest of family history of SpA to help diagnosis and detection of patients at high risk to develop the disease. [ABSTRACT FROM AUTHOR]

Molecular markers for genotyping malaria parasites have enabled detailed and informative studies of infection epidemiology and transmission dynamics. Genotyping delivers critical data for public health to optimize and enhance malaria control and elimination strategies. Whole-genome sequencing (WGS), although comprehensive, is not suitable for epidemiological use cases as it is time-consuming, requires specialist skills, and is not cost effective. Genetic marker approaches are affordable, attainable, and targeted; however, they have specific features that make them suitable for some use cases but not others. Over recent years, progress in molecular markers for genotyping malaria parasites has enabled informative studies of epidemiology and transmission dynamics. Results have highlighted the value of these tools for surveillance to support malaria control and elimination strategies. There are many different types and panels of markers available for malaria parasite genotyping, and for end users, the nuances of these markers with respect to 'use case', resolution, and accuracy, are not well defined. This review clarifies issues surrounding different molecular markers and their application to malaria control and elimination. We describe available marker panels, use cases, implications for different transmission settings, limitations, access, cost, and data accuracy. The information provided can be used as a guide for molecular epidemiology and surveillance of malaria. [ABSTRACT FROM AUTHOR]

To identify age-related macular degeneration (AMD) risk loci and to establish a polygenic prediction model. Genome-wide association study (GWAS) and polygenic risk score (PRS) construction. We included 64 885 European patients with AMD and 568 740 control participants (with overlapped samples) in the UK Biobank, Genetic Epidemiology Research on Aging (GERA), International AMD Consortium, FinnGen, and published early AMD GWASs in meta-analyses, as well as 733 European patients with AMD and 20 487 control participants from the Canadian Longitudinal Study on Aging (CLSA) and non-Europeans from the UK Biobank and GERA for polygenic risk score validation. A multitrait meta-analysis of GWASs comprised 64 885 patients with AMD and 568 740 control participants; the multitrait approach accounted for sample overlap. We constructed a PRS for AMD based on both previously reported as well as unreported AMD loci. We applied the PRS to nonoverlapping data from the CLSA. We identified several single nucleotide polymorphisms associated with AMD and established a PRS for AMD risk prediction. We identified 63 AMD risk loci alongside the well-established AMD loci CFH and ARMS2 , including 9 loci that were not reported in previous GWASs, some of which previously were linked to other eye diseases such as glaucoma (e.g., HIC1). We applied our PRS to nonoverlapping data from the CLSA. A new PRS was constructed using the PRS method, PRS-CS, and significantly improved the prediction accuracy of AMD risk compared with PRSs from previously published datasets. We further showed that even people who carry all the well-known AMD risk alleles at CFH and ARMS2 vary considerably in their AMD risk (ranging from close to 0 in individuals with low PRS to > 50% in individuals with high PRS). Although our PRS was derived in individuals of European ancestry, the PRS shows potential for predicting risk in people of East Asian, South Asian, and Latino ancestry. Our findings improve the knowledge of the genetic architecture of AMD and help achieve better accuracy in AMD prediction. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

This review explores the criteria used for the selection of genetic instruments of sleep traits in the context of Mendelian randomisation studies. This work was motivated by the fact that instrument selection is the most important decision when designing a Mendelian randomisation study. As far as we are aware, no review has sought to address this to date, even though the number of these studies is growing rapidly. The review is divided into the following sections which are essential for genetic instrument selection: 1) Single-gene region vs polygenic analysis; 2) Polygenic analysis: biologically-vs statistically-driven approaches; 3) P-value; 4) Linkage disequilibrium clumping; 5) Sample overlap; 6) Type of exposure; 7) Total (R2) and average strength (F-statistic) metrics; 8) Number of single-nucleotide polymorphisms; 9) Minor allele frequency and palindromic variants; 10) Confounding. Our main aim is to discuss how instrumental choice impacts analysis and compare the strategies that Mendelian randomisation studies of sleep traits have used. We hope that our review will enable more researchers to take a more considered approach when selecting genetic instruments for sleep exposures. • MR studies have shown causal associations between sleep and several health outcomes. • We reviewed the criteria for selecting instruments for sleep traits in MR studies. • We demonstrated the importance of careful genetic instrument selection. [ABSTRACT FROM AUTHOR]

The European Society of Pediatric Infectious Diseases (ESPID) hosted the third Group B Streptococcus (GBS) Research Session in Athens on 11th May 2022, providing researchers and clinicians from around the world an opportunity to share and discuss recent advances in GBS pathophysiology, molecular and genetic epidemiology and how these new insights can help in improving prevention and control of early- and late-onset GBS disease. The meeting provided a state-of-the-art overview of the existing GBS prevention strategies and their limitations, and an opportunity to share the latest research findings. The first presentation provided an overview of current GBS prevention and treatment strategies. In the second presentation, the genomic and antimicrobial resistance profiles of invasive and colonizing GBS strains were presented. The third presentation explained the association of intrapartum antibiotic prophylaxis (IAP) with the development of late-onset disease (LOD) and the interplay of host innate immunity and GBS. The fourth presentation evaluated the role of genomics in understanding horizontal GBS transmission. The fifth presentation focused on the zoonotic links for certain GBS lineages and the last presentation described the protective role of breastmilk. Talks were followed with interactive discussions and concluded with recommendations on what is needed to further GBS clinical research; these included: (i) the development of better risk stratification methods by combining GBS virulence factors, serological biomarkers and clinical risk factors; (ii) further studies on the interplay of perinatal antimicrobials, disturbances in the development of host immunity and late-onset GBS disease; (iii) routine submission of GBS isolates to reference laboratories to help in detecting potential clusters by using genomic sequencing; (iv) collaboration in animal and human GBS studies to detect and prevent the emergence of new pathogenic sequence types; and (v) harnessing the plethora of immune factors in the breastmilk to develop adjunct therapies. [ABSTRACT FROM AUTHOR]

Background: Malaria outbreaks are important public health concerns that can cause resurgence in endemic regions approaching elimination. We investigated a Plasmodium falciparum outbreak in Attapeu Province, Laos, during the 2020-21 malaria season, using genomic epidemiology methods to elucidate parasite population dynamics and identify its causes.Methods: In this genetic analysis, 2164 P falciparum dried blood spot samples were collected from southern Laos between Jan 1, 2017, and April 1, 2021, which included 249 collected during the Attapeu outbreak between April 1, 2020, and April 1, 2021, by routine surveillance. Genetic barcodes obtained from these samples were used to investigate epidemiological changes underpinning the outbreak, estimate population diversity, and analyse population structure. Whole-genome sequencing data from additional historical samples were used to reconstruct the ancestry of outbreak strains using identity-by-descent analyses.Findings: The outbreak parasite populations were characterised by unprecedented loss of genetic diversity, primarily caused by rapid clonal expansion of a multidrug-resistant strain (LAA1) carrying the kelch13 Arg539Thr (R539T) mutation. LAA1 replaced kelch13 Cys580Tyr (C580Y) mutants resistant to dihydroartemisinin-piperaquine (KEL1/PLA1) as the dominant strain. LAA1 inherited 58·8% of its genome from a strain circulating in Cambodia in 2008. A secondary outbreak strain (LAA2) carried the kelch13 C580Y allele, and a genome that is essentially identical to a Cambodian parasite from 2009. A third, low-frequency strain (LAA7) was a recombinant of KEL1/PLA1 with a kelch13 R539T mutant.Interpretation: These results strongly suggest that the outbreak was driven by a selective sweep, possibly associated with multidrug-resistant phenotypes of the outbreak strains. Established resistant populations can circulate at low frequencies for years before suddenly overwhelming dominant strains when the conditions for selection become favourable-eg, when front-line therapies change. Genetic surveillance can support elimination by characterising key properties of outbreaks such as population diversity, drug resistance marker prevalence, and the origins of outbreak strains.Funding: Bill & Melinda Gates Foundation; The Global Fund to Fight AIDS, Tuberculosis and Malaria; Wellcome Trust.Translation: For the Lao translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

