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Large-scale, multi-ethnic whole-genome sequencing (WGS) studies, such as the National Human Genome Research Institute Genome Sequencing Program's Centers for Common Disease Genomics (CCDG), play an important role in increasing diversity for genetic research. Before performing association analyses, assessing Hardy-Weinberg equilibrium (HWE) is a crucial step in quality control procedures to remove low quality variants and ensure valid downstream analyses. Diverse WGS studies contain ancestrally heterogeneous samples; however, commonly used HWE methods assume that the samples are homogeneous. Therefore, directly applying these to the whole dataset can yield statistically invalid results. To account for this heterogeneity, HWE can be tested on subsets of samples that have genetically homogeneous ancestries and the results aggregated at each variant. To facilitate valid HWE subset testing, we developed a semi-supervised learning approach that predicts homogeneous ancestries based on the genotype. This method provides a convenient tool for estimating HWE in the presence of population structure and missing self-reported race and ethnicities in diverse WGS studies. In addition, assessing HWE within the homogeneous ancestries provides reliable HWE estimates that will directly benefit downstream analyses, including association analyses in WGS studies. We applied our proposed method on the CCDG dataset, predicting homogeneous genetic ancestry groups for 60,545 multi-ethnic WGS samples to assess HWE within each group. We developed a semi-supervised machine learning method for predicting homogeneous ancestry groups in diverse whole-genome sequencing studies to facilitate valid Hardy-Weinberg equilibrium (HWE) subset testing. Compared to previous approaches, our method provided substantially better HWE subset testing performance, which can benefit downstream genetic association analyses. [ABSTRACT FROM AUTHOR]

BACKGROUND The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation genetic testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural variants, and aneuploidy. Recent advances have made genome-wide genotyping of IVF embryos feasible and affordable, raising the possibility of screening embryos for their risk of polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called polygenic embryo screening (PES; also PGT-P), it is already available to IVF patients in some countries. Several articles have studied epidemiological, clinical, and ethical perspectives on PES; however, a comprehensive, principled review of this emerging field is missing. OBJECTIVE AND RATIONALE This review has four main goals. First, given the interdisciplinary nature of PES studies, we aim to provide a self-contained educational background about PES to reproductive specialists interested in the subject. Second, we provide a comprehensive and critical review of arguments for and against the introduction of PES, crystallizing and prioritizing the key issues. We also cover the attitudes of IVF patients, clinicians, and the public towards PES. Third, we distinguish between possible future groups of PES patients, highlighting the benefits and harms pertaining to each group. Finally, our review, which is supported by ESHRE, is intended to aid healthcare professionals and policymakers in decision-making regarding whether to introduce PES in the clinic, and if so, how, and to whom. SEARCH METHODS We searched for PubMed-indexed articles published between 1/1/2003 and 1/3/2024 using the terms 'polygenic embryo screening', 'polygenic preimplantation', and 'PGT-P'. We limited the review to primary research papers in English whose main focus was PES for medical conditions. We also included papers that did not appear in the search but were deemed relevant. OUTCOMES The main theoretical benefit of PES is a reduction in lifetime polygenic disease risk for children born after screening. The magnitude of the risk reduction has been predicted based on statistical modelling, simulations, and sibling pair analyses. Results based on all methods suggest that under the best-case scenario, large relative risk reductions are possible for one or more diseases. However, as these models abstract several practical limitations, the realized benefits may be smaller, particularly due to a limited number of embryos and unclear future accuracy of the risk estimates. PES may negatively impact patients and their future children, as well as society. The main personal harms are an unindicated IVF treatment, a possible reduction in IVF success rates, and patient confusion, incomplete counselling, and choice overload. The main possible societal harms include discarded embryos, an increasing demand for 'designer babies', overemphasis of the genetic determinants of disease, unequal access, and lower utility in people of non-European ancestries. Benefits and harms will vary across the main potential patient groups, comprising patients already requiring IVF, fertile people with a history of a severe polygenic disease, and fertile healthy people. In the United States, the attitudes of IVF patients and the public towards PES seem positive, while healthcare professionals are cautious, sceptical about clinical utility, and concerned about patient counselling. WIDER IMPLICATIONS The theoretical potential of PES to reduce risk across multiple polygenic diseases requires further research into its benefits and harms. Given the large number of practical limitations and possible harms, particularly unnecessary IVF treatments and discarded viable embryos, PES should be offered only within a research context before further clarity is achieved regarding its balance of benefits and harms. The gap in attitudes between healthcare professionals and the public needs to be narrowed by expanding public and patient education and providing resources for informative and unbiased genetic counselling. [ABSTRACT FROM AUTHOR]

