Common Loci Research Articles

OA08 GWAS meta-analysis of ankylosing spondylitis and Behçet's disease identifies novel MHC-I-opathy genes

Abstract Background/Aims Spondyloarthropathies (SpA) and Behçet's disease (BD) have clinical and HLA locus overlap and have been grouped under MHC-I-opathy [1]. Genetic overlap can help elucidate MHC-I-opathy pathogenesis. Ankylosing spondylitis (AS) is a primary SpA. Here, a cluster-based approach helps to identify overlapping loci between AS and BD of even modest significance. Methods Association clustering methods such as OASIS [2] reduce the multiple-testing burden and are therefore more powerful than single variant analysis for identifying modest genetic effects. Here, two large genome-wide association studies (GWAS) of AS (921 cases, 907 controls) and BD (1215 cases and 1278 healthy controls) from Turkiye, were subjected to OASIS meta-analyses to identify common non-HLA loci [3, 4]. Statistics used to identify significant loci included the novel OASIS locus index (OLI), defined as the product of maximum -logP at a locus with the ratio of actual to predicted number of significant SNPs. Results GWAS for both diseases had the highest significance at the HLA-locus. OASIS avoids the proportional signals problem, inherent in GWAS, by separately analysing highly significant loci (P < 10-8). Hence, of the 234 independent modestly significant non-HLA loci, there were 16 loci common to both AS and BD (Figure 1). These included known MHC-I-opathy loci, 1p31.3 for IL23R (P = 5.37 E-06, OLI = 52.7) and 13q14.11 for LACC1 (P = 7.41 E-06, OLI= 65.3) [1, 5]. Novel loci included 3p21.31 containing CCR9 (P = 2.46 E-05, OLI=25.8), 3q22.3 containing CLDN18 (P = 5.37 E-05, OLI=31.4) and 4q27-4q28.1 containing FGF2 (P = 1.1 E-04, OLI=29.5). Conclusion Five loci containing pathologically relevant genes for MHC-I-opathy were identified using a cluster-based approach in AS and BD GWAS datasets. These large meta-analyses will help identify pathogenic pathways for MHC-I-opathy, an entity that has so far largely remained elusive [6]. Disclosure M. Saeed: None.

Genetic risk score based on obesity-related genes and progression in weight loss after bariatric surgery: a 60-month follow-up study

BackgroundObesity is a polygenic multifactorial disease. Recent genome-wide association studies have identified several common loci associated with obesity-related phenotypes. Bariatric surgery (BS) is the most effective long-term treatment for patients with severe obesity. The huge variability in BS outcomes between patients suggests a moderating effect of several factors, including the genetic architecture of the patients. ObjectiveTo examine the role of a genetic risk score (GRS) based on 7 polymorphisms in 5 obesity-candidate genes (FTO, MC4R, SIRT1, LEP, and LEPR) on weight loss after BS. SettingUniversity hospital in Spain. MethodsWe evaluated a cohort of 104 patients with severe obesity submitted to BS (Roux-en-Y gastric bypass or sleeve gastrectomy) followed up for >60 months (lost to follow-up, 19.23%). A GRS was calculated for each patient, considering the number of carried risk alleles for the analyzed genes. During the postoperative period, the percentage of excess weight loss total weight loss and changes in body mass index were evaluated. Generalized estimating equation models were used for the prospective analysis of the variation of these variables in relation to the GRS. ResultsThe longitudinal model showed a significant effect of the GRS on the percentage of excess weight loss (P = 1.5 × 10–5), percentage of total weight loss (P = 3.1 × 10–8), and change in body mass index (P = 7.8 × 10–16) over time. Individuals with a low GRS seemed to experience better outcomes at 24 and 60 months after surgery than those with a higher GRS. ConclusionThe use of the GRS in considering the polygenic nature of obesity seems to be a useful tool to better understand the outcome of patients with obesity after BS.

Interpretation of 10years of Alzheimer's disease genetic findings in the perspective of statistical heterogeneity.

