post-GWAS Era Research Articles

CAUSALdb2: an updated database for causal variants of complex traits.

Unraveling the causal variants from genome wide association studies (GWASs) is pivotal for understanding genetic underpinnings of complex traits and diseases. Despite continuous efforts, tools to refine and prioritize GWAS signals need enhancement to address the direct causal implications of genetic variations. To overcome challenges related to statistical fine-mapping in identifying causal variants, CAUSALdb has been updated with novel features and comprehensive datasets, morphing into CAUSALdb2. This expanded repository integrates 15057 updated GWAS summary statistics across 10839 unique traits and implements both LD-based and LD-free fine-mapping approaches, including innovative applications of approximate Bayes Factor and SuSiE. Additionally, by incorporating larger LD reference panels such as TOPMED and UK Biobank, and integrating functional annotations via PolyFun, CAUSALdb2 enhances the accuracy and context of fine-mapping results. The database now supports interrogation of additional causal signals and offers sophisticated visualizations to aid researchers in deciphering complex genetic architectures. By facilitating a deeper and more precise characterisation of causal variants, CAUSALdb2 serves as a crucial tool for advancing the genetic analysis of complex diseases. Available freely, CAUSALdb2 continues to set benchmarks in the post-GWAS era, fostering the development of targeted diagnostics and therapeutics derived from responsible genetic research. Explore these advancements at http://mulinlab.org/causaldb.

Research on the genetic etiology of polycystic ovary syndrome in the post-GWAS era

Great progress has been made in the genetic research of PCOS, thanks to the application of genome association study (GWAS) technology. However, in the post-GWAS era, investigating the pathogenic mechanisms related to numerous genetic loci has become challenging, leading to the current generalized approach to treating PCOS. To address this issue, taking the significantly associated susceptibility gene THADA as an example, we share a series of advancements from the perspectives of genetic evolution, epigenetics, and gene function studies. Our aim is to provide guidance for a better understanding of the essence of PCOS.

Genetic and functional research strategies of non-syndromic cleft lip with or without cleft palate in the post genome-wide association study era

The emergence of genome-wide association studies (GWAS) has greatly promoted the genetic research of non-syndromic cleft lip with or without cleft palate (NSCL/P). There have been more than 40 regions concerning NSCL/P identified by GWAS, whereas specific susceptible loci and their potential function remains unclear. In the post-GWAS era, precise localization of susceptible loci in candidate regions and exploration of underlying biological mechanism will contribute to further understanding of genetic etiology of NSCL/P. The present article reviewed the genetic and functional research strategies of NSCL/P in post-GWAS era.

Disentangling the complexity of psoriasis in the post-genome-wide association era.

In recent years, genome-wide association studies (GWAS) have been instrumental in unraveling the genetic architecture of complex diseases, including psoriasis. The application of large-scale GWA studies in psoriasis has illustrated several associated loci that participate in the cutaneous inflammation, however explaining a fraction of the disease heritability. With the advent of high-throughput sequencing technologies and functional genomics approaches, the post-GWAS era aims to unravel the functional mechanisms underlying the inter-individual variability in psoriasis patients. In this review, we present the key advances of psoriasis GWAS in under-represented populations, rare, non-coding and structural variants and epistatic phenomena that orchestrate the interplay between different cell types. We further review the gene-gene and gene-environment interactions contributing to the disease predisposition and development of comorbidities through Mendelian randomization studies and pleiotropic effects of psoriasis-associated loci. We finally examine the holistic approaches conducted in psoriasis through system genetics and state-of-the-art transcriptomic analyses, discussing their potential implication in the expanding field of precision medicine and characterization of comorbidities.

The potential of integrating human and mouse discovery platforms to advance our understanding of cardiometabolic diseases.

Cardiometabolic diseases encompass a range of interrelated conditions that arise from underlying metabolic perturbations precipitated by genetic, environmental, and lifestyle factors. While obesity, dyslipidaemia, smoking, and insulin resistance are major risk factors for cardiometabolic diseases, individuals still present in the absence of such traditional risk factors, making it difficult to determine those at greatest risk of disease. Thus, it is crucial to elucidate the genetic, environmental, and molecular underpinnings to better understand, diagnose, and treat cardiometabolic diseases. Much of this information can be garnered using systems genetics, which takes population-based approaches to investigate how genetic variance contributes to complex traits. Despite the important advances made by human genome-wide association studies (GWAS) in this space, corroboration of these findings has been hampered by limitations including the inability to control environmental influence, limited access to pertinent metabolic tissues, and often, poor classification of diseases or phenotypes. A complementary approach to human GWAS is the utilisation of model systems such as genetically diverse mouse panels to study natural genetic and phenotypic variation in a controlled environment. Here, we review mouse genetic reference panels and the opportunities they provide for the study of cardiometabolic diseases and related traits. We discuss how the post-GWAS era has prompted a shift in focus from discovery of novel genetic variants to understanding gene function. Finally, we highlight key advantages and challenges of integrating complementary genetic and multi-omics data from human and mouse populations to advance biological discovery.