The American College of Epidemiology held its 2021 Annual Meeting virtually, September 8–10, with a conference theme of 'From Womb to Tomb: Insights from Health Emergencies'. The American College of Epidemiology Ethics Committee hosted a symposium session in recognition of the ethical and social challenges brought to light by the coronavirus disease 2019 pandemic and on the occasion of the publication of the third edition of the classic text, Ethics and Epidemiology. The American College of Epidemiology Ethics Committee invited the book editor and contributing authors to present at the symposium session titled 'Current Ethical and Social Issues in Epidemiology.' The purpose of this paper is to further highlight the ethical challenges and presentations. Three speakers with expertise in ethics, health law, health policy, global health, health information technology, and translational research in epidemiology and public health were selected to present on the social and ethical issues in the current landscape. Dr. S Coughlin presented on the 'Ethical and Social Issues in Epidemiology', Dr. L Beskow presented on 'Ethical Challenges in Genetic Epidemiology', and Dr. K Goodman presented on the 'Ethics of Health Informatics'. New digital sources of data and technologies are driving the ethical challenges and opportunities in epidemiology and public health as it relates to the three emerging topic areas identified: (1) digital epidemiology, (2) genetic epidemiology, and (3) health informatics. New complexities such as the reliance on social media to control infectious disease outbreaks and the introduction of computing advancements are requiring re-evaluation of traditional bioethical frameworks for epidemiology research and public health practice. We identified several cross-cutting ethical and social issues related to informed consent, benefits, risks and harms, and privacy and confidentiality and summarized these alongside more nuanced ethical considerations such as algorithmic bias, group harms related to data (mis)representation, risks of misinformation, return of genomic research results, maintaining data security, and data sharing. We offered an integrated synthesis of the stages of epidemiology research planning and conduct with the ethical issues that are most relevant in these emerging topic areas. New realities exist for epidemiology and public health as professional groups who are faced with addressing population health, and especially given the recent pandemic and the widespread use of digital tools and technologies. Many ethical issues can be understood in the context of existing ethical frameworks; however, they have yet to be clearly identified or connected with the new technical and methodological applications of digital tools and technologies currently in use for epidemiology research and public health practice. To address current ethical challenges, we offered a synthesis of traditional ethical principles in public health science alongside more nuanced ethical considerations for emerging technologies and aligned these with lifecycle stages of epidemiology research. By critically reflecting on the impact of new digital sources of data and technologies on epidemiology research and public health practice, specifically in the control of infectious outbreaks, we offered insights on cultivating these new areas of professional growth while striving to improve population health. [ABSTRACT FROM AUTHOR]

Consumption of nicotine, alcohol, and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability to substance involvement. To elucidate its genetic architecture, we modeled a common liability inferred from genetic correlations among 6 measures of dependence and frequency of use of nicotine, alcohol, and cannabis. Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to substance involvement, of which 67% were novel and not associated with the 6 phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine receptor D 2 gene) and showed enrichment for several components of the central nervous system (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic [gamma-aminobutyric acidergic]) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviors (e.g., risk taking, cocaine use, and opioid use) and mood (e.g., depression, insomnia). These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of substance involvement and help to elucidate the genetic architecture underlying the use of common psychoactive substances. [ABSTRACT FROM AUTHOR]

• There is high genetic variability of human-pathogenic Orientia tsutsugamushi strains from Nepal. • We report the detection of seven distinct Nepalese Orientia clusters. • Interleukin (IL)-6, IL-10, interferon-γ, and C-X-C motif chemokine ligand 10 in serum, but not tumor necrosis factor-α, correlate with bacteremia. • We found an impaired Th2 response and a Th1-skewed chemokine profile in acute scrub typhus. Scrub typhus is an emerging infectious disease in Asia caused by Orientia tsutsugamushi (Ot). From Nepal, only scant data on the genetic epidemiology of this agent is available, and determinants of immunoregulation are poorly understood. Patients (n = 238) referred to the National Public Health Laboratory (Kathmandu, Nepal) from all over Nepal for suspected scrub typhus were enrolled upon positive immunoglobulin (Ig)M testing between July and October 2015. From Ot 16S and 47 kD polymerase chain reaction (PCR)-positive samples, the variable domain I of the 56 kD gene was sequenced and phylogenetically analyzed. T helper (Th) cell-associated cytokines (n = 13) and chemokines (n = 12) were quantified by multiplex bead arrays. In 93/238 (39.1%) IgM-positive samples, Ot DNA was detected by quantitative PCR. Phylogenetic analysis of 56 kD sequences revealed seven distinct clusters, six of them with high homologies to strains detected in other countries. The Th1-related cytokines interferon-γ and C-X-C motif chemokine ligand 10 were strongly upregulated and correlated with bacteremia, while levels of Th2-associated chemokines were reduced. Bacteremia also correlated with concentrations of interleukin (IL)-6 and IL-10 but not tumor necrosis factor-α. We identified a considerable genetic heterogeneity of human-pathogenic Ot strains circulating in Nepal. Acute Nepalese scrub typhus patients showed strong Th1 but impaired Th2 responses, especially on the chemokine level. [ABSTRACT FROM AUTHOR]

[Display omitted] • Black hypertensive patients had higher copeptin levels than White hypertensives. • Copeptin levels fell in Black but not White patients after HCTZ. • Copeptin values remained higher in Black patients after HCTZ than in White patients. • There may be an ADH-related mechanism for hypertension in Black patients. • This may explain the propensity of Black patients to volume-sensitive hypertension. • We could not define a value of copeptin to identify those more responsive to HCTZ. Among hypertensive patients, plasma renin activity is lower and the response to diuretic monotherapy greater in volume responsive hypertensive patients. We hypothesized that hormones influencing extracellular volume such as vasopressin / antidiuretic hormone (ADH) might permit the development of a simple test to identify those with volume-related hypertension. Such a test might be of particular benefit to the Black population which is purported to have a higher incidence of volume-related and responsive hypertension. Thus, using copeptin, a surrogate marker for ADH, we studied if there were differences in this hormone between those with and without volume responsive hypertension. Serum copeptin was measured in biobanked blood samples from the Genetic Epidemiology of Responses to Antihypertensives (GERA) I study and analyzed with other variables from the study dataset. There was no relationship between PRA and copeptin values nor could the response in blood pressure be predicted by the copeptin values. However, baseline copeptin levels were higher in Black than in White subjects (7.5 pmol/L vs 5.4 pmol/L, P < 0.001) while plasma sodium and calculated plasma osmolality were slightly lower in keeping with the concept that Black subjects have more volume-related hypertension. In addition, after hydrochlorothiazide (HCTZ), copeptin was significantly lower in Black (6.2 pmol/L, P = 0.004) but unchanged in White subjects (5.2 pmol/L, P = 0.901) and there were also changes in sodium. The current study suggests differences in ADH physiology between hypertensive Black and White patients. However, the use of copeptin to identify volume responsive patients could not be confirmed. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms (SNPs) that increase late-onset Alzheimer's disease (LOAD) risk. To identify additional LOAD-associated variants and provide insight into underlying disease biology, we performed a phenome-wide association study on 23 known LOAD-associated SNPs and 4:1 matched control SNPs using UK Biobank data. LOAD-associated SNPs were significantly enriched for associations with 8/778 queried traits, including 3 platelet traits. The strongest enrichment was for platelet distribution width (PDW) (p = 1.2 × 10−5), but increased PDW was not associated with LOAD susceptibility in Mendelian randomization analysis. Of 384 PDW-associated SNPs identified by prior GWAS, 36 were nominally associated with LOAD risk (17,008 cases; 37,154 controls) and 5 survived false-discovery rate correction. Associations confirmed known LOAD risk loci near PICALM, CD2AP, SPI1, and NDUFAF6, and identified a novel risk locus in epidermal growth factor receptor. Integrating GWAS and phenome-wide association study data reveals substantial pleiotropy between genetic determinants of LOAD and of platelet morphology, and for the first time implicates epidermal growth factor receptor – a mediator of β-amyloid toxicity – in Alzheimer's disease susceptibility. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence.Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument.Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success. [ABSTRACT FROM AUTHOR]