Both trio and population designs are popular study designs for identifying risk genetic variants in genome-wide association studies (GWASs). The trio design, as a family-based design, is robust to confounding due to population structure, whereas the population design is often more powerful due to larger sample sizes. Here, we propose KnockoffHybrid, a knockoff-based statistical method for hybrid analysis of both the trio and population designs. KnockoffHybrid provides a unified framework that brings together the advantages of both designs and produces powerful hybrid analysis while controlling the false discovery rate (FDR) in the presence of linkage disequilibrium and population structure. Furthermore, KnockoffHybrid has the flexibility to leverage different types of summary statistics for hybrid analyses, including expression quantitative trait loci (eQTL) and GWAS summary statistics. We demonstrate in simulations that KnockoffHybrid offers power gains over non-hybrid methods for the trio and population designs with the same number of cases while controlling the FDR with complex correlation among variants and population structure among subjects. In hybrid analyses of three trio cohorts for autism spectrum disorders (ASDs) from the Autism Speaks MSSNG, Autism Sequencing Consortium, and Autism Genome Project with GWAS summary statistics from the iPSYCH project and eQTL summary statistics from the MetaBrain project, KnockoffHybrid outperforms conventional methods by replicating several known risk genes for ASDs and identifying additional associations with variants in other genes, including the PRAME family genes involved in axon guidance and which may act as common targets for human speech/language evolution and related disorders. We introduce KnockoffHybrid, a statistical method to identify risk genetic variants for the population and trio designs built upon a recently developed knockoff framework. KnockoffHybrid controls the false discovery rate, protects against confounding due to population structure, and is more powerful than conventional methods that control the family-wise error rate. [ABSTRACT FROM AUTHOR]

Microbiome scientists critically need modern tools to explore and analyze microbial evolution. Often this involves studying the evolution of microbial genomes as a whole. However, different genes in a single genome can be subject to different evolutionary pressures, which can result in distinct gene-level evolutionary histories. To address this challenge, we propose to treat estimated gene-level phylogenies as data objects, and present an interactive method for the analysis of a collection of gene phylogenies. We use a local linear approximation of phylogenetic tree space to visualize estimated gene trees as points in low-dimensional Euclidean space, and address important practical limitations of existing related approaches, allowing an intuitive visualization of complex data objects. We demonstrate the utility of our proposed approach through microbial data analyses, including by identifying outlying gene histories in strains of Prevotella , and by contrasting Streptococcus phylogenies estimated using different gene sets. Our method is available as an open-source R package, and assists with estimating, visualizing, and interacting with a collection of bacterial gene phylogenies. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have accelerated the exploration of genotype–phenotype associations, facilitating the discovery of replicable genetic markers associated with specific traits or complex diseases. This narrative review explores the statistical methodologies developed using GWAS data to investigate relationships between various phenotypes, focusing on endometrial cancer, the most prevalent gynecological malignancy in developed nations. Advancements in analytical techniques such as genetic correlation, colocalization, cross-trait locus identification, and causal inference analyses have enabled deeper exploration of associations between different phenotypes, enhancing statistical power to uncover novel genetic risk regions. These analyses have unveiled shared genetic associations between endometrial cancer and many phenotypes, enabling identification of novel endometrial cancer risk loci and furthering our understanding of risk factors and biological processes underlying this disease. The current status of research in endometrial cancer is robust; however, this review demonstrates that further opportunities exist in statistical genetics that hold promise for advancing the understanding of endometrial cancer and other complex diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Approximately 95% of samples analyzed in univariate genome-wide association studies (GWAS) are of European ancestry. This bias toward European ancestry populations in association screening also exists for other analyses and methods that are often developed and tested on European ancestry only. However, existing data in non-European populations, which are often of modest sample size, could benefit from innovative approaches as recently illustrated in the context of polygenic risk scores. Methods Here, we extend and assess the potential limitations and gains of our multi-trait GWAS pipeline, JASS (Joint Analysis of Summary Statistics), for the analysis of non-European ancestries. To this end, we conducted the joint GWAS of 19 hematological traits and glycemic traits across five ancestries (European (EUR), admixed American (AMR), African (AFR), East Asian (EAS), and South-East Asian (SAS)). Results We detected 367 new genome-wide significant associations in non-European populations (15 in Admixed American (AMR), 72 in African (AFR) and 280 in East Asian (EAS)). New associations detected represent 5%, 17% and 13% of associations in the AFR, AMR and EAS populations, respectively. Overall, multi-trait testing increases the replication of European associated loci in non-European ancestry by 15%. Pleiotropic effects were highly similar at significant loci across ancestries (e.g. the mean correlation between multi-trait genetic effects of EUR and EAS ancestries was 0.88). For hematological traits, strong discrepancies in multi-trait genetic effects are tied to known evolutionary divergences: the ARKC1 loci, which is adaptive to overcome p.vivax induced malaria. Conclusions Multi-trait GWAS can be a valuable tool to narrow the genetic knowledge gap between European and non-European populations.