Integrative Genomic Analysis of m6a-SNPs Identifies Potential Functional Variants Associated with Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects 35 million people worldwide. However, no potential therapeutics currently are available for AD because of the multiple factors involved in it, such as regulatory factors with their candidate genes, factors associated with the expression levels of its corresponding genes, and many others. To date, 29 novel loci from GWAS have been reported for AD by the Psychiatric Genomics Consortium (PGC2). Nevertheless, the main challenge of the post-GWAS era, namely to detect significant variants of the target disease, has not been conducted for AD. N6-methyladenosine (m6a) is reported as the most prevalent mRNA modification that exists in eukaryotes and that influences mRNA nuclear export, translation, splicing, and the stability of mRNA. Furthermore, studies have also reported m6a's association with neurogenesis and brain development. We carried out an integrative genomic analysis of AD variants from GWAS and m6a-SNPs from m6AVAR to identify the effects of m6a-SNPs on AD and identified the significant variants using the statistically significance value (p-value <0.05). The cis-regularity variants with their corresponding genes and their influence on gene expression in the gene expression profiles of AD patients were determined, and showed 1458 potential m6a-SNPs (based on p-value <0.05) associated with AD. eQTL analysis showed that 258 m6a-SNPs had cis-eQTL signals that overlapped with six significant differentially expressed genes based on p-value <0.05 in two datasets of AD gene expression profiles. A follow-up study to elucidate the impact of our identified m6a-SNPs in the experimental study would validate our findings for AD, which would contribute to the etiology of AD.

Gene and schizophrenia in the pregenome and postgenome-wide association studies era: a bibliometric analysis and network visualization.

This study aimed to perform a bibliometric analysis on genetic studies in schizophrenia in the pregenome-wide association studies (GWAS) and post-GWAS era. We searched the literature on genes and schizophrenia using the Scopus database. The documents increased with time, especially after the human genome project and International HapMap Project, with the highest citation in 2008. The top occurrence author keywords were discovered to be different in the pre-GWAS and post-GWAS eras, reflecting the progress of genetic studies connected to schizophrenia. Emerging keywords highlighted a trend towards an application of precision medicine, showing an interplay of environmental exposures as well as genetic factors in schizophrenia pathogenesis, progression, and response to therapy. In conclusion, the gene and schizophrenia literature has grown rapidly after the human genome project, and the temporal variation in the author keywords pattern reflects the trend of genetic studies related to schizophrenia in the pre-GWAS and post-GWAS era.

Single-cell omics: A new direction for functional genetic research in human diseases and animal models.

Over the past decade, with the development of high-throughput single-cell sequencing technology, single-cell omics has been emerged as a powerful tool to understand the molecular basis of cellular mechanisms and refine our knowledge of diverse cell states. They can reveal the heterogeneity at different genetic layers and elucidate their associations by multiple omics analysis, providing a more comprehensive genetic map of biological regulatory networks. In the post-GWAS era, the molecular biological mechanisms influencing human diseases will be further elucidated by single-cell omics. This review mainly summarizes the development and trend of single-cell omics. This involves single-cell omics technologies, single-cell multi-omics technologies, multiple omics data integration methods, applications in various human organs and diseases, classic laboratory cell lines, and animal disease models. The review will reveal some perspectives for elucidating human diseases and constructing animal models.

Genome-wide association studies (GWAS) vs functional validation: the challenge of the post-GWAS era

Genome-wide association studies (GWAS) vs functional validation: the challenge of the post-GWAS era

IpaQTL-atlas: an atlas of intronic polyadenylation quantitative trait loci across human tissues.