Genomic loci where recurrent pathogenic copy number variants are associated with psychiatric phenotypes in the population may also be sensitive to the collective impact of multiple functional low-frequency single nucleotide variants (SNVs). We examined the cumulative impact of low-frequency, functional SNVs within the 22q11.2 region on schizophrenia risk in a discovery cohort and an independent replication cohort (N = 1933 and N = 11,128, respectively), as well as the impact on educational attainment (EA) in a third, independent, general population cohort (N = 2081). In the discovery and EA cohorts, SNVs were identified using genotyping arrays; in the replication cohort, whole-exome sequencing was available. For verification, we compared the regional SNV count for schizophrenia cases in the discovery cohort with a normative count distribution derived from a large population dataset (N = 26,500) using bootstrap procedures. In both schizophrenia cohorts, an increased regional SNV burden (≥4 low-frequency SNVs) in the 22q11.2 region was associated with schizophrenia (discovery cohort: odds ratio = 7.48, p =.039; replication cohort: odds ratio = 1.92, p =.004). In the EA cohort, an increased regional SNV burden at 22q11.2 was associated with decreased EA (odds ratio = 4.65, p =.049). Comparing the SNV count for schizophrenia cases with a normative distribution confirmed the unique nature of the distribution for schizophrenia cases (p =.002). In the general population, an increased burden of low-frequency, functional SNVs in the 22q11.2 region is associated with schizophrenia risk and a decrease in EA. These findings suggest that in addition to structural variation, a cumulative regional burden of low-frequency, functional SNVs in the 22q11.2 region can also have a relevant phenotypic impact. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains an important global health issue worldwide. Despite this scourge threatening many human lives, especially in developing countries, thus far, no advanced molecular epidemiology study using recent and more accurate tools has been conducted in Mali. Therefore, this study aimed to use variable-number tandem repeats of mycobacterial interspersed repetitive units (MIRU-VNTR) technology coupled with the spoligotyping method to accurately determine the hot spots and establish the epidemiological transmission links of TB in Bamako, Mali. In a cross-sectional study, 245 isolates of Mycobacterium tuberculosis complex (MTBC) were characterized using spoligotyping and MIRU-VNTR, and an epidemiological investigation was conducted. Of the 245 isolates, 184 (75.1%) were formally identified. The most widespread strain was the Cameroon strain (83; 45.1%). Eight major clusters were identified: Ghana (27; 14.7%), West African 2 (22; 12%), Haarlem (13; 7.1%), H37Rv (t) (8; 4.3%), Latin American Mediterranean (8; 4.3%), and Uganda I and II (6; 3.3%). Statistical analysis showed a significant difference between lineages from the respective referral health centers of Bamako, Mali (P = 0.01). This study establishes, for the first time, an accurate spatial distribution of circulating MTB strains in Bamako, Mali. The data was used to identify strains and "hot spots" causing TB infection and can also be used for more targeted public health responses, particularly for hot spots of drug-resistant strains. [ABSTRACT FROM AUTHOR]

Equine piroplasmosis is a tick-borne disease caused by Theileria equi and Babesia caballi in horses. Because of its impact on horse industry, control of this disease is crucial for endemic countries. The control of equine piroplasmosis may be influenced by the genotypic diversity of T. equi and B. caballi. Mongolia, a country with a thriving livestock industry, is endemic for T. equi and B. caballi. However, nationwide epidemiological surveys have not been conducted to determine the current status of infections and genetic diversity of these two parasite species. Therefore, the objective of this research was to investigate the infection rates and genotypes of T. equi and B. caballi in horses across Mongolia. Blood samples were collected from 1353 horses in 15 of Mongolia's 21 provinces, and their DNAs were analyzed with T. equi - and B. caballi -specific PCR assays. Additionally, blood smears were prepared from 251 horses, stained with Giemsa, and examined under a light microscope to identify T. equi and B. caballi. The microscopy revealed that 30 (11.9%) and 4 (1.6%) of the 251 horses were positive for T. equi and B. caballi , respectively. By contrast, PCR assays detected the T. equi and B. caballi in 1058 (78.2%) and 62 (4.6%) horses, respectively. Phylogenetic analysis of 18S rRNA sequences from 42 randomly selected T. equi -positive DNA samples detected the genotypes A and E. On the other hand, the rap-1 sequences from 19 randomly selected B. caballi -positive DNA samples occurred in clades representing the genotypes A and B1, as well as in a distinct clade closely related to the genotype A. Our findings confirm the widespread occurrence of T. equi and B. caballi infections in Mongolian horses, highlighting the need for a comprehensive control approach. • We surveyed Mongolian horses for Theileria equi and Babesia caballi infections. • PCR detected T. equi in 1058 (78.2%) and B. caballi in 62 (4.6%) of 1353 horses. • Mongolian T. equi 18S rRNA sequences occurred in the genotype A and E clades. • Mongolian B. caballi rap-1 -sequences occurred in A1 and B clades, and a new clade. • Control of T. equi and B. caballi infections is vital for Mongolian horse sector. [ABSTRACT FROM AUTHOR]

Important factors contribute to a gained momentum in candidate gene association studies (CGASs), including the generalized use of next-generation sequencing (NGS), growing opportunities for hospital-based research, and the availability of open-source databases and bioinformatics tools. This article summarizes the general principles and analytical methods as a guide to CGASs in today's favorable context. [ABSTRACT FROM AUTHOR]

The annual epidemics of seasonal influenza is partly attributed to the continued virus evolution. It is challenging to evaluate the effect of influenza virus mutations on evading population immunity. In this study, we introduce a novel statistical and computational approach to measure the dynamic molecular determinants underlying epidemics using effective mutations (EMs), and account for the time of waning mutation advantage against herd immunity by measuring the effective mutation periods (EMPs). Extensive analysis is performed on the sequencing and epidemiology data of H3N2 epidemics in ten regions from season to season. We systematically identified 46 EMs in the hemagglutinin (HA) gene, in which the majority were antigenic sites. Eight EMs were located in immunosubdominant stalk domain, an important target for developing broadly reactive antibodies. The EMs might provide timely information on key substitutions for influenza vaccines antigen design. The EMP suggested that major genetic variants of H3N2 circulated in Southeast Asia for an average duration of 4.5 years (SD 2.4) compared to a significantly shorter 2.0 years (SD 1.0) in temperate regions. The proposed method bridges population epidemics and molecular characteristics of infectious diseases, and would find broad applications in various pathogens mutation estimations. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ ERV ] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery. [ABSTRACT FROM AUTHOR]

Unilateral condylar hyperplasia (UCH) is an abnormal growth process that results in the development of mandibular asymmetry. The aetiopathogenesis of this entity is still unclear. Various factors including hormonal influences, intrauterine factors, trauma, infection, and genetics have been speculated to lead to the development of UCH. In genetic epidemiology, twins have been a valuable resource for investigating the genetic basis of complex traits and diseases. We present a case of mirror-image UCH in a pair of monozygotic twins, providing evidence of a possible genetic link for this mandibular growth disorder. The concordance in the monozygotic twins appears to be reflected by the precise mirror-image presentation of the congenital dentofacial anomalies. Further twin studies would be useful in clarifying the contributions of genetic and environmental factors to the presence and development of UCH. [ABSTRACT FROM AUTHOR]

• Vivax malaria is spreading across Africa, causing symptomatic and asymptomatic cases. • P. vivax infections in Duffy-negative populations have low parasitemia. • Sensitive and standardized methods are needed to detect vivax malaria in Africa. • P. vivax in Duffy-negative Africans have evolved multiple times independently. • The public health significance of vivax malaria in Africa should no longer be neglected. Plasmodium vivax malaria was thought to be rare in Africans who lack the Duffy blood group antigen expression. However, recent studies indicate that P. vivax can infect Duffy-negative individuals and has spread into areas of high Duffy negativity across Africa. Our study compared epidemiological and genetic features of P. vivax between African regions. A standardized approach was used to identify and quantify P. vivax from Botswana, Ethiopia, and Sudan, where Duffy-positive and Duffy-negative individuals coexist. The study involved sequencing the Duffy binding protein (DBP) gene and inferring genetic relationships among P. vivax populations across Africa. Among 1215 febrile patients, the proportions of Duffy negativity ranged from 20–36% in East Africa to 84% in southern Africa. Average P. vivax prevalence among Duffy-negative populations ranged from 9.2% in Sudan to 86% in Botswana. Parasite density in Duffy-negative infections was significantly lower than in Duffy-positive infections. P. vivax in Duffy-negative populations were not monophyletic, with P. vivax in Duffy-negative and Duffy-positive populations sharing similar DBP haplotypes and occurring in multiple, well-supported clades. Duffy-negative Africans are not resistant to P. vivax , and the public health significance of this should not be neglected. Our study highlights the need for a standardized approach and more resources/training directed towards the diagnosis of vivax malaria in Africa. [ABSTRACT FROM AUTHOR]

