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The contributions of mitochondrial and nuclear mitochondrial genetic variation to neuroticism
Genetic variation in mitochondrial DNA can influence human traits, but it is not as well studied in association with complex traits. Here, the authors find associations between mitochondrial haplogroups and genetic variation and neuroticism.
- Charley Xia
- , Sarah J. Pickett
- & W. David Hill
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Article
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meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans
Here, the authors performed a large-scale in-depth cis-meQTL mapping study in 961 African Americans from the GENOA study, investigating the co-regulation of methylation and gene expression in African Americans.
- Lulu Shang
- , Wei Zhao
- & Xiang Zhou
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Article
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A method for an unbiased estimate of cross-ancestry genetic correlation using individual-level data
Cross-ancestry genetic correlation can reveal differences in the genetic basis of traits between populations, but methods can be biased by ancestry-specific genetic architecture. Here, the authors present a method to for estimating cross-ancestry genetic correlations, accounting for ancestry-specific genetic architecture.
- Md. Moksedul Momin
- , Jisu Shin
- & S. Hong Lee
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Article
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Analysis of transcriptional changes in the immune system associated with pubertal development in a longitudinal cohort of children with asthma
Puberty is an important developmental period marked by hormonal, metabolic and immunological changes. Here the authors report gene expression changes in immune cells associated with age and puberty, and that may be relevant for sex differences in susceptibility to asthma, in a longitudinal cohort of 251 children with asthma.
- Justyna A. Resztak
- , Jane Choe
- & Francesca Luca
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Article
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How people wake up is associated with previous night’s sleep together with physical activity and food intake
In a prospective longitudinal study of 833 adults, we demonstrate that how you wake up and regain alertness in the hours after sleep is weakly associated with your genes. Instead, the modifiable factors of how you are sleeping, eating and exercising influence your return to full alertness, free of sleepiness.
- Raphael Vallat
- , Sarah E. Berry
- & Matthew P. Walker
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SUMMIT: An integrative approach for better transcriptomic data imputation improves causal gene identification
Genes with moderate-low expression heritability cannot be sufficiently captured with conventional TWAS. This study introduces a new method, Summary-level Unified Method for Modeling Integrated Transcriptome (SUMMIT), to improve the expression prediction of TWAS by using eQTL summary-level data.
- Zichen Zhang
- , Ye Eun Bae
- & Chong Wu
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Multi-context genetic modeling of transcriptional regulation resolves novel disease loci
Transcriptome-wide association studies (TWAS) often ignore the specificity and sharing of effects across contexts (e.g., tissues). Here, the authors describe a method to split genetic effects into context-shared and context-specific terms. They apply their method to tissue and single-cell RNA-seq and show improved power in TWAS.
- Mike Thompson
- , Mary Grace Gordon
- & Noah Zaitlen
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
Genetic mechanisms influencing COVID-19 susceptibility are not well understood. Here, the authors analyzed whole blood RNA-seq data of 465 Japanese individuals with COVID-19, highlighting thousands of fine-mapped variants affecting expression and splicing of genes, as well as the presence of COVID-19 severity-interaction eQTLs.
- Qingbo S. Wang
- , Ryuya Edahiro
- & Yukinori Okada
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Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers
Understanding how our genes interact with the environment is critical to improving health. Using a large-scale discovery pipeline, here the authors investigate synergies between genetic variants and a broad range of environmental factors impacting cardiometabolic health.
- Kenneth E. Westerman
- , Timothy D. Majarian
- & Joanne B. Cole
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Disentangling the genetic basis of rhizosphere microbiome assembly in tomato
Genetics factors involved in rhizosphere microbiomes assembly remain largely elusive. Here, the authors integrate microbiomics and quantitative plant genetics to reveal genetic loci associated with specific microbes and rhizobacterial traits underlying microbiome assembly in tomato.
- Ben O. Oyserman
- , Stalin Sarango Flores
- & Jos M. Raaijmakers
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Article
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Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci
The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms.