Functional interpretation of disease-associated non-coding variants remains a significant challenge in the post-GWAS era. Our recent study has identified 3'UTR alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) and connects APA events with QTLs as a major driver of human traits and diseases. Besides 3'UTR, APA events can also occur in intron regions, and increasing evidence has connected intronic polyadenylation with disease risk. However, systematic investigation of the roles of intronic polyadenylation in human diseases remained challenging due to the lack of a comprehensive database across a variety of human tissues. Here, we developed ipaQTL-atlas (http://bioinfo.szbl.ac.cn/ipaQTL) as the first comprehensive portal for intronic polyadenylation. The ipaQTL-atlas is based on the analysis of 15 170 RNA-seq data from 838 individuals across 49 Genotype-Tissue Expression (GTEx v8) tissues and contains ∼0.98 million SNPs associated with intronic APA events. It provides an interface for ipaQTLs search, genome browser, boxplots, and data download, as well as the visualization of GWAS and ipaQTL colocalization results. ipaQTL-atlas provides a one-stop portal to access intronic polyadenylation information and could significantly advance the discovery of APA-associated disease susceptibility genes.

A comprehensive comparison of multilocus association methods with summary statistics in genome-wide association studies

BackgroundMultilocus analysis on a set of single nucleotide polymorphisms (SNPs) pre-assigned within a gene constitutes a valuable complement to single-marker analysis by aggregating data on complex traits in a biologically meaningful way. However, despite the existence of a wide variety of SNP-set methods, few comprehensive comparison studies have been previously performed to evaluate the effectiveness of these methods.ResultsWe herein sought to fill this knowledge gap by conducting a comprehensive empirical comparison for 22 commonly-used summary-statistics based SNP-set methods. We showed that only seven methods could effectively control the type I error, and that these well-calibrated approaches had varying power performance under the simulation scenarios. Overall, we confirmed that the burden test was generally underpowered and score-based variance component tests (e.g., sequence kernel association test) were much powerful under the polygenic genetic architecture in both common and rare variant association analyses. We further revealed that two linkage-disequilibrium-free P value combination methods (e.g., harmonic mean P value method and aggregated Cauchy association test) behaved very well under the sparse genetic architecture in simulations and real-data applications to common and rare variant association analyses as well as in expression quantitative trait loci weighted integrative analysis. We also assessed the scalability of these approaches by recording computational time and found that all these methods can be scalable to biobank-scale data although some might be relatively slow.ConclusionIn conclusion, we hope that our findings can offer an important guidance on how to choose appropriate multilocus association analysis methods in post-GWAS era. All the SNP-set methods are implemented in the R package called MCA, which is freely available at https://github.com/biostatpzeng/.

Genetic Modifications to Alter Blood Pressure Level.

Genetic manipulation is one of the indispensable techniques to examine gene functions both in vitro and in vivo. In particular, cardiovascular phenotypes such as blood pressure cannot be evaluated in vitro system, necessitating the creation of transgenic or gene-targeted knock-out and knock-in experimental animals to understand the pathophysiological roles of specific genes on the disease conditions. Although genome-wide association studies (GWAS) in various human populations have identified multiple genetic variations associated with increased risk for hypertension and/or its complications, the causal links remain unresolved. Genome-editing technologies can be applied to many different types of cells and organisms for creation of knock-out/knock-in models. In the post-GWAS era, it may be more worthwhile to validate pathophysiological implications of the risk variants and/or candidate genes by creating genome-edited organisms.

Target sequencing reveals the association between variants in VAX1 and NSCL/P in Chinese population.

A significant genetic association between rs7078160 in VAX1 and NSCL/P has been established through genome-wide association studies (GWAS), and we previously replicated the association in the Chinese population. The critical issue in the post-GWAS era is to identify functional variations that have a real impact on disease in the susceptible regions highlighted by GWAS. This study aimed to elucidate functional variants in VAX1 fully. Firstly, target sequencing was performed on 159NSCL/P patients, followed by association analysis to discover disease-associated single-nucleotide polymorphisms (SNPs); we then replicated the findings using a larger sample (1626 cases, 2255 controls) and investigated how candidate SNPs affect disease occurrence using extensive annotation databases. Additionally, we compared the genetic profiles of NSCL/P subtypes. In this study, 6 SNPs in VAX1 were identified to be associated with NSCL/P in the Western Han Chinese population. Five of them were predicted to influence transcriptional factor-biding ability and were expression quantitative trait loci (eQTLs) of nearby genes in multiple tissues. The previously reported association between rs7078160 and NSCL/P was successfully replicated. Moreover, our findings firstly revealed that 5 SNPs in VAX1 are associated with NSCL/P in the Western Han Chinese population. Original Reports.