• Two-sample Mendelian randomization approaches have been utilized to explore the causal relationship between accelerometer-measured physical activity and 3 common neurodegenerative diseases. • We found no evidence for the casual effect of physical activity on the risk of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in the European population. • Genetically predicted physical activity was not robustly associated with the risk of 3 common neurodegenerative disorders. Physical activity has been hypothesized to play a protective role in neurodegenerative diseases. However, effect estimates previously derived from observational studies were prone to confounding or reverse causation. We performed a two-sample Mendelian randomization (MR) analysis to explore the causal association of accelerometer-measured physical activity with 3 common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We selected genetic instrumental variants reaching genome-wide significance (p < 5 × 10−8) from 2 largest meta-analyses of about 91,100 UK Biobank participants. Summary statistics for AD, PD, and ALS were retrieved from the up-to-date studies in European ancestry led by the international consortia. The random-effect, inverse-variance weighted MR was employed as the primary method, while MR pleiotropy residual sum and outlier (MR-PRESSO), weighted median, and MR-Egger were implemented as sensitivity tests. All statistical analyses were performed using the R programming language (Version 3.6.1; R Foundation for Statistical Computing, Vienna, Austria). Primary MR analysis and replication analysis utilized 5 and 8 instrumental variables, which explained 0.2% and 0.4% variance in physical activity, respectively. In each set, one variant at 17q21 was significantly associated with PD, and MR sensitivity analyses indicated them it as an outlier and source of heterogeneity and pleiotropy. Primary results with the removal of outlier variants suggested odds ratios (ORs) of neurodegenerative diseases per unit increase in objectively measured physical activity were 1.52 for AD (95% confidence interval (95%CI): 0.88–2.63, p = 0.13) and 3.35 for PD (95%CI: 1.32–8.48, p = 0.01), while inconsistent results were shown in the replication set for AD (OR = 1.06, 95%CI: 1.01–1.12, p = 0.02) and PD (OR = 0.99, 95%CI: 0.88–0.12, p = 0.97). Similarly, the beneficial effect of physical activity on ALS (OR = 0.51, 95%CI: 0.29–0.91, p = 0.02) was not confirmed in the replication analysis (OR = 0.96, 95%CI: 0.91–1.02, p = 0.22). Genetically predicted physical activity was not robustly associated with risk of neurodegenerative disorders. Triangulating evidence across other studies is necessary in order to elucidate whether enhancing physical activity is an effective approach in preventing the onset of AD, PD, or ALS. [Display omitted] [ABSTRACT FROM AUTHOR]

• Wuchereria bancrofti DNA can be extracted and sequenced from materials collected during lymphatic filariasis surveillance. • No substantial genetic population structure was found in W. bancrofti collected on American Samoa in 2016. • Differences in genetic diversity of W. bancrofti from American Samoa were observed between sampling years. • Results were consistent with recent expansion of a single worm population across the main island of American Samoa. • Wuchereria bancrofti parasite populations in the Pacific appear large enough to retain ancestral haplotypes. Over 892 million people in 48 countries are at risk of infection by nematodes that cause lymphatic filariasis. As part of the Global Programme to Eliminate Lymphatic Filariasis, mass drug administration is distributed to communities until surveillance indicates infection rates are below target prevalence thresholds. In some countries, including American Samoa, lymphatic filariasis transmission persists despite years of mass drug administration and/or has resurged after cessation. Nothing is known about the population genetics of Wuchereria bancrofti worms in Polynesia, or whether local transmission is persisting and/or increasing due to inadequate mass drug administration coverage, expansion from residual hotspots, reintroduction from elsewhere, or a combination. We extracted DNA from microfilariae on blood slides collected during prevalence surveys in 2014 and 2016, comprising 31 pools of five microfilariae from 22 persons living in eight villages. We sequenced 1104 bp across three mitochondrial markers (ND4, COI, CYTB). We quantified parasite genetic differentiation using variant calls and estimated haplotypes using principal components analysis, F-statistics, and haplotype networks. Of the variants called, all but eight were shared across the main island of Tutuila, and three of those were from a previously described hotspot village, Fagali'i. Genotypic data did not support population genetic structure among regions or villages in 2016, although differences were observed between worms collected in Fagali'i in 2014 and those from 2016. Because estimated haplotype frequency varied between villages, these statistics suggested genetic differentiation, but were not consistent among villages. Finally, haplotype networks demonstrated American Samoan sequence clusters were related to previously published sequences from Papua New Guinea. These are, to our knowledge, the first reports of W. bancrofti genetic variation in Polynesia. The resurgent parasites circulating on the main island of American Samoa represent a single population. This study is the first step towards investigating how parasite population structure might inform strategies to manage resurgence and elimination of lymphatic filariasis. [ABSTRACT FROM AUTHOR]

Now, more than a decade into the genome-wide association study (GWAS) era, continued progress in genomic discovery for psychiatric traits is easily taken for granted. The winning formula of large-scale collaborative science, uncompromising methodological rigor, and brute force sample size accumulation has become well established, and its regular empirical returns have become progressively less headline-making. However, we should not be complacent. As the results of the systematic review by Akingbuwa et al.1 in this issue of the Journal make clear, accumulating the necessary numbers of genotyped cases to identify the majority of common risk variants remains a daunting and distant prospect for many psychiatric traits relevant to children and adolescents. But more than this, the challenge of providing clinically and societally meaningful returns on the considerable investments of the GWAS era will require a continued and concerted research effort well into the future. [ABSTRACT FROM AUTHOR]

• CV-A6 and CV-A16 were two major non-EV-A71 enteroviruses causing HFMD in Vietnam, 2008–2017. • Vietnamese CV-A6 and CV-A16 belonged to the largest sub-genogroups, D3 and B1, respectively. • Vietnamese strains have been evolving in a manner similar to the strains circulating worldwide. • Amino acid residues of the functional loops on VPs of Vietnamese strains were highly conserved. • The functional loop patterns of VP1 were similar to the dominant patterns found worldwide. Development of multivalent hand, foot, and mouth disease (HFMD) vaccines against enterovirus A71 (EV-A71) and several non-EV-A71 enteroviruses is needed for this life-threatening disease with a huge economic burden in Asia-Pacific countries. Comprehensive studies on the molecular epidemiology and genetic and antigenic characterization of major causative enteroviruses will provide information for rational vaccine design. Compared with molecular studies on EV-A71, that for non-EV-A71 enteroviruses remain few and limited in Vietnam. Therefore, we conducted a 10-year study on the circulation and genetic characterization of coxsackievirus A16 (CV-A16) and CV-A6 isolated from patients with HFMD in Northern Vietnam between 2008 and 2017. Enteroviruses were detected in 2228 of 3212 enrolled patients. Of the 42 serotypes assigned, 28.4% and 22.4% accounted for CV-A6 and CV-A16, being the second and the third dominant serotypes after EV-A71 (31.7%), respectively. The circulation of CV-A16 and CV-A6 showed a wide geographic distribution and distinct periodicity. Phylogenetic analyses revealed that the majority of Vietnamese CV-A6 and CV-A16 strains were located within the largest sub-genotypes or sub-genogroups. These comprised strains isolated from patients with HFMD worldwide during the past decade and the Vietnamese strains have been evolving in a manner similar to the strains circulating worldwide. Amino acid sequences of the putative functional loops on VP1 and other VPs among Vietnamese CV-A6 and CV-A16 isolates were highly conserved. Moreover, the functional loop patterns of VP1 were similar to the dominant patterns found worldwide, except for the T164K substitution on the EF loop in Vietnamese CV-A16. The findings suggest that the development of a universal HFMD vaccine, at least in Vietnam, must target CV-A6 and CV-A16 as two of the three major HFMD-causing serotypes. Vietnamese isolates or their genome sequences can be considered for rational vaccine design. [ABSTRACT FROM AUTHOR]

