The Role of BAG3 Protein Interactions in Cardiomyopathies.

Bcl-2-associated athanogene 3 (BAG3) plays an important function in cellular protein quality control (PQC) maintaining proteome stability. Mutations in the BAG3 gene result in cardiomyopathies. Due to its roles in cardiomyopathies and the complexity of BAG3-protein interactions, it is important to understand these protein interactions given the importance of the multifunctional cochaperone BAG3 in cardiomyocytes, using an in vitro cardiomyocyte model. The experimental assay was conducted using high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in the human AC16 cardiomyocyte cell line with BioID technology. Proteins with BAG3-interaction were identified in all the 28 hallmark gene sets enriched in idiopathic cardiomyopathies and/or ischemic disease. Among the 24 hallmark gene sets enriched in both idiopathic cardiomyopathies and ischemic disease, 15 gene sets had at least 3 proteins with BAG3-interaction. This study highlights BAG3 protein interactions, unveiling the key gene sets affected in cardiomyopathies, which help to explain the molecular mechanisms of the cardioprotective effects of BAG3. In addition, this study also highlighted the complexity of proteins with BAG3 interactions, implying unwanted effects of BAG3.

Implications of the non-neuronal cholinergic system for therapeutic interventions of inflammatory skin diseases.

The pivotal roles of acetylcholine (ACh) in physiological processes encompass both the nervous and non-neuronal cholinergic systems (NNCS). This review delineates the synthesis, release, receptor interactions, and degradation of ACh within the nervous system, and explores the NNCS in depth within skin cells including keratinocytes, endothelial cells, fibroblasts, macrophages, and other immune cells. We highlight the NNCS's essential functions in maintaining epidermal barrier integrity, promoting wound healing, regulating microcirculation, and modulating inflammatory responses. The potential of the NNCS as a therapeutic target for localized ACh regulation in the skin is discussed, though the translation of these findings into clinical practice remains uncertain due to the complexity of cholinergic signalling and the lack of comprehensive human studies. The review progresses to therapeutic modulation strategies of the NNCS, including AChE inhibitors, nicotinic and muscarinic receptor agonists and antagonists, choline uptake enhancers, and botulinum toxin, highlighting their relevance in dermatology. We highlight the impact of the NNCS on prevalent skin diseases such as psoriasis, atopic dermatitis, rosacea, acne, bullous diseases, hyperhidrosis and hypohidrosis, illustrating its significance in disease pathogenesis and therapy. This comprehensive overview aims to enhance understanding of the NNCS's role in skin health and disease, offering a foundation for future research and therapeutic innovation.

Navigating Complexity in Postural Orthostatic Tachycardia Syndrome.

Postural Orthostatic Tachycardia Syndrome (POTS) affects up to 1% of the US population, predominantly women, and is characterized by a complex, elusive etiology and heterogeneous phenotypes. This review delves into the intricate physiology and etiology of POTS, decoding the roles of the sinoatrial node, the autonomic nervous system, fluid dynamics, and the interplay between the immune and endocrine systems. It further examines key contributing factors such as dysautonomia, thoracic hypovolemia, autonomic neuropathies, sympathetic denervation, autoimmune responses, and associations with conditions such as small-fiber neuropathy and mast cell activation syndrome. Given the numerous mysteries surrounding POTS, we also cautiously bring attention to sinoatrial node and myocardial function, particularly in how the heart responds to stress despite exhibiting a normal cardiac phenotype at rest. The potential of genomic research in elucidating the underlying mechanisms of POTS is emphasized, suggesting this as a valuable approach that is likely to improve our understanding of the genetic underpinnings of POTS. The review introduces a tentative classification system for the etiological factors in POTS, which seeks to capture the condition's diverse aspects by categorizing various etiological factors and acknowledging co-occurring conditions. This classification, while aiming to enhance understanding and optimize treatment targets, is presented as a preliminary model needing further study and refinement. This review underscores the ongoing need for research to unravel the complexities of POTS and to develop targeted therapies that can improve patient outcomes.

Copy number variations contribute to malignant tumor development in children with serious birth defects.