Simultaneous test and estimation of total genetic effect in eQTL integrative analysis through mixed models.

Integration of expression quantitative trait loci (eQTL) into genome-wide association studies (GWASs) is a promising manner to reveal functional roles of associated single-nucleotide polymorphisms (SNPs) in complex phenotypes and has become an active research field in post-GWAS era. However, how to efficiently incorporate eQTL mapping study into GWAS for prioritization of causal genes remains elusive. We herein proposed a novel method termed as Mixed transcriptome-wide association studies (TWAS) and mediated Variance estimation (MTV) by modeling the effects of cis-SNPs of a gene as a function of eQTL. MTV formulates the integrative method and TWAS within a unified framework via mixed models and therefore includes many prior methods/tests as special cases. We further justified MTV from another two statistical perspectives of mediation analysis and two-stage Mendelian randomization. Relative to existing methods, MTV is superior for pronounced features including the processing of direct effects of cis-SNPs on phenotypes, the powerful likelihood ratio test for assessment of joint effects of cis-SNPs and genetically regulated gene expression (GReX), two useful quantities to measure relative genetic contributions of GReX and cis-SNPs to phenotypic variance, and the computationally efferent parameter expansion expectation maximum algorithm. With extensive simulations, we identified that MTV correctly controlled the type I error in joint evaluation of the total genetic effect and proved more powerful to discover true association signals across various scenarios compared to existing methods. We finally applied MTV to 41 complex traits/diseases available from three GWASs and discovered many new associated genes that had otherwise been missed by existing methods. We also revealed that a small but substantial fraction of phenotypic variation was mediated by GReX. Overall, MTV constructs a robust and realistic modeling foundation for integrative omics analysis and has the advantage of offering more attractive biological interpretations of GWAS results.

Parallel single-nucleus chromatin accessibility and transcriptomic profiling of human late-onset Alzheimer's disease brains.

In the post-GWAS era for late-onset Alzheimer's disease (LOAD), the precise disease-causing genes, the specific causal variants, and molecular mechanisms mediating their pathogenic effects remain unknown. Recent studies using single-nucleus (sn)RNA-seq on human LOAD tissue have achieved unprecedented resolution in identifying cell type-specific gene dysregulation, however the regulatory mechanisms and genetic variability underlying these LOAD-specific transcriptomic signatures remain to be identified. Nuclei were isolated from frozen post-mortem human temporal cortex tissue from LOAD patients and cognitively healthy controls (n = 24, all Caucasian and APOE 3/3). 10X Genomics technology was used to generate single-nucleus (sn)RNA-seq and snATAC-seq libraries in parallel from the same pool of nuclei isolated from each brain sample. Uniform manifold approximation and projection (UMAP) analysis showed a total of 29 clusters assigned to 8 cell types including astrocytes, excitatory neurons, inhibitory neurons, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) in both snRNA-seq and snATAC-seq datasets. We identified differentially expressed genes (DEGs) and differentially accessible peaks (DAPs) for each cluster and found overlaps with known LOAD GWAS regions (SNP+/- 1Mb) as well as new LOAD loci that were not discovered previously. We next performed co-accessibility analysis and identified co-accessible peaks that were more open in LOAD and corresponded to dysregulation of nearby target genes. This analysis also produced networks of co-accessible LOAD peaks that were enriched in transcription factor (TF) motifs of TFs that are specifically overexpressed in LOAD samples. Integrative multi-omics is a powerful strategy to identify regulatory elements underlying gene dysregulation in LOAD. By integrating single-nucleus transcriptomic and open chromatin profiles from the same pool of nuclei, we are able to identify cell subtype-specific molecular mechanisms contributing to LOAD pathogenesis. This new genetic knowledge will progress the identification of new therapeutic targets.

Revisiting tandem repeats in psychiatric disorders from perspectives of genetics, physiology, and brain evolution.