Background: Lipoprotein(a) is an atherogenic low-density lipoprotein-like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why.Objectives: This study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically.Methods: We investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486).Results: Patients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH.Conclusions: These results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized. [ABSTRACT FROM AUTHOR]

• The epigenome of identical twins can serve as a perfect laboratory for studying the environmental impact on behavioral traits. • The discordant twin design is a powerful tool for epigenetic association study. • The use of the design in linking specific environmental exposures with epigenetic modification should be encouraged. • Twins are useful for causal inference in behavioral epigenetics for finding effective biomarkers as targets for intervention and prevention. The debate upon the relative importance of nature vs nurture in the development of human behaviour can be traced back to ancient times. Traditional epidemiology and genetic epidemiology have confirmed the association of environmental and genetic factors with behavioural traits. Current genomic studies are identifying genetic variants associated with various behavioural traits. However, exploring the relationship of abundant environmental factors with the complex epigenome that mediates human behaviour is just at its beginning. Identical twins can serve as perfect experiments for studying the environmental impact on behavioural epigenetics advantaged by enriched power in association analysis due to controlling of their genetic make-ups. Recent development in causal inference using twin-based models adds more values in twins. This review briefly introduces the various approaches in making use of twins in studying behavioural epigenetics from experiment design to practical applications. Exploring the epigenome of twins using the powerful twin-based study designs and analytical approaches will help identifying causal epigenetic markers mediating environmental exposures and behavioural traits enabling both pharmaceutical intervention and effective prevention. [ABSTRACT FROM AUTHOR]

Although attention-deficit/hyperactivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study, we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs such as bulimia nervosa. We applied different genetically informative designs to register-based information of a Swedish nationwide population (N = 3,550,118). We first examined the familial coaggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores and ED symptoms, and between AN polygenic risk scores and ADHD symptoms, in a genotyped population-based sample (N = 13,472). Increased risk of all types of EDs was found in individuals with ADHD (any ED: odds ratio [OR] = 3.97, 95% confidence interval [CI] = 3.81, 4.14; AN: OR = 2.68, 95% CI = 2.15, 2.86; other EDs: OR = 4.66, 95% CI = 4.47, 4.87; bulimia nervosa: OR = 5.01, 95% CI = 4.63, 5.41) and their relatives compared with individuals without ADHD and their relatives. The magnitude of the associations decreased as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with other EDs (.37, 95% CI =.31,.42) than with AN (.14, 95% CI =.05,.22). ADHD polygenic risk scores correlated positively with ED symptom measures overall and with the subscales Drive for Thinness and Body Dissatisfaction despite small effect sizes. We observed stronger genetic association with ADHD for non-AN EDs than for AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders. [ABSTRACT FROM AUTHOR]

Genetic testing for prostate cancer (PCa) patients is in constant development. Specific genetic alterations indicate personalized managing strategies, requiring clinicians to refer appropriate patients for genetic testing. However, our understanding of genetic epidemiology of PCa is mainly based on data from Caucasian populations. In addition, there is evidence that alterations in DNA repair genes (DRGs) may be ethnic specific in other cancers such as breast cancer. Thus, whether Caucasian-based genetic information can be used to guide clinical practice in Chinese population remains unknown. Aiming to clarify the landscape of germline DRG mutation in Chinese patients with PCa, we sequenced 316 patients for 18 DRGs. Among all cases, 9.8% (31/316, 95% confidence interval [CI]: 6.5–13%) carried pathogenic mutations in 18 PCa-related DRGs: 6.3% in BRCA2 , 0.63% in BRCA1 , 0.63% in ATM , and 2.5% in 15 other genes. Overall, we observed similar germline DRG mutation frequencies, although there is large disparity in the risk of PCa between China and the West. Our study called for a comprehensive analysis in detailed mutation spectra to refine management strategies further, given the ethnic diversity. We sequenced germline pathogenic mutations in 18 DNA repair genes in 316 patients and elucidated the mutation landscape of Chinese prostate cancer (PCa) patients. Our study confirmed the necessity of genetic testing in Chinese PCa and called for a comprehensive analysis in detailed mutation spectra to refine management strategies further, given the ethnic diversity. Germline DNA repair gene pathogenic mutation frequency is 12% in Chinese metastatic prostate cancer cases and 8.1% in high-risk localized patients. A similar prevalence was observed, although there is large disparity in the risk of prostate cancer between China and the West. [ABSTRACT FROM AUTHOR]

• Geographic isolates are the ideal setting to calculate the frequency of epilepsy and assess the role of genetic background. • The prevalence of pediatric epilepsy in the Ischia island is 4.3 per 1,000 and the incidence is 51.7/100,000/year. • 60% of interviewed patients report at least one family member with epilepsy (first-degree relatives, 26.6% of total). Geographic isolates are the ideal setting to study the genetic background and the epidemiology of epilepsy. There are only few published reports on the epidemiology of pediatric epilepsy in geographic isolates. This study was performed in the Ischia island, district of Napoli (Southern Italy). The local population includes 61,086 individuals, 8381 of them aged from 0 to 14 years. We included children with two or more unprovoked seizures or one unprovoked seizure associated to a high risk of relapse, observed from 2004 to 2017. Neonatal, febrile and acute symptomatic seizures were excluded. Eligible patients were identified through the local pediatricians' medical records. All probands and their parents underwent a face-to-face interview. Clinical charts were reviewed and electroclinical diagnoses were confirmed by two authors (AC, VB). Thirty-six children and adolescents were included. Overall, the prevalence of epilepsy in the Ischia island was 4.3 per 1,000 (95% CI 3.0–5.9). Incidence was 51.7 per 100,000 person-years (95% CI 36.2–71.6). Sixteen (44.4%) patients had a genetic (idiopathic) origin and 20 (55.6%) a symptomatic (structural/metabolic) etiology. Nine probands (25%) had at least one family member with epilepsy (including third-degree relatives). Their pedigrees were suggestive of dominant inheritance in six and of recessive inheritance in three families. The epidemiological features of pediatric epilepsy in this geographic isolate are similar to the general population. A family history was reported in one fourth of the patients with a wide clinical heterogeneity, likely reflecting genetic heterogeneity in this population. [ABSTRACT FROM AUTHOR]

Highlights • First report on the prevalence and genetic characteristics of ESBL producing E. coli isolates from waterfowl birds in China. • In this study, 92.9% of the E. coli isolates were confirmed as ESBL phenotypes by double-disk synergy testing. • CTX-M, belonging to STs associated with E. coli infections should be of concern to animal and public health. Abstract The epidemiology and genetic characteristics of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (E. coli) have been widely studied in human and veterinary settings. ESBL-producing E. coli are generally reported in pigs, poultry, and dairy farm animals. Here, we report on the prevalence and genetic characteristics of beta-lactamase producing E. coli isolated from waterfowl birds in Hainan, China. After phenotypic confirmation, genes encoding bla CTX- M , bla SHV and bla TEM were detected by polymerase chain reaction (PCR). The isolates were assigned to different phylogenetic groups, and multi-locus sequence typing (MLST). Taken as a whole, 289 (92.9%) out of 311 E. coli isolates from waterfowl birds were confirmed as ESBL phenotypes by double-disk synergy testing. Subsequent PCR analysis revealed that bla CTX- M was the predominant ESBL gene identified in 146 (46.9%) isolates, followed by the combination of bla CTX- M and bla TEM in 70 (22.5%) isolates. The majority of these positive isolates were assigned to phylogroup B2 (46.2%) followed by phylogroup A (43.6%). In addition, MLST assigned representative ESBL positive isolates (n = 40) to 18 STs, and ST410 (ST23cplx) was the most prevalent population (22.5%). The high prevalence of CTX-M and STs frequently associating with E. coli infections should be of concern as it poses threats to animal and public health. To the best of our knowledge, this is the first comprehensive study to report on the occurrence of ESBL producing E. coli from waterfowl birds in China. [ABSTRACT FROM AUTHOR]