There are two key signatures of pediatric cancers: (a) higher prevalence of germline alterations and (b) heterogeneity in alteration types. Recent population-based assessments have demonstrated that children with birth defects (BDs) are more likely to develop cancer even without chromosomal anomalies; therefore, explorations of genetic alterations in children with BDs and cancers could provide new insights into the underlying mechanisms for pediatric tumor development. We performed whole-genome sequencing (WGS) on blood-derived DNA for 1556 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumor, 757 cancer-free children with BDs, and 345 healthy individuals, focusing on copy number variation (CNV) analysis. Roughly half of the children with BD-cancer have CNVs that are not identified in BD-only/healthy individuals, and CNVs are not evenly distributed among these patients. Strong heterogeneity was observed, with a limited number of cancer predisposition genes containing CNVs in more than three patients. Moreover, functional enrichments of genes with CNVs showed that dozens of patients have variations related to the same biological pathways, such as deletions of genes with neurological functions and duplications of immune response genes. Phenotype clustering uncovered recurrences of patients with sarcoma: A notable enrichment was observed involving non-coding RNA regulators, showing strong signals related to growth and cancer regulations in functional analysis. In conclusion, we conducted one of the first genomic studies exploring the impact of CNVs on cancer development in children with BDs, unveiling new insights into the underlying biological processes.

Single-Cell Omics for Transcriptome CHaracterization (SCOTCH): isoform-level characterization of gene expression through long-read single-cell RNA sequencing.

The advent of long-read single-cell transcriptome sequencing (lr-scRNA-Seq) represents a significant leap forward in single-cell genomics. With the recent introduction of R10 flowcells by Oxford Nanopore, we propose that previous computational methods designed to handle high sequencing error rates are no longer relevant, and that the prevailing approach using short reads to compile "barcode space" (candidate barcode list) to de-multiplex long reads are no longer necessary. Instead, computational methods should now shift focus on harnessing the unique benefits of long reads to analyze transcriptome complexity. In this context, we introduce a comprehensive suite of computational methods named Single-Cell Omics for Transcriptome CHaracterization (SCOTCH). Our method is compatible with the single-cell library preparation platform from both 10X Genomics and Parse Biosciences, facilitating the analysis of special cell populations, such as neurons, hepatocytes and developing cardiomyocytes. We specifically re-formulated the transcript mapping problem with a compatibility matrix and addressed the multiple-mapping issue using probabilistic inference, which allows the discovery of novel isoforms as well as the detection of differential isoform usage between cell populations. We evaluated SCOTCH through analysis of real data across different combinations of single-cell libraries and sequencing technologies (10X + Illumina, Parse + Illumina, 10X + Nanopore_R9, 10X + Nanopore_R10, Parse + Nanopore_R10), and showed its ability to infer novel biological insights on cell type-specific isoform expression. These datasets enhance the availability of publicly available data for continued development of computational approaches. In summary, SCOTCH allows extraction of more biological insights from the new advancements in single-cell library construction and sequencing technologies, facilitating the examination of transcriptome complexity at the single-cell level.

Shared molecular mechanisms and transdiagnostic potential of neurodevelopmental disorders and immune disorders.

The co-occurrence and familial clustering of neurodevelopmental disorders and immune disorders suggest shared genetic risk factors. Based on genome-wide association summary statistics from five neurodevelopmental disorders and four immune disorders, we conducted genome-wide, local genetic correlation and polygenic overlap analysis. We further performed a cross-trait GWAS meta-analysis. Pleotropic loci shared between the two categories of diseases were mapped to candidate genes using multiple algorithms and approaches. Significant genetic correlations were observed between neurodevelopmental disorders and immune disorders, including both positive and negative correlations. Neurodevelopmental disorders exhibited higher polygenicity compared to immune disorders. Around 50%-90% of genetic variants of the immune disorders were shared with neurodevelopmental disorders. The cross-trait meta-analysis revealed 154 genome-wide significant loci, including 8 novel pleiotropic loci. Significant associations were observed for 30 loci with both types of diseases. Pathway analysis on the candidate genes at these loci revealed common pathways shared by the two types of diseases, including neural signaling, inflammatory response, and PI3K-Akt signaling pathway. In addition, 26 of the 30 lead SNPs were associated with blood cell traits. Neurodevelopmental disorders exhibit complex polygenic architecture, with a subset of individuals being at a heightened genetic risk for both neurodevelopmental and immune disorders. The identification of pleiotropic loci has important implications for exploring opportunities for drug repurposing, enabling more accurate patient stratification, and advancing genomics-informed precision in the medical field of neurodevelopmental disorders.

NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways.

BACKGROUND: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology. METHODS: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene. RESULTS: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene. CONCLUSION: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.