Genome-wide association studies (GWASs) have revealed substantial genetic components comprised of single nucleotide polymorphisms (SNPs) in the heritable risk of psychiatric disorders. However, genetic risk factors not covered by GWAS also play pivotal roles in these illnesses. Tandem repeats, which are likely functional but frequently overlooked by GWAS, may account for an important proportion in the "missing heritability" of psychiatric disorders. Despite difficulties in characterizing and quantifying tandem repeats in the genome, studies have been carried out in an attempt to describe impact of tandem repeats on gene regulation and human phenotypes. In this review, we have introduced recent research progress regarding the genomic distribution and regulatory mechanisms of tandem repeats. We have also summarized the current knowledge of the genetic architecture and biological underpinnings of psychiatric disorders brought by studies of tandem repeats. These findings suggest that tandem repeats, in candidate psychiatric risk genes or in different levels of linkage disequilibrium (LD) with psychiatric GWAS SNPs and haplotypes, may modulate biological phenotypes related to psychiatric disorders (e.g., cognitive function and brain physiology) through regulating alternative splicing, promoter activity, enhancer activity and so on. In addition, many tandem repeats undergo tight natural selection in the human lineage, and likely exert crucial roles in human brain evolution. Taken together, the putative roles of tandem repeats in the pathogenesis of psychiatric disorders is strongly implicated, and using examples from previous literatures, we wish to call for further attention to tandem repeats in the post-GWAS era of psychiatric disorders.

Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer\u2019s disease brains

BackgroundIn the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer’s disease (LOAD) and translate the associations to causation.MethodsWe conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner.ResultsWe identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets.ConclusionsUsing brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci.Graphical

Genetics of coronary artery disease in the post-GWAS era.

During the past decade, genome-wide association studies (GWAS) have transformed our understanding of many heritable traits. Three recent large-scale GWAS meta-analyses now further markedly expand the knowledge on coronary artery disease (CAD) genetics in doubling the number of loci with genome-wide significant signals. Here, we review the unprecedented discoveries of CAD GWAS on low-frequency variants, underrepresented populations, sex differences and integrated polygenic risk. We present the milestones of CAD GWAS and post-GWAS studies from 2007 to 2021, and the trend in identification of variants with smaller odds ratio by year due to the increasing sample size. We compile the 321 CAD loci discovered thus far and classify candidate genes as well as distinct functional pathways on the road to indepth biological investigation and identification of novel treatment targets. We draw attention to systems genetics in integrating these loci into gene regulatory networks within and across tissues. We review the traits, biomarkers and diseases scrutinized by Mendelian randomization studies for CAD. Finally, we discuss the potentials and concerns of polygenic scores in predicting CAD risk in patient care as well as future directions of GWAS and post-GWAS studies in the field of precision medicine.

Cardiovascular susceptibility LOCI through the lens of single-cells in plaques: Discovery of crucial cell populations and candidate genes for atherosclerosis.

Background and Aims: We recently reported on the cellular landscape of advanced carotid atherosclerotic plaques, providing detailed insight on plaque pathology while creating a vast resource for further studies. Large-scale GWAS have identified hundreds of common variants for atherosclerotic disease and cardiovascular risk factors. One of the major challenges in the post-GWAS era remains decoding of susceptibility loci to targets that have the ability to translate into clinical care.

Functional Mapping of Genetic Interactions between HLA-Cw6 and LCE3A in Psoriasis

Functional studies to delineate the molecular mechanisms of causal genetic variants are the main focus in the post-GWAS era. Previous GWASs have identified >50 susceptibility loci associated with psoriasis. Functional understanding of the biology underlying the disease risk of most of these associated loci is unclear. In this study, we identified a regulatory SNP at the putative enhancer of the LCE3A gene within the epidermal differentiation complex that showed epistatic interaction with HLA-Cw6. The variant allele disrupted signal transducer and activator of transcription 3 binding to the region, thereby regulating the expression of the downstream LCE3A gene. Electrophoretic mobility shift and pulldown assay confirmed the preferential binding of signal transducer and activator of transcription 3 to the DNA with a wild-type allele compared with the DNA with a variant allele. The reporter assay further validated the IL-6‒stimulated phosphorylated signal transducer and activator of transcription 3‒mediated LCE3A activation in the presence of the wild-type allele. Interestingly, the presence of the HLA-Cw6 allele leads to IL-6‒mediated phosphorylation of signal transducer and activator of transcription 3, followed by its nuclear localization in the epidermal keratinocytes of psoriatic skin, suggesting indirect interaction of the HLA-Cw6 allele and a regulatory SNP upstream of the LCE3A gene. This study reflects an interesting approach to dissecting the molecular mechanism underlying the genetic interaction observed between HLA-Cw6 and LCE3A in psoriasis pathogenesis.