Common genetic variants and susceptibility loci associated with Alzheimer's disease (AD) have been discovered through large-scale genome-wide association studies (GWAS), GWAS by proxy (GWAX) and meta-analysis of GWAS and GWAX (GWAS+GWAX). However, due to the very low repeatability of AD susceptibility loci and the low heritability of AD, these AD genetic findings have been questioned. We summarize AD genetic findings from the past 10years and provide a new interpretation of these findings in the context of statistical heterogeneity. We discovered that only 17% of AD risk loci demonstrated reproducibility with a genome-wide significance of P < 5.00E-08 across all AD GWAS and GWAS+GWAX datasets. We highlighted that the AD GWAS+GWAX with the largest sample size failed to identify the most significant signals, the maximum number of genome-wide significant genetic variants or maximum heritability. Additionally, we identified widespread statistical heterogeneity in AD GWAS+GWAX datasets, but not in AD GWAS datasets. We consider that statistical heterogeneity may have attenuated the statistical power in AD GWAS+GWAX and may contribute to explaining the low repeatability (17%) of genome-wide significant AD susceptibility loci and the decreased AD heritability (40-2%) as the sample size increased. Importantly, evidence supports the idea that a decrease in statistical heterogeneity facilitates the identification of genome-wide significant genetic loci and contributes to an increase in AD heritability. Collectively, current AD GWAX and GWAS+GWAX findings should be meticulously assessed and warrant additional investigation, and AD GWAS+GWAX should employ multiple meta-analysis methods, such as random-effects inverse variance-weighted meta-analysis, which is designed specifically for statistical heterogeneity.

Assessing the interaction effects of mitochondrial DNA polymorphisms and lifestyle on heel bone mineral density.

Bone mineral density (BMD) is a major predictor of osteoporotic fractures, and previous studies have reported the effects of mitochondrial dysfunction and lifestyle on BMD, respectively. However, their interaction effects on BMD are still unclear. Therefore, we aimed to investigate the possible interaction of mitochondrial DNA (mtDNA) and common lifestyles contributing to osteoporosis. Our analysis included 119,120 white participants (Nfemale=65,949 and Nmale=53,171) from the UK Biobank with heel BMD phenotype data. A generalized linear regression model of PLINK was performed to assess the interaction effects of mtDNA and five life environmental factors on heel BMD, including smoking, drinking, physical activity, dietary diversity score, and vitamin D. In addition, we also performed linear regression analysis for total body BMD. Finally, we assessed the potential causal relationships between mtDNA copy number (mtDNA-CN) and life environmental factors using Mendelian randomization (MR) analysis. Our study identified four mtDNA loci showing suggestive evidence of heel BMD, such as m.16356T>C (MT-DLOOP; P =1.50×10-3) in total samples. Multiple candidate mtDNA×lifetsyle interactions were also detected for heel BMD, such as MT-ND2×physical activity (P = 2.88×10-3) in total samples and MT-ND1×smoking (P = 8.54×10-4) in males. Notably, MT-CYB was a common candidate mtDNA loci for heel BMD to interact with five life environmental factors. Multivariable MR analysis indicated a causal effect of physical activity on heel BMD when mtDNA-CN was considered (P =1.13×10-3). Our study suggests the candidate interaction between mitochondria and lifestyles on heel BMD, providing novel clues for exploring the pathogenesis of osteoporosis.

Integrating Student Reasoning and Mathematics in Instruction: A New Research Perspective

Traditional mathematics education prioritizes content transmission, often overlooking the intricate ways students’ reasoning and understanding are constructed. This research perspective proposes Integrating Student Reasoning and Mathematics in Instruction (ISRMI) as a novel approach that centers student thinking, integrating it seamlessly with formal mathematical concepts and procedures. ISRMI emphasizes tasks promoting explanation and justification, enabling educators to uncover and build upon existing student reasoning patterns. By challenging teacher-centered knowledge transfer, ISRMI empowers students to apply reasoning skills to solve problems, ultimately fostering deeper conceptual understanding and motivation in learning mathematics. While potential challenges lie in teacher training, curriculum design, and assessment of student reasoning, the potential benefits of improved problem-solving, engagement, and critical thinking skills necessitate further exploration and development of effective ISRMI implementation strategies. Design/Methodology/Approach: The research questions of this study are pursued using a systematic research analysis. We stress the importance of advancing research on integrating student reasoning and mathematics in instruction. We discuss many methods for incorporating student reasoning and mathematics into classroom instruction. We conducted this research by systematically searching and screening for relevant research articles through secondary sources and analyzing them to answer our scientific question. This research is a descriptive study. Secondary data was collected from various sources, such as magazines, journals, other publications, etc. This data was then analyzed and reviewed for inferences and conclusions. Findings/Result: Integrating student reasoning and mathematics in instruction can be the foundation for building a common locus between mathematics and reasoning abilities in educational practice.