- Xianyong Yin
- , Lap Sum Chan
- & Michael Boehnke
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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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Functional dissection of inherited non-coding variation influencing multiple myeloma risk
The causality and functional roles of disease-associated variants revealed by genome-wide association studies (GWAS) are mostly unexplored. Here the authors identify putative causal variants in multiple myeloma and find their association with gene expression and chromatin accessibility.
- Ram Ajore
- , Abhishek Niroula
- & Björn Nilsson
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Synergistic insights into human health from aptamer- and antibody-based proteomic profiling
Broad-capture affinity-based proteomic technologies inform how the readout of our genes affects human health. Here, the authors integrate aptamer- and antibody-based profiling to understand the mechanisms underlying gene-protein-disease associations.
- Maik Pietzner
- , Eleanor Wheeler
- & Claudia Langenberg
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Quantifying the contribution of Neanderthal introgression to the heritability of complex traits
We lack a comprehensive understanding of how Neanderthal ancestry influences human traits. This study finds that regions with Neanderthal ancestry are broadly depleted of trait-associated variation; yet, introgressed variants likely contributed to human adaptation in a few traits, like skin color and immune response modulation.
- Evonne McArthur
- , David C. Rinker
- & John A. Capra
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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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Genome sequencing unveils a regulatory landscape of platelet reactivity
Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.
- Ali R. Keramati
- , Ming-Huei Chen
- & Andrew D. Johnson
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Selection on heritable social network positions is context-dependent in Drosophila melanogaster
The evolvability of sociality requires that some variation in social groups is heritable. Experiments on fly social groups find that genotypic differences in network position are largely robust to changes in the environment flies experience, while selection on network position varies across environments.
- Eric Wesley Wice
- & Julia Barbara Saltz
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Population-specific causal disease effect sizes in functionally important regions impacted by selection
Trans-ethnic genetic correlation is significantly less than 1 for many diseases. Here, the authors stratify this correlation by genomic annotations, finding that loci whose causal disease effect sizes differ between ethnicities are likely impacted by selection, particularly positive selection.
- Huwenbo Shi
- , Steven Gazal
- & Alkes L. Price
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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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Identity-by-descent detection across 487,409 British samples reveals fine scale population structure and ultra-rare variant associations
Accurately measuring genetic relatedness by Identical-By-Descent (IBD) segments is challenging in biobank-level genome data. The authors present IBD method FastSMC, which when applied to the UK Biobank gives a detailed picture of genetic relatedness and evolutionary history in the UK over the past 2000 years.
- Juba Nait Saada
- , Georgios Kalantzis
- & Pier Francesco Palamara
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Population-scale study of eRNA transcription reveals bipartite functional enhancer architecture
Enhancer RNAs are transcribed bidirectionally from core transcription initiation regions. Here, by employing nascent RNA sequencing, the authors identify quantitative trait loci (QTLs) associated with enhancer RNA level and directionality, revealing the bipartite architecture of enhancers.
- Katla Kristjánsdóttir
- , Alexis Dziubek
- & Hojoong Kwak
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Efficient variance components analysis across millions of genomes
Variance components analysis may be used for a variety of applications including heritability estimation and association mapping. Here, the authors present a computationally efficient method, scalable to extremely large GWAS datasets, and use it for heritabilty analysis of 22 traits from UK Biobank
- Ali Pazokitoroudi
- , Yue Wu
- & Sriram Sankararaman
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Distinct genetic architectures and environmental factors associate with host response to the γ2-herpesvirus infections
Disease prognosis after infection with Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr Virus is highly variable. Here the authors carry out epidemiological and genetic analysis of a Ugandan cohort and suggest complex interactions may influence pathogenesis and transmission.
- Neneh Sallah
- , Wendell Miley
- & Inês Barroso
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Multivariate genomic scan implicates novel loci and haem metabolism in human ageing
Ageing phenotypes are of great interest but are difficult to study genetically, partly due to the sample sizes required. Here, the authors present a multivariate framework to combine GWAS summary statistics and increase statistical power, identifying additional loci enriched for aging.
- Paul R. H. J. Timmers
- , James F. Wilson
- & Joris Deelen
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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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Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data
Promoter-anchored chromatin interaction (PAI) is a mechanism by which gene expression is regulated, but methods to measure PAIs are costly and currently not scalable. Here, the authors develop an approach by which PAIs can be predicted using summary-level data from methylation QTL studies.
- Yang Wu
- , Ting Qi
- & Jian Yang
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Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression
Studying the genetic effects on early stages of human development is challenging due to a scarcity of biological material. Here, the authors utilise induced pluripotent stem cells from 125 donors to track gene expression changes and expression quantitative trait loci at single cell resolution during in vitro endoderm differentiation.
- Anna S. E. Cuomo
- , Daniel D. Seaton
- & Oliver Stegle
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Heritability estimates for 361 blood metabolites across 40 genome-wide association studies
Blood metabolite levels are under the influence of environmental and genetic factors. Here, Hagenbeek et al. perform heritability estimations for metabolite measures and determine the contribution of known metabolite loci to metabolite levels using data from 40 genome-wide association studies.
- Fiona A. Hagenbeek
- , René Pool
- & Dorret I. Boomsma
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Article
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Structural variants exhibit widespread allelic heterogeneity and shape variation in complex traits
Rare structural variants may account for a significant fraction of variation in complex traits. Here the authors analyse 14 Drosophila melanogaster genomes and find that structural variants are common, found in functionally important genes, and associated with QTLs.
- Mahul Chakraborty
- , J. J. Emerson
- & Anthony D. Long
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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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The transferability of lipid loci across African, Asian and European cohorts
The majority of published GWAS was performed in European ancestry populations. Here, Kuchenbaecker et al., test to which extent lipid loci are shared and find that the major lipid loci are mostly transferrable between Europeans and Asians while there are notable exceptions for African populations.
- Karoline Kuchenbaecker
- , Nikita Telkar
- & Dieter Wolke
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Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease
Differentially methylated CpGs can inform on disease mechanisms and be useful as biomarkers. Here, the authors perform GWAS for DNA methylation in whole blood, cis- and trans-meQTL mapping, followed by Mendelian randomization analysis that links meQTLs with cardiovascular diseases.
- Tianxiao Huan
- , Roby Joehanes
- & Daniel Levy
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Gene-diet interactions associated with complex trait variation in an advanced intercross outbred mouse line
Complex traits associate with genetic variation and environment and their interaction. Here, the authors study the influence of different diets on trait variability in 1154 outbred mice from an advanced intercross line and find gene-diet interactions associated with spontaneous autoimmunity development in these animals.
- Artem Vorobyev
- , Yask Gupta
- & Ralf J. Ludwig
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Functional genetic variants can mediate their regulatory effects through alteration of transcription factor binding
Functional variants have been proposed to alter transcription factor binding. Here, the authors provide direct evidence that functional variants within the TBC1D4 gene, encoding an NFκB binding site, can alter transcription factor binding, and use CRISPR-Cas9 to reveal localization of the transcription factor to be the regulator of chromatin accessibility and p65 binding and ultimately TBC1D4 expression.
- Andrew D. Johnston
- , Claudia A. Simões-Pires
- & John M. Greally
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The effect of X-linked dosage compensation on complex trait variation
Dosage compensation (DC) on the X chromosome has predictable effects on genetic and phenotypic trait variance. Here, the authors use information for 20 quantitative traits in the UK Biobank and across-tissue gene expression to compare X-linked heritability and the effects of trait-associated SNPs between the sexes.
- Julia Sidorenko
- , Irfahan Kassam
- & Peter M. Visscher
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Facial recognition from DNA using face-to-DNA classifiers
Prediction of face from DNA followed by matching to facial images has been proposed for forensic applications. Here, Sero et al. present a different approach that can establish facial identity from DNA without directly predicting the face but is based on classifying given faces by individual DNA-encoded traits.
- Dzemila Sero
- , Arslan Zaidi
- & Peter Claes
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Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis
Estimated glomerular filtration rate (eGFR) is a measure of kidney function and used to characterize chronic kidney disease. Here, Graham et al. identify 53 novel loci for eGFR in a GWAS meta-analysis, a subset of which are associated with other common diseases, such as diabetes and hypertension, based on PheWAS.
