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Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-differential effects via GAUDI
Most polygenic risk score (PRS) methods focus only on individuals with distinct primary continental ancestry, without accommodating recently-admixed individuals. Here, the authors develop a novel penalized regression-based PRS method specifically designed for admixed individuals.
- Quan Sun
- , Bryce T. Rowland
- & Yun Li
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Article
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Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping
Genetic association studies with affinity proteomics face challenges when dealing with protein altering variants. Suhre et al. show that nanoparticle enrichment mass-spectrometry can distinguish between epitope effects and bona fide protein quantitative traits.
- Karsten Suhre
- , Guhan Ram Venkataraman
- & Frank Schmidt
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Molecular quantitative trait loci in reproductive tissues impact male fertility in cattle
Investigating the genetics of male fertility requires comprehensive genotype and phenotype data. Here, the authors characterize the transcriptional complexity of bovine male reproductive tissues to identify loci associated with male fertility.
- Xena Marie Mapel
- , Naveen Kumar Kadri
- & Hubert Pausch
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Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape
The genetic architecture of normal-range cranial vault shape in humans is poorly understood. Here, the authors extract cranial vault shape from MRI and conduct a multi-ancestry GWAS, identifying 30 independently associated genomic loci of which 29 are novel.
- Seppe Goovaerts
- , Hanne Hoskens
- & Peter Claes
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Article
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Leveraging information between multiple population groups and traits improves fine-mapping resolution
Statistical fine-mapping helps to pinpoint likely causal variants underlying genetic association signals, and can be enhanced by using multi-ancestry datasets. Here, the authors introduce MGflashfm, a fine-mapping method for pinpointing likely causal variants amongst multiple traits and population groups.
- Feng Zhou
- , Opeyemi Soremekun
- & Jennifer L. Asimit
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Leveraging data from the Genomes-to-Fields Initiative to investigate genotype-by-environment interactions in maize in North America
The Genomes-to-Fields (G2F) initiative has collected large amount of maize phenotype and genotype data. Here, the authors develop an automated workflow for curating the data, matching it with public weather and soil data, and generating environmental covariates for phenotypic data, which pave the way for several GxE investigations.
- Marco Lopez-Cruz
- , Fernando M. Aguate
- & Gustavo de los Campos
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Robotized indoor phenotyping allows genomic prediction of adaptive traits in the field
Robotized indoor phenotyping allows measuring of plant physiological traits at high throughput, but is often considered as non-relevant for field conditions. Here, the authors show that maize traits measured indoor translate to the field and can be inferred via genomic prediction.
- Jugurta Bouidghaghen
- , Laurence Moreau
- & François Tardieu
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A versatile, fast and unbiased method for estimation of gene-by-environment interaction effects on biobank-scale datasets
Identification of gene-by-environment interactions is crucial to understand the interplay of environmental effects on complex traits. Here, the authors present MonsterLM, a method for estimating the proportion of trait variance explained by gene-by-environment interactions in a fast, unbiased manner on biobank-scale datasets.
- Matteo Di Scipio
- , Mohammad Khan
- & Guillaume Paré
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Article
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Genome-wide association studies identify OsWRKY53 as a key regulator of salt tolerance in rice
Only a few genetic variants have been identified to mediate salt tolerance in major crops and their molecular mechanisms are largely unknown. Here, the authors identify WRKY53 as a negative regulator of salt tolerance in rice, and show that it directly trans-regulates expression of MKK10.2 and HKT1;5 to meditate salt tolerance.
- Jun Yu
- , Chengsong Zhu
- & Jianmin Wan
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A computational method for cell type-specific expression quantitative trait loci mapping using bulk RNA-seq data
Detecting cell type-specific genetic effects on gene expression is challenging in bulk RNA-seq data. Here, the authors develop a method to increase power which incorporates allele-specific expression and does not transform the gene expression data.
- Paul Little
- , Si Liu
- & Wei Sun
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Fine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease
The mechanisms underlying many genetic variants associated with human traits are often unknown. Here, the authors identify the developmental stage-, organ-, tissue- and cell type-specific associations between genetic variation and gene expression in cardiac tissues, and describe how these associations affect complex cardiac traits and disease.
- Matteo D’Antonio
- , Jennifer P. Nguyen
- & Kelly A. Frazer
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Impact of diet and host genetics on the murine intestinal mycobiome
In this study, 591 mice from an advanced-intercross mouse line were used to provide evidence that fungi are regulated by host genetics, while uncovering a regulatory role of diet on the composition of fungi in the murine gut.