Genetic influences on circulating retinol and its relationship to human health

Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identify eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supports novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homoeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggests that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and serum creatinine. Finally, we demonstrate how a retinol polygenic score could identify individuals more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further investigation with respect to retinol related therapies or nutritional intervention.

Deciphering temporal growth patterns in maize: integrative modeling of phenotype dynamics and underlying genomic variations.

Quantifying the temporal or longitudinal growth dynamics of crops in diverse environmental conditions is crucial for understanding plant development, requiring further modeling techniques. In this study, we analyzed the growth patterns of two different maize (Zea mays L.) populations using high-throughput phenotyping with a maize population consisting of 515 recombinant inbred lines (RILs) grown in Texas and a hybrid population containing 1090 hybrids grown in Missouri. Two models, Gaussian peak and functional principal component analysis (FPCA), were employed to study the Normalized Green-Red Difference Index (NGRDI) scores. The Gaussian peak model showed strong correlations (c. 0.94 for RILs and c. 0.97 for hybrids) between modeled and non-modeled temporal trajectories. Functional principal component analysis differentiated NGRDI trajectories in RILs under different conditions, capturing substantial variability (75%, 20%, and 5% for RILs; 88% and 12% for hybrids). By comparing these models with conventional BLUP values, common quantitative trait loci (QTLs) were identified, containing candidate genes of brd1, pin11, zcn8 and rap2. The harmony between these loci's additive effects and growing degree days, as well as the differentiation of RIL haplotypes across growth stages, underscores the significant interplay of these loci in driving plant development. These findings contribute to advancing understanding of plant-environment interactions and have implications for crop improvement strategies.

Elevated incidence of somatic mutations at prevalent genetic sites.

The common loci represent a distinct set of the human genome sites that harbor genetic variants found in at least 1% of the population. Small somatic mutations occur at the common loci and non-common loci, i.e. csmVariants and ncsmVariants, are presumed with similar probabilities. However, our work revealed that within the coding region, common loci constituted only 1.03% of all loci, yet they accounted for 5.14% of TCGA somatic mutations. Furthermore, the small somatic mutation incidence rate at these common loci was 2.7 times that observed in the non-common. Notably, the csmVariants exhibited an impressive recurrent rate of 36.14%, which was 2.59 times of the ncsmVariants. The C-to-T transition at the CpG sites accounted for 32.41% of the csmVariants, which was 2.93 times for the ncsmVariants. Interestingly, the aging-related mutational signature contributed to 13.87% of the csmVariants, 5.5 times that of ncsmVariants. Moreover, 35.93% of the csmVariants contexts exhibited palindromic features, outperforming ncsmVariant contexts by 1.84 times. Notably, cancer patients with higher csmVariants rates had better progression-free survival. Furthermore, cancer patients with high-frequency csmVariants enriched with mismatch repair deficiency were also associated with better progression-free survival. The accumulation of csmVariants during cancerogenesis is a complex process influenced by various factors. These include the presence of a substantial percentage of palindromic sequences at csmVariants sites, the impact of aging and DNA mismatch repair deficiency. Together, these factors contribute to the higher somatic mutation incidence rates of common loci and the overall accumulation of csmVariants in cancer development.

Reviewing migraine-associated pathophysiology and its impact on elevated stroke risk.

Migraine affects up to 20 percent of the global population and ranks as the second leading cause of disability worldwide. In parallel, ischemic stroke stands as the second leading cause of mortality and the third leading cause of disability worldwide. This review aims to elucidate the intricate relationship between migraine and stroke, highlighting the role of genetic, vascular, and hormonal factors. Epidemiological evidence shows a positive association between migraine, particularly with aura, and ischemic stroke (IS), though the link to hemorrhagic stroke (HS) remains inconclusive. The shared pathophysiology between migraine and stroke includes cortical spreading depression, endothelial dysfunction, and genetic predispositions, such as mutations linked to conditions like CADASIL and MELAS. Genetic studies indicate that common loci may predispose individuals to both migraine and stroke, while biomarkers such as endothelial microparticles and inflammatory cytokines offer insights into the underlying mechanisms. Additionally, hormonal influences, particularly fluctuations in estrogen levels, significantly impact migraine pathogenesis and stroke risk, highlighting the need for tailored interventions for women. The presence of a patent foramen ovale (PFO) in migraineurs further complicates their risk profile, with device closure showing promise in reducing stroke occurrence. Furthermore, white matter lesions (WMLs) are frequently observed in migraine patients, suggesting potential cognitive and stroke risks. This review hopes to summarize the links between migraine and its associated conditions and ischemic stroke, recognizing the profound implications for clinical management strategies for both disorders. Understanding the complex relationship between migraine and ischemic stroke holds the key to navigating treatment options and preventive interventions to enhance overall patient outcomes.

Linking Angelman and dup15q data for expanded research (LADDER) database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions.

Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database - including challenges, lessons learned, and preliminary feasibility - and how it can be used as a model for other rare conditions.

Diaporthe species on palms – integrative taxonomic approach for species boundaries delimitation in the genus Diaporthe, with the description of D. pygmaeae sp. nov.

The application of traditional morphological and ecological species concepts to closely related, asexual fungal taxa is challenging due to the lack of distinctive morphological characters and frequent cosmopolitan and plurivorous behaviour. As a result, multilocus sequence analysis (MLSA) has become a powerful and widely used tool to recognise and delimit independent evolutionary lineages (IEL) in fungi. However, MLSA can mask discordances in individual gene trees and lead to misinterpretation of speciation events. This phenomenon has been extensively documented in Diaporthe, and species identifications in this genus remains an ongoing challenge. However, the accurate delimitation of Diaporthe species is critical as the genus encompasses several cosmopolitan pathogens that cause serious diseases on many economically important plant hosts. In this regard, following a survey of palm leaf spotting fungi in Lisbon, Portugal, Diaporthe species occurring on Arecaceae hosts were used as a case study to implement an integrative taxonomic approach for a reliable species identification in the genus. Molecular analyses based on the genealogical concordance phylogenetic species recognition (GCPSR) and DNA-based species delimitation methods revealed that speciation events in the genus have been highly overestimated. Most IEL identified by the GCPSR were also recognised by Poisson tree processes (PTP) coalescent-based methods, which indicated that phylogenetic lineages in Diaporthe are likely influenced by incomplete lineage sorting (ILS) and reticulation events. Furthermore, the recognition of genetic recombination signals and the evaluation of genetic variability based on sequence polymorphisms reinforced these hypotheses. New clues towards the intraspecific variation in the common loci used for phylogenetic inference of Diaporthe species are discussed. These results demonstrate that intraspecific variability has often been used as an indicator to introduce new species in Diaporthe, which has led to a proliferation of species names in the genus. Based on these data, 53 species are reduced to synonymy with 18 existing Diaporthe species, and a new species, D. pygmaeae, is introduced. Thirteen new plant host-fungus associations are reported, all of which represent new host family records for Arecaceae. This study has recognised and resolved a total of 14 valid Diaporthe species associated with Arecaceae hosts worldwide, some of which are associated with disease symptoms. This illustrates the need for more systematic research to examine the complex of Diaporthe taxa associated with palms and determine their potential pathogenicity. By implementing a more rational framework for future studies on species delimitation in Diaporthe, this study provides a solid foundation to stabilise the taxonomy of species in the genus. Guidelines for species recognition, definition and identification in Diaporthe are included.

Recognizing and Treating Major Depression in Fibromyalgia: A Narrative Primer for the Non-Psychiatrist.

Fibromyalgia (FM) affects 2% to 8% of the general population. FM patients often experience self-stigma and feel rejected by healthcare providers and families, resulting in isolation and distressing symptoms of pain, fatigue, and poor cognitive functioning, increasing the risk of depressive symptoms. Major Depressive Disorder (MDD) is the most common comorbidity in FM patients (Any depression: 43%; MDD: 32%). Genome-wide association studies (GWAS) have identified a common genetic risk loci for major depression and fibromyalgia. Given that even minor symptoms of depression worsen the outcomes of FM patients, clinicians are challenged to identify and manage depression in these patients. However, due to overlapping symptoms, limited screening, and contamination bias, MDD often goes undiagnosed and presents a critical challenge. Unrecognized and untreated MDD in FM patients can exacerbate fatigue, sleep disturbances, and pain, reduce physical functioning, and increase the risk of developing comorbid conditions, such as substance abuse and cardiovascular disease. These comorbidities are associated with a lower treatment response rate, a higher dropout rate, and a greater risk of relapse. Clinicians may effectively identify and treat MDD in FM patients with appropriate pharmacologic agents combined with aerobic exercise and cognitive-behavioral therapies for core FM symptoms, thus significantly reducing symptom severity for both MDD and FM. Such a comprehensive approach will result in a much-improved quality of life. MedLine content was searched via PubMed to identify eligible articles between 1995 and 2023 using search terms fibromyalgia, major depressive disorder, and treatment of depression in fibromyalgia, and the most current information is presented. In this primer for clinicians caring for FM patients, we describe clinically relevant pharmacologic and non-pharmacologic management approaches for treating MDD in FM patients.

ТЕЛЕОЛОГИЧЕСКИЙ СЮЖЕТ В ПРОИЗВЕДЕНИЯХ ДОСТОЕВСКОГО И ТОЛСТОГО О ДЕТСТВЕ

The article discusses the teleological plot in the works of F.M. Dostoevsky's "A Little Hero" and Leo Tolstoy's Childhood. This plot includes the motives of the test, the choice of the hero and his movement to salvation. During the choice, the dominant character, based on self-sacrifice, is revealed. Freeing himself from Dvoikin, the hero who makes a moral choice, according to the teachings of A.A. Ukhtomsky, takes the path of the Interlocutor. A common locus for the works of Tolstoy and Dostoevsky is the garden park, which is associated with autobiographical allusions (memories of childhood in Yasnaya Polyana and Darovoe). The garden becomes a symbol of the lost paradise and a place of "revelation", the spiritual ascent of the little hero. In both works, the little heroes behave like "knights", fighting for the heart of their Beautiful lady. At the same time, in Tolstoy's story there is a prediction of a fool and a prophetic dream of a mother about death, which she accepts with humility. The commandments of the Gospel, which are observed by the hero's mother and nanny Natalia Savishna, become a model for the narrator. Dostoevsky's little hero also shows freedom of choice, following the Gospel Truth. Both works were written in a situation of ordeal: Dostoevsky was in the Peter and Paul Fortress, Tolstoy was in the Caucasian War. In both works, the writers reflect on salvation and lead the reader.

Dissecting the shared genetic basis of Alzheimer’s disease and hippocampal volumes