CRISPR/Cas9 screenings unearth protein arginine methyltransferase 7 as a novel essential gene in prostate cancer metastasis.

Due to the limited effectiveness of current treatments, the survival rate of patients with metastatic castration-resistant prostate cancer (mCRPC) is significantly reduced. Consequently, it is imperative to identify novel therapeutic targets for managing these patients. Since the invasive ability of cells is crucial for establishing and maintaining metastasis, the aim of this study was to identify the essential regulators of invasive abilities of mCRPC cells by conducting two independent high-throughput CRISPR/Cas9 screenings. Furthermore, some of the top hits were validated using siRNA technology, with protein arginine methyltransferase 7 (PRMT7) emerging as the most promising candidate. We demonstrated that its inhibition or depletion via genetic or pharmacological approaches significantly reduces invasive, migratory and proliferative abilities of mCRPC cells in vitro. Moreover, we confirmed that PRMT7 ablation reduces cell dissemination in chicken chorioallantoic membrane and mouse xenograft assays. Molecularly, PRMT7 reprograms the expression of several adhesion molecules by methylating various transcription factors, such as FoxK1, resulting in the loss of adhesion from the primary tumor and increased motility of mCRPC cells. Furthermore, PRMT7 higher expression correlates with tumor aggressivity and poor overall survival in prostate cancer patients. Thus, this study demonstrates that PRMT7 is a potential therapeutic target and potential biomarker for mPCa.

Revealing novel genomic insights and therapeutic targets for juvenile idiopathic arthritis through omics.

BACKGROUND: The genetic architecture of JIA remains only partially comprehended. There is a clear imperative for continued endeavours to uncover insights into the underlying causes of JIA. METHODS: This study encompassed a comprehensive spectrum of endeavours, including conducting a JIA genome-wide association study (GWAS) meta-analysis that incorporated data from 4550 JIA cases and 18 446 controls. We employed in silico and genome-editing approaches to prioritizing target genes. To investigate pleiotropic effects, we conducted phenome-wide association studies. Cell-type enrichment analyses were performed by integrating bulk and single-cell sequencing data. Finally, we delved into potential druggable targets for JIA. RESULTS: Fourteen genome-wide significant non-HLA loci were identified, including four novel loci, each exhibiting pleiotropic associations with other autoimmune diseases or musculoskeletal traits. We uncovered strong genetic correlation between JIA and BMD traits at 52 genomic regions, including three GWAS loci for JIA. Candidate genes with immune functions were captured by in silico analyses at each novel locus, with additional findings identified through our experimental approach. Cell-type enrichment analysis revealed 21 specific immune cell types crucial for the affected organs in JIA, indicating their potential contribution to the disease. Finally, 24 known or candidate druggable target genes were prioritized. CONCLUSIONS: Our identification of four novel JIA-associated genes, CD247, RHOH, COLEC10 and IRF8, broadens the novel potential drug repositioning opportunities. We established a new genetic link between COLEC10, TNFRSF11B and JIA/BMD. Additionally, the identification of RHOH underscores its role in positive thymocyte selection, thereby illuminating a critical facet of JIA's underlying biological mechanisms.

Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency.

BACKGROUND: CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). OBJECTIVES: This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. METHODS: The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array. RESULTS: This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation. CONCLUSIONS: Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

A Protective Role of Low Polygenic Risk Score in Healthy Individuals Carrying Attention-Deficit/Hyperactivity Disorder-Associated Copy Number Variations.

BACKGROUND: Previous studies have implicated both rare copy number variations (CNVs) and common variants in liability for attention-deficit/hyperactivity disorder (ADHD). However, how common and rare genetic variants jointly contribute to individual liability requires further investigation in larger cohorts. METHODS: This study comprises 9385 participants of European descent and 7810 participants of African American ancestry who were recruited from the greater Philadelphia area by the Children's Hospital of Philadelphia. The polygenic risk score (PRS) of each participant was estimated by linkage disequilibrium pruning and p-value thresholding (P + T) methods using PRSice-2. We investigated whether the risk of ADHD follows a polygenic liability threshold model wherein 1) the risk of ADHD requires less contribution from common variants in the presence of a rare CNV, and 2) control carriers of ADHD-associated CNVs have lower common risk allele burden than noncarriers. RESULTS: CNVs previously reported in ADHD cases were significantly associated with ADHD risk in both the European American cohort and the African American cohort. Healthy control participants carrying those same risk CNVs had lower PRSs than those without risk CNVs in the European American cohort. This result was replicated in the African American cohort. However, PRSs were not significantly different in case participants carrying risk CNVs versus those without risk CNVs. CONCLUSIONS: These findings provide evidence in support of interactive effects of PRS and ADHD-associated CNVs on disease risk and add novel insights into the genetic basis of ADHD by highlighting a protective role of low PRS in ADHD.