- Yask Gupta
- , Anna Lara Ernst
- & Tanya Sezin
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Sample multiplexing-based targeted pathway proteomics with real-time analytics reveals the impact of genetic variation on protein expression
Targeted proteomics enables robust hypothesis-driven research. Here, Yu et al. present a multiplexed approach for targeted pathway proteomics and apply it to quantify protein families across 480 fully genotyped Diversity Outbred mice, revealing impacts of genetic variation on protein expression and lipid metabolism.
- Qing Yu
- , Xinyue Liu
- & Steven P. Gygi
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Integrative genetic analysis illuminates ALS heritability and identifies risk genes
ALS is somewhat heritable, but the genetic basis is not completely understood. Here, the authors identify alterations in splicing in neurons associated with amyotrophic lateral sclerosis and uncover several associated genetic loci, with a potential link to nuclear pore defects.
- Salim Megat
- , Natalia Mora
- & Luc Dupuis
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Genetic analysis of seed traits in Sorghum bicolor that affect the human gut microbiome
Diet affects the human gut microbiome, but studies linking crop genetics to seed traits that influence the human gut microbiome are lacking. Here, the authors develop an in vitro microbiome screening method and reveal the association between sorghum genes regulating condensed tannin biosynthesis and human gut microbiome.
- Qinnan Yang
- , Mallory Van Haute
- & Andrew K. Benson
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Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci
Splicing QTL (sQTL), genetic variants regulating alternative splicing, can be biologically important, but complex to detect and interpret. Here, the authors identify sQTL by focusing on protein coding sequences, as an alternative to junction-based approaches.
- Kensuke Yamaguchi
- , Kazuyoshi Ishigaki
- & Yuta Kochi
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Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities
Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.
- Catherine M. Francis
- , Matthias E. Futschik
- & Paul M. Matthews
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Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity
Natural Killer cells are key mediators of anti-tumour immunosurveillance and anti-viral immunity. Here, the authors map regulatory genetic variation in primary Natural Killer cells, providing new insights into their role in human health and disease.
- James J. Gilchrist
- , Seiko Makino
- & Benjamin P. Fairfax
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Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure
Not just differential gene expression but also differential gene regulation in immune cells account for individual differences in the immune response. Authors show here by single-cell RNA-sequencing of peripheral blood mononuclear cells from a large cohort of genetically diverse individuals that gene expression and regulatory changes in these cells depend on the context of and interactions between cell types, genetics, type of pathogen and time after exposure.
- Roy Oelen
- , Dylan H. de Vries
- & Monique G. P. van der Wijst
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Meta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits
Genetic associations and polygenic scores for lipid traits have low transferability to African individuals. Here, the authors perform a large sub-Sarahan African lipid GWAS and find that larger datasets and better global representation in discovery GWAS help to bridge this gap.
- Ananyo Choudhury
- , Jean-Tristan Brandenburg
- & Michèle Ramsay
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The interplay of additivity, dominance, and epistasis on fitness in a diploid yeast cross
Heritable traits can be affected by additive, dominance, and epistatic effects at genetic loci. Here, the authors use chromosomally-encoded barcodes to perform linkage mapping in diploid cross progeny in budding yeast, finding that epistasis in diploids frequently modifies both additivity and dominance.
- Takeshi Matsui
- , Martin N. Mullis
- & Ian M. Ehrenreich
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A genome-wide association study of serum proteins reveals shared loci with common diseases
Circulating proteins have been linked to many conditions, and understanding their genetic control can lead to understanding of disease. Here, the authors associate common genetic variants with protein levels, finding overlap of genetic associations with circulating proteins and complex disease.
- Alexander Gudjonsson
- , Valborg Gudmundsdottir
- & Vilmundur Gudnason
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Multiple stages of evolutionary change in anthrax toxin receptor expression in humans
Animal husbandry and hunting has increased human exposure to pathogens. Here, the authors investigate the evolution of human host gene expression to Bacillus anthracis infection, the bacterium that causes anthrax disease. They observe recent positive selection, suggestive of human genome adaptation to anthrax disease.
- Lauren A. Choate
- , Gilad Barshad
- & Charles G. Danko
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The flashfm approach for fine-mapping multiple quantitative traits
Genetic signals from quantitative traits could be a challenge to finemap. Flashfm uses summary-level data in a Bayesian framework to favour shared causal variants and capitalises on information between traits, providing an accurate and efficient joint fine-mapping tool for up to six traits.
- N. Hernández
- , J. Soenksen
- & J. L. Asimit
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The cichlid oral and pharyngeal jaws are evolutionarily and genetically coupled
Modular, rather than integrated systems are classically thought to allow functional diversity to evolve rapidly. A study of cichlid fish shows integration between divergent jaw systems at the phylogenetic, population, and genetic scales, suggesting integration can and does facilitate rapid, coordinated trait evolution.