AbstractBackgroundHippocampal atrophy is an important pathophysiological event in Alzheimer’s disease (AD) etiopathology. Still the mechanistic link between these volumetric abnormalities and AD remains poorly understood. In this study, we estimated polygenic overlap with mixed effect directions between AD and bilateral hippocampal volumes, and identified commonly shared genetic variants between two traits, involved in several synaptic and immunomodulatory genes.MethodFor this study we used GWAS summary statistics on AD (1,11,326 cases and 6,77,663 controls) (Bellenguezet et al., 2022) and hippocampal volumes (33,224 populations controls) (Smith et al., 2021). First, we applied Bivariate causal mixture model (MiXeR version1.3, Frei et al., 2021) to quantify the polygenic overlap between AD and bilateral hippocampal volumes. For each AD‐volume pair, MiXeR estimated the shared polygenic architecture between two traits, irrespective of the direction of individual variants effects.To explore the MiXeR estimated shared genetic basis at individual variant level, we used the conjunctional false discovery rate (conjFDR) analysis (Andreassen et al., 2013) on the association of AD with bilateral hippocampal volumes, and vice versa. The conjFDR analysis is built on an empirical Bayesian statistical framework. Four regions (MHC, 8p23.1, MAPT, APOE) with complex LD patterns were excluded from the analyses because complex correlations in regions with intricate LD might bias the estimation.ResultMiXeR univariate analysis estimated the number of AD risk variants to be around 343 genetic variants, and the number of variants for bilateral hippocampal volumes between 901 and 942 variants. MiXeR bivariate analysis estimated that the number of shared variants between AD and bilateral hippocampal volumes was around 75 and 96 variants (see Figure 1). At conjFDR &lt; 0.05, we identified 10 common loci shared by AD and left hippocampal volume,6 lead SNPs had consistent effect directions, while 4 loci have opposite effect directions according to their Z value. 8 common loci shared by AD and right hippocampal volume, 5 lead SNPs have consistent effect directions, 3 have opposite effect directions. (see Figure 2 and Table 1)ConclusionThis study provides evidence of a shared genetic architecture between AD and bilateral hippocampal volumes. The identification of common loci helps to understand the role of hippocampus in AD pathology.

Extended genome‐wide association study employing the African Genome Resources Panel identifies novel susceptibility loci for Alzheimer’s Disease in individuals of African ancestry

AbstractBackgroundAlthough African Americans are twice as likely to develop Alzheimer’s Disease (AD), individuals with African ancestry are under‐represented in genetic research of the disease. In the largest AD genome‐wide association studies to date for African‐Americans (Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified several novel susceptibility loci in addition to APOE, including ABCA7, API5, RBFOX1, and IGF1R.MethodWe performed a genome‐wide association meta‐analysis of 2,844 AD cases and 6,251 cognitively healthy controls of African ancestry (AA) assembled across 17 different cohorts. Single‐variant association analysis was conducted adjusting for age, sex, principal components, and subsequently APOE, applying logistic regression for case‐control and general estimating equations for family‐based datasets. Within‐study results were meta‐analyzed using METAL, and followed by gene‐based, pathway, scRNA‐seq, and colocalization analyses.ResultSingle variant meta‐analysis identified a novel genome‐wide significant AD risk locus in the MPDZ gene on chromosome 9p23 (rs141610415, MAF = .002, P = 3.68×10−9). MPDZ (MUPP1) is a vital component of the NMDAR signaling complex in excitatory synapses of hippocampal neurons critical for learning and memory. Two additional novel common loci and 9 novel rare loci approached genome‐wide significance at P&lt;9×10−7. Genes at these loci are acting in biologically plausible pathways: signal transduction (PLEKHG1), synaptic transmission (CNTNAP4), synaptic connectivity (SDK1), neural development/function (SRGAP3, KIDINS220, UNC5C, TSSC1, TANC2), and neuronal differentiation (ASCL1). Single‐cell RNA‐sequence analysis shows that all genes are expressed in the brain, and that expression of the orthologs of SRGAP3, TANC2, and MMP16 is upregulated with amyloid toxicity in zebrafish. Pathway analyses support the notion that immune response, transcription/DNA repair, lipid processing, and intracellular trafficking are major AD‐associated pathways in African Americans. Except for SIPA1L2 and ACER3, all previously reported loci, including ABCA7, API5, RBFOX1 and IGF1R, remain genome‐wide or close to genome‐wide significant.ConclusionWe identified several novel loci for AD in individuals with African ancestry with the strongest association observed for MPDZ involved in hippocampal synaptic signaling. Identification of a significant number of loci at suggestive significance indicates that future studies with further increased sample size will be critical to identify additional disease‐associated loci in individuals of African ancestry.

A Genome‐Wide Search for Pleiotropy in More Than 100,000 Harmonized Longitudinal Cognitive Domain Scores

AbstractBackgroundMore than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD‐related endophenotypes.MethodWe conducted genome‐wide scans for cognitive domain performance using harmonized and co‐calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community‐based (FHS, ACT, ROSMAP) and clinic‐based (ADRCs, ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP×age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP’s main effect and interaction with age. Results across datasets were combined using inverse‐variance meta‐analysis. Genome‐wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software.ResultIndividual domain and pleiotropy analyses revealed genome‐wide significant (GWS) associations with five established loci for AD and AD‐related disorders (BIN1, CR1, GRN, MS4A6A, APOE) and eight novel loci. ULK2 was associated with executive function in the community‐based cohorts (rs157405, P = 2.19×10−9). GWS associations for language were identified with CDK14 in the clinic‐based cohorts (rs705353, P = 1.73×10−8) and LINC02712 in the total sample (rs145012974, P = 3.66×10−8). GRN (rs5848, P = 4.21×10−8) and PURG (rs117523305, P = 1.73×10−8) were associated with memory in the total and community‐based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12×10−8) in the clinic‐based cohorts, and with NCALD (rs56162098, P = 1.23×10−9) and PTPRD (rs145989094, P = 8.34×10−9) in the community‐based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09×10−8) and PTPRD (rs145989094, P = 3.85×10−8) in the community‐based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD.ConclusionOur results provide some insight into genes associated with domain‐specific cognitive impairment and AD, as well as a conduit toward a syndrome‐specific precision medicine approach to AD. Increasing the size of datasets by applying the confirmatory factor analysis approach to derive harmonized measures of cognitive performance would likely enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.

Significance of the Rhoa G17V Mutation Detected By Ddpcr in Diagnostic and Monitor of Angioimmunoblastic T-Cell Lymphoma

Introduction Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) that originates from T follicular helper cells (TFH). RHOA G17V mutation is the most common hotspot locus which could be detected in 50%-70% of cases, showing its potential value for the diagnosis and clinical monitor of this disease. Methods RHOA G17V mutation were detected by Droplet digital PCR (ddPCR) in available samples from PTCL patients, at baseline and before every cycle. Response assessments were done by PET/CT and evaluated according to Lugano criteria after 3 cycles and end of first line chemotherapy(EOT), or at suspicious of disease progression. All data analyses were performed using SPSS 20.0 software (SPSS, Inc.) and GraphPad Prism 9.0 software (GraphPad software). p-Value &amp;lt; 0.05 was considered statistically significant. Results 30 patients with PTCL were included in our center from 2021-01-01 to 2023-07-01,21 were confirmed as AITL and 9 were PTCL-NOS by pathologist review. In whole cohort, RHOA G17V mutation could be detected in 46.7%(14/30) of all patients, also was positive in 61.9%(13/21) and negative in 38.1% (9/21) of patients with AITL. The sensitivity and specificity of RHOA G17V mutation in AITL by ddPCR is 61.9% and 88.9%, with a positive predictive value of 92.9%, and a negative predictive value of 50%. Hyperglobulinemia, positive direct Coombs test, elevated LDH, elevated β2-MG were founded in 76.9%(10/13),61.5%(8/13) ,61.5%(8/13) and 76.9% (10/13) of AITL patients with RHOA G17V mutation, which were significantly higher than those without RHOA G17V mutation(P=0.002,0.019,0.019,0.026). Furthermore, all of the of RHOA G17V mutated AITL patients were in clinical stage III or IV(100%, 13/13), 76.9%(10/13) of them with detectable whole-blood EBV-DNA(≥500 copies/mL) and all have three or more TFH markers(100%,13/13). We next evaluated the baseline and dynamical changes in RHOA G17V VAF-positive patients with AITL. Pretreatment VAF was significantly lower for patients who achieved complete remission or partial remission at EOT compared with that of patients with progressive disease or stable disease (mean VAF, 20.75% vs. 4.31%, p = 0.0028). (Figure 1). In addition, the median PFS in AITL patients with and without RHOA G17V mutation was 9.157 months and 15.154 months respectively(P=0.32).Finally, in 10 AITL patients with dynamic results of RHOA G17V mutation (Figure 2) , a good correlation was found in between dynamic changes of VAF of RHOA G17V mutation and response assessment by PET/CT, rerise of RHOA G17V mutation VAF could be detected prior to clinical progression in two patients，showing for the its protentional value for disease monitor. Conclusions Our study first reported the diagnostic value of single hotspot detection of G17V RHOA mutation by ddPCR in PTCL. Monitoring of G17V RHOA mutation in AITL has predictive value of assess tumor burden and response, also can complement the longitudinal supervise of disease.