Abstract Alkhurma hemorrhagic fever, caused by Alkhurma hemorrhagic fever virus (ALKV), is an arboviral infection which is further expanding in tropical and subtropical regions of the Western Asia. A number of Alkhurma hemorrhagic fever virus (ALKV) strains have been isolated from clinical cases representing Saudi Arabia and Egypt; however, the phylogenetic relationship of these particular isolates to those reported previously elsewhere in the world remains elusive. Based on the analysis of the envelope (E), and non-structural gene (NS3 and NS5), the phylogenetic and PASC analysis revealed the circulation of three sub-lineages (I-III) suggesting a continuous evolution. Also, the comparative genome analysis revealed the envelope gene to be a reliable genetic marker to elucidate the molecular epidemiology and genetic diversity of discrete strains of ALKV. Highlights • Over the past 24 years, human infection has become more predominant and, virus was isolated from clinical cases. • A number of alkhumra hemorrhagic fever virus (ALKV) has been isolated from different geography. • Despite of an increase in genetic diversity, its phylogenetic depiction is still incomplete • Study revealed that envelope gene can be a reliable evolutionary marker for classification at sub-lineage level. • The findings will be useful for global researchers to establish an accurate evolutionary link among prevailing strains. [ABSTRACT FROM AUTHOR]

Aims: T2DM reach epidemic levels in the Arab countries. In this study, we aimed to perform a systematic review and meta-analysis to underline the susceptibility genetic profile of Arab patients with T2DM that result from SNPs.Methods: We searched four literature databases (PubMed, Scopus, Science Direct and Web of Science) through January 2019. We included all SNPs in candidate genes with an OR > 1 that were associated with T2DM among Arab patients with T2DM. Statistical programs such as software Review Manager (Version 5.02) and STATA (Version 15.1) were used. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a random effects model or a fixed effect model depending on the heterogeneity among studies. I2 statistics and Egger's tests were performed to assess heterogeneity and publication bias.Results: Out of 2245 studies, 47 were used for meta-analysis. We captured 31,307 cases and 26,464 controls in which we collected 71 SNPs in 32 genes. A pooled meta-analysis demonstrated 24-69% increase in T2DM risk. Among the 57 SNPs (in 32 genes) that were not included in the meta-analysis, the OR for diabetes ranged from 1.02 to 5.10, with a median of 1.38 (interquartile range 1.33-2.09). Ten studies examined the association between the TCF7L2 polymorphism rs7903146 and T2DM, leading to an aggregated OR of 1.34 (95%CI 1.27-1.41).Conclusion: The genetic profile that confer susceptibility to T2DM in Arab patients is diverse. This study may serve as a platform for designing a gene panel for testing the susceptibility to T2DM. [ABSTRACT FROM AUTHOR]

Background: Co-morbid substance use is very common. Despite a historical focus using genetic epidemiology to investigate comorbid substance use and misuse, few studies have examined substance-substance associations using polygenic risk score (PRS) methods.Methods: Using summary statistics from the largest substance use GWAS to date (258,797- 632,802 subjects), GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), we constructed PRSs for smoking initiation (PRS-SI), age of initiation of regular smoking (PRS-AI), cigarettes per day (PRS-CPD), smoking cessation (PRS-SC), and drinks per week (PRS-DPW). We then estimated the fixed effect of individual PRSs on 22 lifetime substance use and substance use disorder phenotypes collected in an independent sample of 2463 young Australian adults using genetic restricted maximal likelihood (GREML) in Genome-wide Complex Trait Analysis (GCTA), separately in females, males and both sexes together.Results: After accounting for multiple testing, PRS-SI significantly explained variation in the risk of cocaine (0.67%), amphetamine (1.54%), hallucinogens (0.72%), ecstasy (1.66%) and cannabis initiation (0.97%), as well as DSM-5 alcohol use disorder (0.72%). PRS-DPW explained 0.75%, 0.59% and 0.90% of the variation of cocaine, amphetamine and ecstasy initiation respectively. None of the 22 phenotypes including emergent classes of substance use were significantly predicted by PRS-AI, PRS-CPD, and PRS-SC.Conclusions: To our knowledge, this is the first study to report significant genetic overlap between the polygenic risks for smoking initiation and alcohol consumption and the risk of initiating major classes of illicit substances. PRSs constructed from large discovery GWASs allows the detection of novel genetic associations. [ABSTRACT FROM AUTHOR]

Abstract This work presents the design, development and optimization of a screening method based on single-base extension sequencing to simultaneously analyze a panel of 52 mitochondrial SNPs. This enables to recognize the main mitochondrial haplogroups and to discriminate even between lineages from the same phylogenetic branch that diverged in different continents. The unavailability of individuals harboring infrequent variants was a limitation to optimize the panel. To overcome this, we have modified DNA by site-directed mutagenesis to create the unavailable allelic variants. This allowed us to verify the reliability of this panel and its usefulness to be applied in biomedicine, forensic and population genetic studies. Highlights • Development of a single minisequencing reaction to analyze in parallel 52 SNPs of main human mtDNA phylogeny subhaplogroups. • This 52 mtSNPs minisequencing panel avoids the laborious Sanger sequencing method. • This panel covers the main mitochondrial (sub) haplogroups at continental level. • Site-directed mutagenesis used to produce unavailable allelic variants for panel optimization. [ABSTRACT FROM AUTHOR]

Abstract Cardiovascular diseases, particularly coronary artery disease (CAD) and myocardial infarction, are the leading cause of death among people worldwide. CAD is exceedingly complex in its interplay of environment and genetics, with numerous genetic loci contributing to its heritability. Here, we aim at looking into the effects of the NOS3 c.894G>T and 27-bp VNTR polymorphisms on susceptibility to CAD in a population of Turkish Cypriots, at seeing whether these effects correlate with plasma lipid levels and at predicting the functional consequences of each polymorphism tested. A total of 50 subjects with CAD and 100 otherwise healthy subjects were included in the present case–control study. Genomic DNA was extracted from peripheral blood samples, and the two NOS3 polymorphisms were determined by restriction endonuclease analysis of PCR amplicons. Complementary methods of statistical analysis and computational modeling were employed accordingly to achieve the aims above. Our findings show that the 27-bp VNTR polymorphic locus, but not the c.894G>T polymorphic locus, is associated with CAD and that it may regulate NOS3 pre-mRNA splicing in a length-dependent manner. Overall, along with additional, yet-to-be ascertained susceptibility markers the 27-bp VNTR 4a/4b marker may be employed in risk stratification in community-level screening for CAD among Turkish Cypriots. [ABSTRACT FROM AUTHOR]

Abstract Ovarian cancer (OC) is a common disease among Arabs, with one of the highest incidences in the world. OC is underdiagnosed, underreported, and mostly reported with breast cancer. This study aimed to conduct a systematic review to estimate the published knowledge about the genetic epidemiology of OC in the 22 Arab countries. Therefore, we systematically searched seven literature databases (Web of science, PubMed, Science Direct, ProQuest, Embase, Scopus, and Google scholar) from the time of inception until June 2018 to collect all the information related to the incidence and pathogenic mutations spectrum for OC among Arabs. Our search strategy identified 3645 studies, of which 44 studies met our inclusion criteria, which cover the past 25 years (1993–2018). OC incidence among Arabs ranged from a low of 0.9/100,000/year in Saudi Arabia to a high of 8.0/100,000/year in Sudan. The total number of OC patients captured was 802; of these, 53 and five families carry 22 mutations in BRCA1/2 genes. Of these, eight mutations were unique to the Arab populations, and five mutations were commonly circulated among Arabs (BRCA1 : c.5266dupC, c.5095C>T, c.68_69delAG, and c.4041_4042delAG; BRCA 2 c.1310_1313delAAGA). The ratio of BRCA1 (77.3%) mutations was higher than BRCA2 mutations (22.7%). This is the first systematic review to focus on the genetic epidemiology of only OC as an understudied disease that is common among Arabs. This study is expected to serve as a platform for further well-controlled genetic epidemiological studies for OC in the Arab world. [ABSTRACT FROM AUTHOR]