- Andrew J. Conith
- & R. Craig Albertson
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Estimating direct and indirect genetic effects on offspring phenotypes using genome-wide summary results data
Estimating direct and indirect effects of genotypes on phenotypes is important for genetic analyses such as Mendelian randomization. Here the authors compare five different methods to estimate direct and indirect genetic effects using summary results statistics that account for sample overlap.
- Nicole M. Warrington
- , Liang-Dar Hwang
- & David M. Evans
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Inferring multilayer interactome networks shaping phenotypic plasticity and evolution
Genetic plasticity drives phenotypic differences. Here, the authors develop a framework to quantify the individual and combinatorial contributions of SNPs on a phenotype of interest and use it to identify SNP-SNP interactions associated with variations in bacteria’s response to external changes.
- Dengcheng Yang
- , Yi Jin
- & Rongling Wu
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Genome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk
The authors provide a comprehensive, single base resolution view of association between genetic variation and DNA methylation in human brain. They also show that heritability attributed to schizophrenia GWAS-associated variants reflects the epigenetic plasticity of the brain.
- Kira A. Perzel Mandell
- , Nicholas J. Eagles
- & Andrew E. Jaffe
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Improved genetic prediction of complex traits from individual-level data or summary statistics
Existing genetic prediction tools typically assume that genetic variants contribute equally towards the phenotype. The authors develop eight prediction tools that allow the user to specify the heritability model, and show that these tools enable substantially improved prediction of complex traits.
- Qianqian Zhang
- , Florian Privé
- & Doug Speed
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Cryptic genetic variation in a heat shock protein modifies the outcome of a mutation affecting epidermal stem cell development in C. elegans
How the genetic background modifies the expression of mutations is a key question that is addressed in this study in the context of seam cell development in Caenorhabditis elegans isolates. One amino acid deletion in a conserved heat shock protein is sufficient to shape phenotype expressivity upon mutation of a GATA transcription factor.
- Sneha L. Koneru
- , Mark Hintze
- & Michalis Barkoulas
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O-linked N-acetylglucosamine transferase is involved in fine regulation of flowering time in winter wheat
Little is known about genes that regulate flowering time difference among winter wheat cultivars. Here, via map-based cloning, the authors show the role of an O-linked N-acetylglucosamine (O-GlcNAc) transferase TaOGT1 in regulating flowering time difference among winter wheat cultivars.
- Min Fan
- , Fang Miao
- & Liuling Yan
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Widespread signatures of natural selection across human complex traits and functional genomic categories
Methods to study how natural selection shapes genetic architecture of complex traits rely on individual level genome-wide association study (GWAS) data. Here, the authors present a Bayesian method using GWAS summary statistics to study genetic architecture and apply this to 155 complex traits.
- Jian Zeng
- , Angli Xue
- & Jian Yang
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Article
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Phenotypic covariance across the entire spectrum of relatedness for 86 billion pairs of individuals
Assigning inter-individual similarities to genetic and non-genetic factors is central to quantitative genetics. Here, the authors look at phenotypic covariance among pairs of individuals for 32 traits across the UK Biobank, from nominally unrelated pairs through to monozygotic twins.
- Kathryn E. Kemper
- , Loic Yengo
- & Peter M. Visscher
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Genome-wide analyses of behavioural traits are subject to bias by misreports and longitudinal changes
Conflicting reports have found disease to sometimes be positively and sometimes negatively correlated with alcohol consumption. Here, the authors show that misreporting and reduction of alcohol consumption is associated with disease, leading to misleading associations between alcohol and disease.
- Angli Xue
- , Longda Jiang
- & Jian Yang
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
- Vasiliki Lagou
- , Reedik Mägi
- & Inga Prokopenko
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Optimized design of single-cell RNA sequencing experiments for cell-type-specific eQTL analysis
Single cell RNA-sequencing can be a powerful approach to characterizing cell composition in a population of cells but is thought to be too expensive for population-scale analyses. Here, the authors show how lower coverage of more samples can increase the power to detect cell-type-specific eQTL.
- Igor Mandric
- , Tommer Schwarz
- & Eran Halperin
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Genotype by environment interaction for gene expression in Drosophila melanogaster
Huang et al. show that developing under different temperatures changes the genetic architecture of regulatory variation in Drosophila melanogaster gene expression yet the co-expression network remains robust. Data suggest that stabilizing selection on gene expression may promote co-expression network robustness.
- Wen Huang
- , Mary Anna Carbone
- & Trudy F. C. Mackay
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Article
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Integrative genomic analysis reveals mechanisms of immune evasion in P. falciparum malaria
Here, the authors identify signatures of miRNA expression differentiation associated with Plasmodium falciparum infection and parasitemia in a longitudinal pediatric cohort in Burkina Faso. In particular, expression of several miRNAs known to promote lymphocyte cell death is affected during infection.
- Mame Massar Dieng
- , Aïssatou Diawara
- & Youssef Idaghdour
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Biophysical ambiguities prevent accurate genetic prediction
In quantitative genetics, it is widely assumed that mutations combine additively or epistasis can be predicted with statistical or mechanistic models. Here, the authors use the phage lambda repressor model to show how biophysical ambiguity and non-monotonic functions confound phenotypic prediction.
- Xianghua Li
- & Ben Lehner
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Article
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Properties of structural variants and short tandem repeats associated with gene expression and complex traits
Genetic variation associated with gene expression changes has mostly been studied in the context of single nucleotide variants. Here, Jakubosky et al. report eQTL analysis of structural variants and short tandem repeats and find properties, such as length of variation, that affect the association.
- David Jakubosky
- , Matteo D’Antonio
- & Kelly A. Frazer
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Article
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A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome
Gene expression and how genetic variants can influence gene expression are tissue-specific processes with important implications for phenotypes. Here, Richardson et al. use eQTL data from GTEx and the eQTLGen project in a two-sample SMR + HEIDI framework for causal inference of gene expression associations with complex trait.
- Tom G. Richardson
- , Gibran Hemani
- & George Davey Smith
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| Open Access
Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits
DNA methylation is associated with complex traits and the expression of genes and proteins. Here, Zaghlool et al. perform epigenome-wide association studies for 1,123 plasma proteins, replicate obtained protein (p)QTMs in an independent cohort and find overlap of pQTMs with expression QTMs and previously reported disease associations.
- Shaza B. Zaghlool
- , Brigitte Kühnel
- & Karsten Suhre
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Article
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The indica nitrate reductase gene OsNR2 allele enhances rice yield potential and nitrogen use efficiency
Indica rice has higher nitrate assimilation and nitrogen use efficiency (NUE) than japonica rice, but the mechanism is unclear. Here, the authors reveal that the difference is partly due to allelic variation of a nitrate reductase encoding gene and this indica allele can increase yield potential and NUE.
- Zhenyu Gao
- , Yufeng Wang
- & Qian Qian
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Article
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Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders
Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals. Here, Oetjens et al. systematically study the contribution of common genetic variation to variable expressivity of RGDs and find it is frequently influenced by polygenic factors identified in genome-wide association studies of relevant traits.
- M. T. Oetjens
- , M. A. Kelly
- & D. H. Ledbetter
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| Open Access
Sequence variants with large effects on cardiac electrophysiology and disease
Aberrant morphology of the QRS complex in an electrocardiogram can be associated with cardiac morbidity and mortality. Here, the authors perform genome-wide association studies for ten measures of the QRS complex in 81,192 individuals and find 86 previously unreported loci that associate with at least one parameter.
- Kristjan Norland
- , Gardar Sveinbjornsson
- & Kari Stefansson
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Article
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Characterizing rare and low-frequency height-associated variants in the Japanese population
Thousands of genetic loci are known to associate with human height, but these are mainly based on studies in European ancestry populations. Here, Akiyama et al. construct a genotype reference panel for the Japanese population followed by GWAS and report 573 height associated variants in 191,787 Japanese.
- Masato Akiyama
- , Kazuyoshi Ishigaki
- & Yoichiro Kamatani
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Article
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Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
Many genetic variants identified in genome-wide association studies are associated with gene expression. Here, Porcu et al. propose a transcriptome-wide summary statistics-based Mendelian randomization approach (TWMR) that, applied to 43 human traits, uncovers hundreds of previously unreported gene–trait associations.
- Eleonora Porcu
- , Sina Rüeger
- & Zoltán Kutalik
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Fast genetic mapping of complex traits in C. elegans using millions of individuals in bulk
QTL mapping in multicellular animals usually requires generation, maintenance, and phenotyping large panels of recombinant individuals. Here, the authors develop ceX-QTL mapping, a method for fast genetic mapping via bulk selection on millions of unique recombinant C. elegans individuals.
- Alejandro Burga
- , Eyal Ben-David
- & Leonid Kruglyak
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Article
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Parent of origin genetic effects on methylation in humans are common and influence complex trait variation
Parent-of-origin effects (POE) are observed when there are different effects from alleles inherited from the two parents on phenotypic measures. Here, Zeng et al. study POE on DNA methylation in 5,101 individuals and identify genetic variants that associate with methylation variation via POE and their potential phenotypic consequences.
- Yanni Zeng
- , Carmen Amador
- & Chris S. Haley
Genetic gains underpinning a little-known strawberry Green Revolution