Unveiling the common loci for six body measurement traits in Chinese Wenshan cattle

Introduction: Body measurement traits are integral in cattle production, serving as pivotal criteria for breeding selection. Wenshan cattle, a local breed in China’s Yunnan province, exhibit remarkable genetic diversity. However, the molecular mechanisms regulating body measurement traits in Wenshan cattle remain unexplored.Methods: In this study, we performed a genome-wide association method to identify genetic architecture for body height body length hip height back height (BAH), waist height and ischial tuberosity height using the Bovine 50 K single nucleotide polymorphism Array in 1060 Wenshan cattles.Results: This analysis reveals 8 significant SNPs identified through the mixed linear model (MLM), with 6 SNPs are associated with multiple traits and 4 SNPs are associated with all 6 traits. Furthermore, we pinpoint 21 candidate genes located in proximity to or within these significant SNPs. Among them, Scarb1, acetoacetyl-CoA synthetase and HIVEP3 were implicated in bone formation and rarely encountered in livestock body measurement traits, emerge as potential candidate genes regulating body measurement traits in Wenshan cattle.Discussion: This investigation provides valuable insights into the genetic mechanisms underpinning body measurement traits in this unique cattle breed, paving the way for further research in this domain.

A large meta-analysis identifies genes associated with anterior uveitis

Anterior Uveitis (AU) is the inflammation of the anterior part of the eye, the iris and ciliary body and is strongly associated with HLA-B*27. We report AU exome sequencing results from eight independent cohorts consisting of 3,850 cases and 916,549 controls. We identify common genome-wide significant loci in HLA-B (OR = 3.37, p = 1.03e-196) and ERAP1 (OR = 0.86, p = 1.1e-08), and find IPMK (OR = 9.4, p = 4.42e-09) and IDO2 (OR = 3.61, p = 6.16e-08) as genome-wide significant genes based on the burden of rare coding variants. Dividing the cohort into HLA-B*27 positive and negative individuals, we find ERAP1 haplotype is strongly protective only for B*27-positive AU (OR = 0.73, p = 5.2e-10). Investigation of B*27-negative AU identifies a common signal near HLA-DPB1 (rs3117230, OR = 1.26, p = 2.7e-08), risk genes IPMK and IDO2, and several additional candidate risk genes, including ADGFR5, STXBP2, and ACHE. Taken together, we decipher the genetics underlying B*27-positive and -negative AU and identify rare and common genetic signals for both subtypes of disease.

Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Prior genome-wide association studies (GWAS) identified few genomic loci and disease genes due to limited sample size. Purpose To discover novel genetic loci, genes and mechanisms implicated in HCM using a large scale GWAS and multi-trait analysis of GWAS (MTAG). Methods and results We performed the largest HCM GWAS meta-analysis and MTAG to date including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We estimated the heritability of HCM attributable to common genetic variation (h2SNP) to be 0.25±0.02 using genome-based restricted maximum likelihood (GREML), with higher h2SNP in non-sarcomeric (0.29±0.02) compared to sarcomeric HCM (0.16±0.04). We identified a total of 70 loci (50 novel) associated with HCM (Figure 1), and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin. We performed rare variant burden analysis including 1,845 clinically-diagnosed unrelated HCM cases and 37,481 controls and demonstrated a 10.5-fold (95% CI: 4.1-26.8; P=0.0000002) excess burden of SVIL loss of function (LoF) variants in HCM cases. Two-sample mendelian randomization analyses using LV contractility as exposure and obstructive (oHCM) and non-obstructive HCM (nHCM) as outcomes support a causal role of increased LV contractility in both oHCM and nHCM (Figure 2), suggesting common disease mechanisms and anticipating shared response to therapy. Conclusion We identify 50 novel genomic loci associated with HCM. Our data suggest that LoF variants in SVIL are a cause of HCM, and that increased contractility mediate both nHCM and oHCM. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.Figure 1Figure 2