Background: The risk of neural tube defect (NTD)-affected pregnancies is reduced with adequate folic acid intake during early pregnancy. However, NTDs have been observed among offspring of women with adequate folic acid intake. Some of these women are possibly not absorbing enough folic acid. Because lactase deficiency can lead to poor nutrient absorption, we hypothesized that lactase-deficient women will be at increased risk of having offspring with NTDs.Objective: We examined the association between maternal rs4988235 (a lactase deficiency genetic marker) and NTDs in offspring.Methods: We conducted a case-control study using data from the National Birth Defects Prevention Study, United States, 1997-2009, restricting to non-Hispanic white (NHW) and Hispanic women. Cases were women with an offspring with an NTD (n = 378 NHW, 207 Hispanic), and controls were women with an offspring without a birth defect (n = 461 NHW, 165 Hispanic). Analyses were conducted separately by race/ethnicity, using logistic regression. Women with the CC genotype were categorized as being lactase deficient. To assess potential effect modification, analyses were stratified by lactose intake, folic acid supplementation, dietary folate, and diet quality.Results: Among NHW women, the odds of being lactase deficient were greater among cases compared with controls (OR: 1.37; 95% CI: 1.02, 1.82). Among Hispanic women, the odds of being lactase deficient were significantly lower among cases compared with controls (OR: 0.50, 95% CI: 0.33, 0.77). The association differed when stratified by lactose intake in NHW women (higher odds among women who consumed ≥12 g lactose/1000 kcal) and by dietary folate in Hispanic women (opposite direction of associations). The association did not differ when stratified by folic acid supplementation or diet quality.Conclusions: Our findings suggest that maternal lactase deficiency is associated with NTDs in offspring. However, we observed opposite directions of effect by race/ethnicity that could not be definitively explained. [ABSTRACT FROM AUTHOR]

Abstract Background Variants in the desmoglein-2 (DSG2) gene account for a significant proportion of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The aim of this study was to evaluate the genetic epidemiology of DSG2 and the impact of a frequent homozygous DSG2 variant in East Asia. Methods Genetic screening of 14 ARVC related genes was performed in 118 unrelated index patients using next-generation sequencing. Following that, family screening, clinical evaluation and haplotype analysis were performed among eight probands who carry the same homozygous DSG2 variant. We also examined the histopathology and protein expression using immunofluorescence staining on the myocardial tissue of two probands undergoing heart transplant. Results Eighteen (15.2%) patients bear rare putatively deleterious variants in DSG2 , among which 8 patients shared the homozygous DSG2 p.Phe531Cys variant. Family screening demonstrated that only homozygous variant carriers exhibited definite ARVC phenotype with 100% penetrance, while heterozygous variant carriers were either unaffected or only presented mild ARVC related symptoms in 25% relatives. Left ventricular involvement and bi-ventricular failure were common among homozygous p. Phe531Cys variant patients even at early age. Haplotype analysis demonstrated p. Phe531Cys was a founder variant in East Asia population with an allele frequency of 0.12%. Conclusions We identified, for the first time, a homozygous founder variant of DSG2 in East Asia, which was at surprisingly high frequency of 8.47% among Chinese ARVC patients with a full penetrance. This result suggested an urgent demand of genetic counseling for the probands and their relatives with heterozygous variant. Highlights • This study demonstrates the first founder mutation (p.F531C) of DSG2 among ARVC patients in East Asia; • This homozygous founder mutation has a full penetrance, while heterozygotes are not affected or presented mild symptoms. • This founder mutation is highly frequent (8.47%) in Chinese ARVC cohort, which could explain about 10 percent patients. [ABSTRACT FROM AUTHOR]

Abstract Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of hereditary polyneuropathies. Variants in more than 80 different genes have been associated with the disorder. In recent years, the introduction of next generation sequencing (NGS) techniques have completely changed the genetic diagnostic approach from the analysis of a handful of genes to the analysis of all genes associated with CMT in a single run. In this study we describe the CMT diagnostics in Denmark in 1992–2012, prior to the implementation of NGS, by combining laboratory- and national registry data. We investigate the effect of implementing a targeted NGS approach of 63 genes associated with CMT in the diagnostic laboratory setting. This was performed by analyzing a cohort of 195 samples from patients previously analyzed by Sanger sequencing and quantitative analysis for the common causes of CMT without reaching a molecular diagnosis. A total of 1442 CMT analyses were performed in Denmark in the period 1992–2012; a disease-causing variant was detected in 21.6% of the cases. Interestingly, the diagnosis was genetically confirmed in significantly more women than men; 25.9% compared to18.5%. In our study cohort, we found a 5.6% increase in the diagnostic yield with the introduction of a targeted NGS approach. [ABSTRACT FROM AUTHOR]

Abstract Malaria is a life-threatening blood disease caused by the protozoan Plasmodium. Infection may lead to several different patterns of symptoms in the host: asymptomatic state, uncomplicated disease or severe disease. Severe malaria occurs mostly in young children and is a major cause of death. Disease is thought to result from the sequestration of parasites in the small blood vessels of the brain and the deregulation of key immune system elements. The cellular and molecular regulatory mechanisms underlying the pathogenesis of disease are however not fully understood. What is known it is that the genetic determinants of the host play an important role in the severity of the disease and the outcome of infection. Here we review the most convincing results obtained through genetic epidemiology studies concerning the genetic control of malaria in human caused by Plasmodium falciparum infection. The identification of genes conferring susceptibility or resistance to malaria might improve diagnosis and treatment. Highlights • Complex genetic control of human susceptibility to malaria • 5q31-q33 region is involved in the control of blood Plasmodium falciparum levels. • Role of TNF and NCR3 in mild malaria • HbS plays an important role in resistance to severe malaria. • Genome-wide association studies on large cohort with severe malaria were recently performed to identify new genes. [ABSTRACT FROM AUTHOR]

• Family studies established the high heritability of SpA and its polygenic transmission. • Family-based designs are a powerful tool to detect association of rare variants with SpA. • Family history of SpA might improve diagnostic and referral strategies. Spondyloarthritis (SpA) is an immune-mediated disease characterized by a high heritability, reflected by strong familial aggregation. Therefore, family studies are a powerful tool for elucidating the genetic basis of SpA. First, they helped to assess the relative importance of genetic and environmental factors and established the polygenic character of the disease. Family-based designs were also historically used to identify genetic factors of susceptibility through linkage analyses. In SpA, three whole-genome linkage studies were published in the 1990's, unfortunately with few consistent results. After having been put aside for several years in favour of case-control GWAS, there is a renewed interest in family-based designs in particular to detect rare variant associations. This review aims at summarizing what family studies have brought to the field of SpA genetics, from genetic epidemiology studies to the most recent rare variant analyses. It also highlights the potential interest of family history of SpA to help diagnosis and detection of patients at high risk to develop the disease. [ABSTRACT FROM AUTHOR]

• CA10 is one of the main agents associated with HFMD in zhejiang during 2017 to 2022. • Non EV71 associated HFMD cases, like CA10, increased after the use of EV71 vaccine. • Molecular epidemiology of HFMD and genetic features of CA10 were investigated. • Phylogenetic characteristics and evolutionary patterns for the CA10 were inferred. • We provided information for HFMD prevention and control. Coxsackievirus A10 (CA10) is one of the etiological agents associated with hand, foot and mouth disease (HFMD). We aimed to perform a retrospective analysis of the molecular epidemiological characteristics and genetic features of HFMD associated with CA10 infections in Zhejiang Province from 2017 to 2022. Epidemiologic features were summarized. Throat swab specimens were collected and tested. The VP1 regions were sequenced for genotyping. CA10 positive samples were isolated. Whole genomes of CA10 isolations were sequenced. Nucleotide and amino acid changes were characterized. Phylogenetic trees were constructed. The number of HFMD cases fluctuated from 2017 to 2022. Children aged below 3 years accounted for the majority (66.29%) and boys were more frequently affected than girls. Cases peaked in June. The positivity rate of HEV was 62.69%. A total of 90 strains of CA10 were isolated and 53 genomes were obtained. All CA10 in this study could be assigned to two genogroups, C (C2) and F (F1 and F3). The clinical manifestations of HFMD associated with HEV are complex and diverse. CA10 infection may be emerging as a new and major cause of HFMD because an upward trend was observed in the proportion of CA10 cases after the use of EV71 vaccines. Different genogroups of CA10 had different geographic distribution patterns. Surveillance should be strengthened and further comprehensive studies should be continued to provide a scientific basis for HFMD prevention and control. [ABSTRACT FROM AUTHOR]