- Sarah E. Graham
- , Jonas B. Nielsen
- & Cristen J. Willer
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Whole genome sequencing of canids reveals genomic regions under selection and variants influencing morphology
Being man’s best friend, dogs have been bred and selected for certain morphologic traits and breed-associated behaviours. Here, Plassais et al. analyse 722 canine whole genome sequences including modern breeds, wild canids and village dogs by GWAS and search for signatures of selection.
- Jocelyn Plassais
- , Jaemin Kim
- & Elaine A. Ostrander
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Longevity defined as top 10% survivors and beyond is transmitted as a quantitative genetic trait
While human lifespan is only moderately heritable, “getting old” runs in families. Here, van den Berg et al. study mortality data from three-generation cohorts to define a threshold for longevity and find that individuals have an increasing survival advantage with each additional relative in the top 10% survivors of their birth cohort.
- Niels van den Berg
- , Mar Rodríguez-Girondo
- & P. Eline Slagboom
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Dissection of genetic variation and evidence for pleiotropy in male pattern baldness
Male pattern baldness (MPB) is a polygenic trait that affects the majority of European men. Here, Yap et al. estimate heritability, partitioned by autosomes and the X-chromosome, of MPB in the UK Biobank cohort, perform GWAS for MPB and find genetic correlation with other sex-specific traits.
- Chloe X. Yap
- , Julia Sidorenko
- & Peter M. Visscher
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Article
| Open Access
Latin Americans show wide-spread Converso ancestry and imprint of local Native ancestry on physical appearance
Latin Americans trace their ancestry to the admixture of Native Americans, Europeans and Sub-Saharan Africans. Here, the authors develop a novel haplotype-based approach and analyse over 6,500 Latin Americans to infer the geographically-detailed genetic structure of this population.
- Juan-Camilo Chacón-Duque
- , Kaustubh Adhikari
- & Andrés Ruiz-Linares
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Article
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Genome wide association analysis in a mouse advanced intercross line
Multigenerational outbred populations from an advanced intercross line (AIL) of mice represent useful resources for genome wide association analysis. Here, the authors analyze 1,063 LG x SM AIL mice to identify significant associations for 50 traits relevant to human health and disease.
- Natalia M. Gonzales
- , Jungkyun Seo
- & Abraham A. Palmer
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Article
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Carotid intima-media thickness (cIMT) and plaque are associated with subclinical atherosclerosis and coronary heart disease (CHD). Here, the authors identify and prioritize genetic loci for cIMT and plaque by GWAS and colocalization approaches and further demonstrate genetic correlation with CHD and stroke.
- Nora Franceschini
- , Claudia Giambartolomei
- & Christopher J. O’Donnell
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Article
| Open Access
Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume
An increase in the volume of the brain lateral ventricles is a sign of normal aging, but can also be associated with neurological and psychiatric disorders. Here, Vojinovic et al. identify seven genetic loci in a GWA study for ventricular volume in 23,500 individuals and find correlation with thalamus volume.
- Dina Vojinovic
- , Hieab H. Adams
- & Myriam Fornage
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Article
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Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes
GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.
- Angli Xue
- , Yang Wu
- & Jian Yang
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Article
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Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks
Disease risk variants can exert their influence on phenotypes by altering epigenome function. Here, Pelikan et al. show that variants inducing allelic imbalance in histone marks in lymphoblastoid cell lines from lupus patients are enriched in autoimmune disease haplotypes and influence gene expression.
- Richard C. Pelikan
- , Jennifer A. Kelly
- & Patrick M. Gaffney
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Correspondence
| Open Access
Misestimation of heritability and prediction accuracy of male-pattern baldness
- Chloe X. Yap
- , Julia Sidorenko
- & Peter M. Visscher
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Article
| Open Access
Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness
Hand grip strength as a proxy of muscular fitness is a clinical predictor of mortality and morbidity. In a large-scale GWA study, the authors find 16 robustly associated genetic loci that highlight roles in muscle fibre structure and function, neuronal maintenance and nervous system signal transduction.
- Sara M. Willems
- , Daniel J. Wright
- & Robert A. Scott
A landscape of gene expression regulation for synovium in arthritis