Single-Cell RNA Sequencing Technology Landscape in 2023.

Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cellular heterogeneity and the dynamics of gene expression, bearing profound significance in stem cell research. Depending on the starting materials used for analysis, scRNA-seq encompasses scRNA-seq and single-nucleus RNA sequencing (snRNA-seq). scRNA-seq excels in capturing cellular heterogeneity and characterizing rare cell populations within complex tissues, while snRNA-seq is advantageous in situations where intact cell dissociation is challenging or undesirable (eg, epigenomic studies). A number of scRNA-seq technologies have been developed as of late, including but not limited to droplet-based, plate-based, hydrogel-based, and spatial transcriptomics. The number of cells, sequencing depth, and sequencing length in scRNA-seq can vary across different studies. Addressing current technical challenges will drive the future of scRNA-seq, leading to more comprehensive and precise insights into cellular biology and disease mechanisms informing therapeutic interventions.

High Comorbidity of Pediatric Cancers in Patients with Birth Defects: Insights from Whole Genome Sequencing Analysis of Copy Number Variations.

BACKGROUND: Patients with birth defects (BD) exhibit an elevated risk of cancer. We aimed to investigate the potential link between pediatric cancers and BDs, exploring the hypothesis of shared genetic defects contributing to the coexistence of these conditions. METHODS: This study included 1454 probands with BDs (704 females and 750 males), including 619 (42.3%) with and 845 (57.7%) without co-occurrence of pediatric onset cancers. Whole genome sequencing (WGS) was done at 30X coverage through the Kids First/Gabriella Miller X01 Program. RESULTS: 8211 CNV loci were called from the 1454 unrelated individuals. 191 CNV loci classified as pathogenic/likely pathogenic (P/LP) were identified in 309 (21.3%) patients, with 124 (40.1%) of these patients having pediatric onset cancers. The most common group of CNVs are pathogenic deletions covering the region ChrX:52,863,011-55,652,521, seen in 162 patients including 17 males. Large recurrent P/LP duplications >5MB were detected in 33 patients. CONCLUSIONS: This study revealed that P/LP CNVs were common in a large cohort of BD patients with high rate of pediatric cancers. We present a comprehensive spectrum of P/LP CNVs in patients with BDs and various cancers. Notably, deletions involving E2F target genes and genes implicated in mitotic spindle assembly and G2/M checkpoint were identified, potentially disrupting cell-cycle progression and providing mechanistic insights into the concurrent occurrence of BDs and cancers.

Mitochondrial DNA Haplogroup K Is Protective Against Autism Spectrum Disorder Risk in Populations of European Ancestry.

OBJECTIVE: Accumulative evidence indicates a critical role of mitochondrial function in autism spectrum disorders (ASD), implying that ASD risk may be linked to mitochondrial dysfunction due to DNA (mtDNA) variations. Although a few studies have explored the association between mtDNA variations and ASD, the role of mtDNA in ASD is still unclear. Here, we aimed to investigate whether mitochondrial DNA haplogroups are associated with the risk of ASD. METHOD: Two European cohorts and an Ashkenazi Jewish (AJ) cohort were analyzed, including 2,062 ASD patients in comparison with 4,632 healthy controls. DNA samples were genotyped using Illumina HumanHap550/610 and Illumina 1M arrays, inclusive of mitochondrial markers. Mitochondrial DNA (mtDNA) haplogroups were identified from genotyping data using HaploGrep2. A mitochondrial genome imputation pipeline was established to detect mtDNA variants. We conducted a case-control study to investigate potential associations of mtDNA haplogroups and variants with the susceptibility to ASD. RESULTS: We observed that the ancient adaptive mtDNA haplogroup K was significantly associated with decreased risk of ASD by the investigation of 2 European cohorts including a total of 2,006 cases and 4,435 controls (odds ratio = 0.64, P=1.79 × 10-5), and we replicated this association in an Ashkenazi Jewish (AJ) cohort including 56 cases and 197 controls (odds ratio = 0.35, P = 9.46 × 10-3). Moreover, we demonstrate that the mtDNA variants rs28358571, rs28358584, and rs28358280 are significantly associated with ASD risk. Further expression quantitative trait loci (eQTLs) analysis indicated that the rs28358584 and rs28358280 genotypes are associated with expression levels of nearby genes in brain tissues, suggesting those mtDNA variants may confer risk for ASD via regulation of expression levels of genes encoded by the mitochondrial genome. CONCLUSION: This study helps to shed light on the contribution of mitochondria in ASD and provides new insights into the genetic mechanism underlying ASD, suggesting the potential involvement of mtDNA-encoded proteins in the development of ASD.