Canine circovirus (CanineCV) is a DNA virus affecting domestic dogs and other wild carnivore species. Despite the potential implications for dogs' health and wildlife conservation, data on CanineCV presence, epidemiology and genetic features from Africa is still poor. In the present study, biological specimens collected between 2020 and 2022 from a total of 32 jackals and 575 domestic dogs were tested for the presence of CanineCV DNA to evaluate its frequency. Furthermore, sequencing was conducted on positive samples to characterize the strains and compare them with publicly available sequences through phylogenetic analysis. A high CanineCV prevalence was observed both in jackals (43.75%; 95 CI: 28.17% - 60.67%) and domestic dogs (27.13%; 95 CI: 23.66% - 30.91%). All aside from one Namibian strain formed an independent clade, suggestive of extremely rare introduction events, followed by local persistence, circulation, and evolution. Remarkably, different recombination events were observed involving strains from both jackals and domestic dogs, which testify to the likely strain exchange between these populations. Distinctive amino acid residues were also observed in jackals. The limitations of the considered host populations however prevent a definitive conclusion on host adaptation, biological, and clinical features. Further studies should be performed to expand our current knowledge of the CanineCV disease scenario in Namibia, other African regions, and associated host species in Africa. • First report of Canine circovirus in Namibia, Africa. • High detection frequency both in domestic dogs and jackals. • Frequent recombination events were observed. • Namibian strains likely originate from one or few introduction events. • Local evolution occurred after the first introduction. [ABSTRACT FROM AUTHOR]

Recent reports on identification of canine coronavirus (CCoV) in humans have emphasized the urgency to strengthen surveillance of animal CoVs. The fact that recombinations between CCoV with feline, porcine CoVs brought about new types of CoVs indicated that more attention should be paid to domestic animals like dogs, cats and pigs, and the CoVs they carried. However, there are about ten kinds of CoVs that infect above animals, and thus representative CoVs with zoonotic potentials were considered in this study. Multiplex RT-PCR against CCoV, Feline coronavirus (FCoV), porcine deltacoronavirus and porcine acute diarrhea syndrome coronavirus was developed to investigate the prevalence of CoVs from domestic dogs in Chengdu, Southwest China. Samples from a total of 117 dogs were collected from a veterinary hospital, and only CCoV (34.2%, 40/117) was detected. Therefore, this study focused on CCoV and its characteristics of S , E , M , N and ORF3abc genes. Compared with CoVs that are capable of infecting humans, CCoV strains showed highest nucleotide identity with the novel canine-feline recombinant detected from humans (CCoV-Hupn-2018). Phylogenetic analysis based on S gene, CCoV strains were not only clustered with CCoV-II strains, but also closely related to FCoV-II strains ZJU1617 and SMU-CD59/2018. As for assembled ORF3abc , E , M , N sequences, CCoV strains had the closest relationship with CCoV-II (B203_GZ_2019, B135_JS_2018 and JS2103). What's more, specific amino acid variations were found, especially in S and N proteins, and some mutations were consistent with FCoV, TGEV strains. Altogether, this study provided a novel insight into the identification, diversification and evolution of CoVs from domestic dogs. It is of top priority to recognize zoonotic potential of CoVs, and continued comprehensive surveillance will help better understand the emergence, spreading, and ecology of animal CoVs. • Multiplex RT-PCR against CCoV, FCoV, PDCoV and SADS-CoV was developed. • comparable asymptomatic infections (30.0%) vs. overall detect rate (34.2%) were identified. • characteristics of S, E, M and N all four structural protein genes and ORF3abc genes from 13 strains were obtained. [ABSTRACT FROM AUTHOR]

Porcine circovirus 4 (PCV4) is a recently discovered circovirus that was first reported in 2019 in several pigs with severe clinical disease in Hunan province of China, and also identified in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). To further investigate the epidemic profile and genetic characteristics of the two viruses, 150 clinical samples were collected from 9 swine farms in Shaanxi and Henan provinces of China, and a SYBR Green I-based duplex quantitative real-time polymerase chain reaction (qPCR) was developed for detecting PCV4 and PRRSV simultaneously. The results showed the limits of detection were 41.1 copies/μL and 81.5 copies/μL for PCV4 and PRRSV, respectively. The detection rates of PCV4 and PRRSV were 8.00% (12/150) and 12.00% (18/150) respectively, and a case of co-infection with PCV4 and PRRSV was found in the lung tissue of a suckling pig with respiratory symptom. Subsequently, the complete genomic sequences of five PCV4 strains were obtained, of which one PCV4 strain (SX-ZX) was from Shaanxi province, and these strains were 1770 nucleotides in length and had 97.7%−99.4% genomic identity with 59 PCV4 reference strains. The genome characteristic of the SX-ZX strain was evaluated from three aspects, a "stem-loop" structure, ORF1 and ORF2. As essential elements for the replication, the 17-bp iterative sequence was predicted as the stem structure, in which three non-tandem hexamers were found at downstream with H1/H2 (12-CGGCACACTTCGGCAC-27) as the minimal binding site. Three of the five PCV4 strains were clustered into PCV4b, which was composed of Suidae, fox, dairy cow, dog and raccoon dog. Phylogenetic analysis revealed that seven PRRSV strains from the present study were clustered into the PRRSV-2 genotype. Collectively, these data extend our understanding of the genome characteristic of PCV4 as well as the molecular epidemiology and the genetic profile of PCV4 and PRRSV. • A duplex qPCR assay was developed for the simultaneous detection of PCV4 and PRRSV. • Limits of detection were 41.1 copies/μL and 81.5 copies/μL for PCV4 and PRRSV, respectively. • A case of co-infection with PCV4 and PRRSV was found in lung tissue of a suckling pig with respiratory symptom. • The 17-bp iterative sequence was predicted as the stem structure. [ABSTRACT FROM AUTHOR]

Reduction of BCL11A in hematopoietic stem cells through gene editing: new strategy to ameliorate the severe -globin disorders sickle cell disease CRISPR/Cas9 systems are important in gene editing for therapy of genetic diseases because of their highly programmable DNA binding and cleavage activity. With the development of CRISPR/Cas9 system in biomedical field, researchers used CRISPR/Cas9 to successfully correct human genetic diseases ranging from single base mutations to large insertions and it is also applied in therapy of chromosomal inversion [2]. [Extracted from the article]

Background Testosterone supplementation has been linked to increased cardiovascular disease risk in some observational studies. The causal role of testosterone can be investigated using a Mendelian randomization approach. Methods and results We assessed genetic associations of variants in two gene regions ( SHBG and JMJD1C ) with several cardiovascular risk factors (lipids, adiponectin, blood pressure, anthropometric traits) plus male pattern baldness, including control outcomes and potential mediators. We assessed genetic associations with coronary artery disease (CAD) risk in the CARDIoGRAMplusC4D consortium (171,191 individuals including 60,801 cases), and associations with CAD and ischaemic stroke risk in the UK Biobank (367,643 individuals including 25,352 CAD cases and 3650 ischaemic stroke cases). Genetic predictors of increased serum testosterone were associated with lipids, blood pressure, and height. There was some evidence of an association with risk of CAD ( SHBG gene region: odds ratio (OR) 0.95 per 1 unit increase in log-transformed testosterone [95% confidence interval: 0.81–1.12, p = 0.55]; JMJD1C gene region: OR 1.24 [1.01–1.51, p = 0.04]) and ischaemic stroke both overall ( SHBG : OR 1.05 [0.64, 1.73, p = 0.83]; JMJD1C : OR 2.52 [1.33, 4.77, p = 0.005]) and in men. However, associations with some control outcomes were in the opposite direction to that expected. Conclusions Sex hormone-related mechanisms appear to be relevant to cardiovascular risk factors and for stroke (particularly for men). However, the extent that these findings are specifically informative about endogenous testosterone or testosterone supplementation is unclear. These findings underline a fundamental limitation for the use of Mendelian randomization where biological knowledge about the function of genetic variants is uncertain. [ABSTRACT FROM AUTHOR]