Low‐coverage whole‐genome sequencing (WGS) is increasingly used for the study of evolution and ecology in both model and non‐model organisms; however, effective application of low‐coverage WGS data requires the implementation of probabilistic frameworks to account for the uncertainties in genotype likelihoods.Here, we present a probabilistic framework for using genotype likelihoods for standard population assignment applications. Additionally, we derive the Fisher information for allele frequency from genotype likelihoods and use that to describe a novel metric, the effective sample size, which figures heavily in assignment accuracy. We make these developments available for application through WGSassign, an open‐source software package that is computationally efficient for working with whole‐genome data.Using simulated and empirical data sets, we demonstrate the behaviour of our assignment method across a range of population structures, sample sizes and read depths. Through these results, we show that WGSassign can provide highly accurate assignment, even for samples with low average read depths (<0.01X) and among weakly differentiated populations.Our simulation results highlight the importance of equalizing the effective sample sizes among source populations in order to achieve accurate population assignment with low‐coverage WGS data. We further provide study design recommendations for population assignment studies and discuss the broad utility of effective sample size for studies using low‐coverage WGS data. [ABSTRACT FROM AUTHOR]

Regions under balancing selection are characterized by dense polymorphisms and multiple persistent haplotypes, along with other sequence complexities. Successful identification of these patterns depends on both the statistical approach and the quality of sequencing. To address this challenge, at first, a new statistical method called LD-ABF was developed, employing efficient Bayesian techniques to effectively test for balancing selection. LD-ABF demonstrated the most robust detection of selection in a variety of simulation scenarios, compared against a range of existing tests/tools (Tajima's D , HKA, D ng, BetaScan, and BalLerMix). Furthermore, the impact of the quality of sequencing on detection of balancing selection was explored, as well, using: (i) SNP genotyping and exome data, (ii) targeted high-resolution HLA genotyping (IHIW), and (iii) whole-genome long-read sequencing data (Pangenome). In the analysis of SNP genotyping and exome data, we identified known targets and 38 new selection signatures in genes not previously linked to balancing selection. To further investigate the impact of sequencing quality on detection of balancing selection, a detailed investigation of the MHC was performed with high-resolution HLA typing data. Higher quality sequencing revealed the HLA-DQ genes consistently demonstrated strong selection signatures otherwise not observed from the sparser SNP array and exome data. The HLA-DQ selection signature was also replicated in the Pangenome samples using considerably less samples but, with high-quality long-read sequence data. The improved statistical method, coupled with higher quality sequencing, leads to more consistent identification of selection and enhanced localization of variants under selection, particularly in complex regions. [ABSTRACT FROM AUTHOR]

The highly polygenic and pleiotropic nature of behavioural traits, psychiatric disorders and structural and functional brain phenotypes complicate mechanistic interpretation of related genome‐wide association study (GWAS) signals, thereby obscuring underlying causal biological processes. We propose genomic principal and independent component analysis (PCA, ICA) to decompose a large set of univariate GWAS statistics of multimodal brain traits into more interpretable latent genomic components. Here we introduce and evaluate this novel methods various analytic parameters and reproducibility across independent samples. Two UK Biobank GWAS summary statistic releases of 2240 imaging‐derived phenotypes (IDPs) were retrieved. Genome‐wide beta‐values and their corresponding standard‐error scaled z‐values were decomposed using genomic PCA/ICA. We evaluated variance explained at multiple dimensions up to 200. We tested the inter‐sample reproducibility of output of dimensions 5, 10, 25 and 50. Reproducibility statistics of the respective univariate GWAS served as benchmarks. Reproducibility of 10‐dimensional PCs and ICs showed the best trade‐off between model complexity and robustness and variance explained (PCs: |rz − max| = 0.33, |rraw − max| = 0.30; ICs: |rz − max| = 0.23, |rraw − max| = 0.19). Genomic PC and IC reproducibility improved substantially relative to mean univariate GWAS reproducibility up to dimension 10. Genomic components clustered along neuroimaging modalities. Our results indicate that genomic PCA and ICA decompose genetic effects on IDPs from GWAS statistics with high reproducibility by taking advantage of the inherent pleiotropic patterns. These findings encourage further applications of genomic PCA and ICA as fully data‐driven methods to effectively reduce the dimensionality, enhance the signal to noise ratio and improve interpretability of high‐dimensional multitrait genome‐wide analyses. [ABSTRACT FROM AUTHOR]

Most human complex phenotypes result from multiple genetic and environmental factors and their interactions. Understanding the mechanisms by which genetic and environmental factors interact offers valuable insights into the genetic architecture of complex traits and holds great potential for advancing precision medicine. The emergence of large population biobanks has led to the development of numerous statistical methods aiming at identifying gene–environment interactions (G × E). In this review, we present state‐of‐the‐art statistical methodologies for G × E analysis. We will survey a spectrum of approaches for single‐variant G × E mapping, followed by various techniques for polygenic G × E analysis. We conclude this review with a discussion on the future directions and challenges in G × E research. This article is categorized under:Applications of Computational Statistics > Genomics/Proteomics/GeneticsData: Types and Structure > Massive DataStatistical Models > Linear Models [ABSTRACT FROM AUTHOR]

Background: Human endogenous retroviruses (HERVs) are sequences in the human genome that originated from infections with ancient retroviruses during our evolution. Previous studies have linked HERVs to neurodegenerative diseases, but defining their role in aetiology has been challenging. Here, we used a retrotranscriptome-wide association study (rTWAS) approach to assess the relationships between genetic risk for neurodegenerative diseases and HERV expression in the brain, calculated with genomic precision., Methods: We analysed genetic association statistics pertaining to Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's disease, using HERV expression models calculated from 792 cortical samples. Robust risk factors were considered those that survived multiple testing correction in the primary analysis, which were also significant in conditional and joint analyses, and that had a posterior inclusion probability above 0.5 in fine-mapping analyses., Results: The primary analysis identified 12 HERV expression signatures associated with neurodegenerative disease susceptibility. We found one HERV expression signature robustly associated with amyotrophic lateral sclerosis on chromosome 12q14 (MER61&#95;12q14.2) and one robustly associated with multiple sclerosis on chromosome 1p36 (ERVLE&#95;1p36.32a). A co-expression analysis suggested that these HERVs are involved in homophilic cell adhesion via plasma membrane adhesion molecules., Conclusions: We found HERV expression profiles robustly associated with amyotrophic lateral sclerosis and multiple sclerosis susceptibility, highlighting novel risk mechanisms underlying neurodegenerative disease, and offering potential new targets for therapeutic intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Approximately 95% of samples analyzed in univariate genome-wide association studies (GWAS) are of European ancestry. This bias toward European ancestry populations in association screening also exists for other analyses and methods that are often developed and tested on European ancestry only. However, existing data in non-European populations, which are often of modest sample size, could benefit from innovative approaches as recently illustrated in the context of polygenic risk scores., Methods: Here, we extend and assess the potential limitations and gains of our multi-trait GWAS pipeline, JASS (Joint Analysis of Summary Statistics), for the analysis of non-European ancestries. To this end, we conducted the joint GWAS of 19 hematological traits and glycemic traits across five ancestries (European (EUR), admixed American (AMR), African (AFR), East Asian (EAS), and South-East Asian (SAS))., Results: We detected 367 new genome-wide significant associations in non-European populations (15 in Admixed American (AMR), 72 in African (AFR) and 280 in East Asian (EAS)). New associations detected represent 5%, 17% and 13% of associations in the AFR, AMR and EAS populations, respectively. Overall, multi-trait testing increases the replication of European associated loci in non-European ancestry by 15%. Pleiotropic effects were highly similar at significant loci across ancestries (e.g. the mean correlation between multi-trait genetic effects of EUR and EAS ancestries was 0.88). For hematological traits, strong discrepancies in multi-trait genetic effects are tied to known evolutionary divergences: the ARKC1 loci, which is adaptive to overcome p.vivax induced malaria., Conclusions: Multi-trait GWAS can be a valuable tool to narrow the genetic knowledge gap between European and non-European populations., (© 2024. The Author(s).)