The Circassians and the Chechens in Jordan: results of a decade of epidemiological and genetic studies.

Circassians and Chechens in Jordan, both with Caucasian ancestry, are genetically isolated due to high rate of endogamous marriages. Recent interest in these populations has led to studies on their genetic similarities, differences, and epidemiological differences in various diseases. Research has explored their predisposition to conditions like diabetes, hypertension, and cancer. Moreover, pharmacogenetic (PGx) studies have also investigated medication response variations within these populations, and forensic studies have further contributed to understanding these populations. In this review article, we first discuss the background of these minority groups. We then show the results of a principle component analysis (PCA) to investigate the genetic relationships between Circassian and Chechen populations living in Jordan. We here present a summary of the findings from the 10 years of research conducted on them. The review article provides a comprehensive summary of research findings that are truly valuable for understanding the unique genetic characteristics, diseases' prevalence, and medication responses among Circassians and Chechens living in Jordan. We believe that gaining deeper comprehension of the root causes of various diseases and developing effective treatment methods that benefit the society as a whole are imperative to engaging a wide range of ethnic groups in genetic research.

Genomic variants exclusively identified in children with birth defects and concurrent malignant tumors predispose to cancer development.

Children with birth defects (BD) express distinct clinical features that often have various medical consequences, one of which is predisposition to the development of cancers. Identification of the underlying genetic mechanisms related to the development of cancer in BD patients would allow for preventive measures. We performed a whole genome sequencing (WGS) study on blood-derived DNA samples from 1566 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumors, 767 cancer-free BD probands, and 345 healthy individuals. Exclusive recurrent variants were identified in BD-cancer and BD-only patients and mapped to their corresponding genomic regions. We observed statistically significant overlaps for protein-coding/ncRNA with exclusive variants in exons, introns, ncRNAs, and 3'UTR regions. Exclusive exonic variants, especially synonymous variants, tend to occur in prior exons locus in BD-cancer children. Intronic variants close to splicing site (< 500 bp from exon) have little overlaps in BD-cancer and BD-only patients. Exonic variants in non-coding RNA (ncRNA) tend to occur in different ncRNAs exons regardless of the overlaps. Notably, genes with 5' UTR variants are almost mutually exclusive between the two phenotypes. In conclusion, we conducted the first genomic study to explore the impact of recurrent variants exclusive to the two distinguished clinical phenotypes under study, BD with or without cancer, demonstrating enrichment of selective protein-coding/ncRNAs differentially expressed between these two phenotypes, suggesting that selective genetic factors may underlie the molecular processes of pediatric cancer development in BD children.

Trans-ethnic genomic informed risk assessment for Alzheimer's disease: An International Hundred K+ Cohorts Consortium study.

BACKGROUND: As a collaboration model between the International HundredK+ Cohorts Consortium (IHCC) and the Davos Alzheimer's Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for Alzheimer's disease (AD). METHODS: The GIRA model was created to include polygenic risk score calculated from the AD genome-wide association study loci, the apolipoprotein E haplotypes, and non-genetic covariates including age, sex, and the first three principal components of population substructure. RESULTS: We validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD. CONCLUSIONS: As the initial effort by the IHCC to leverage existing large-scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA for AD with the potential of identifying individuals at high risk of developing AD for future clinical applications.

Trans-ethnic polygenic risk scores for body mass index: An international hundred K+ cohorts consortium study.

BACKGROUND: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort. METHODS: The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis. RESULTS: We show that in the absence of a well powered trans-ethnic GWAS from which to derive marker SNPs and effect estimates for PRS, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred, by adjusting the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort. CONCLUSIONS: Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians.