Genetic association study

  • Article
    | Open Access

    Perilla is a young allotetraploid species within the mint family Lamiaceae. Here, the authors assemble the genomes of a tetraploid species and its diploid progenitor, characterize the incipient diploidization of the tetraploid, conduct population genetics analyses, and identify loci associate with pigmentation and oil content.

    • Yujun Zhang
    • , Qi Shen
    •  & Shilin Chen
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Genome-wide association studies of COVID-19 have identified genetic loci affecting disease severity, but the mechanisms remain to be fully described. Here, the authors use genetically predicted transcriptome, splicing and proteome data to identify potential genes and pathways underlying COVID- 19 severity.

    • Gita A. Pathak
    • , Kritika Singh
    •  & Nicholas Mancuso
  • Article
    | Open Access

    Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

    • John Pluta
    • , Louise C. Pyle
    •  & Christian Kubisch
  • Article
    | Open Access

    While polygenic risk scores have been shown to be correlated with disease risk, there is little agreement on how the score should be calculated. Here the authors investigate risk scores for Alzheimer’s disease, finding that the most effective approach includes an APOE score and a polygenic score excluding APOE.

    • Ganna Leonenko
    • , Emily Baker
    •  & Valentina Escott-Price
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.

    • Kira J. Stanzick
    • , Yong Li
    •  & Thomas W. Winkler
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Mosaic loss of chromosome Y (LOY) is a common form of clonal mosaicism in leukocytes. Here, the authors extend genetic association analyses to rare variation using exome-sequence data from 82,277 males, finding that loss-of-function alleles in GIGYF1 are associated with six-fold higher susceptibility to both LOY and Type 2 Diabetes.

    • Yajie Zhao
    • , Stasa Stankovic
    •  & John R. B. Perry
  • Article
    | Open Access

    Pernicious anemia shows co-incidence with autoimmune disorders, yet the genetic basis for this condition is understudied. Here, the authors perform a genome-wide association study meta-analysis on pernicious anemia, identifying five susceptibility loci that map to genes with known roles in autoimmune disease.

    • Triin Laisk
    • , Maarja Lepamets
    •  & Reedik Mägi
  • Article
    | Open Access

    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
  • Article
    | Open Access

    Longhua Shui Mi (LHSM) is a representative of the Chinese Cling peaches that have been central in global peach genetic improvement. Here, the authors assemble the genome of LHSM and show convergent selection for sweetness yet divergent selection for acidity in eastern vs. western cultivars through population genomics analyses.

    • Yang Yu
    • , Jiantao Guan
    •  & Hua Xie
  • Article
    | Open Access

    Age at onset of X-linked dystonia-parkinsonism is 50% explained by the length of a repeat in an SVA insert. The authors perform a GWAS for genetic modifiers and discover three more loci, accounting for another 13% of variability in age at onset with the protective alleles delaying onset by seven years.

    • Björn-Hergen Laabs
    • , Christine Klein
    •  & Ana Westenberger
  • Article
    | Open Access

    Quantifying the effects of individual loci on the human phenome is a challenging task. Here, the authors introduce a modelling technique, TGCA, that assesses total genetic contribution per locus and apply this to UK Biobank phenotype domains, revealing top loci and links to tissue-specific gene expression.

    • Ting Li
    • , Zheng Ning
    •  & Xia Shen
  • Article
    | Open Access

    While coffee and tea consumption has been associated with risk of diseases, their mechanisms of action remain elusive. Here the authors present a large EWAS on coffee and tea consumption in cohorts of European and African-American ancestries, finding that coffee consumption is associated with differential DNA methylation levels at multiple CpGs.

    • Irma Karabegović
    • , Eliana Portilla-Fernandez
    •  & Mohsen Ghanbari
  • Article
    | Open Access

    Gene regulatory networks are a useful means of inferring functional interactions from large-scale genomic data. Here, the authors develop a Bayesian framework integrating GWAS summary statistics with gene regulatory networks to identify genetic enrichments and associations simultaneously.

    • Xiang Zhu
    • , Zhana Duren
    •  & Wing Hung Wong
  • Article
    | Open Access

    Most genome-wide association studies assume an additive model, exclude the X chromosome, and use one reference panel. Here, the authors implement a strategy including non-additive models and find that the number of loci for age-related traits increases as compared to the additive model alone.

    • Marta Guindo-Martínez
    • , Ramon Amela
    •  & David Torrents
  • Article
    | Open Access

    The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

    • Pradeep Natarajan
    • , Akhil Pampana
    •  & Gina M. Peloso
  • Article
    | Open Access

    Despite linguistic and geographic diversity in South Eastern Bantu-speaking (SEB) groups of South Africa, genetic variation in these groups has not been investigated in depth. Here, the authors analyse genome-wide data from 5056 individuals, providing insights into demographic history across SEB groups.

    • Dhriti Sengupta
    • , Ananyo Choudhury
    •  & Michèle Ramsay
  • Article
    | Open Access

    Genetic correlation analyses give insight on complex disease, yet are limited by oversimplification. Here, the authors present LOGODetect, a method using summary statistics from genome-wide association studies to identify genomic regions with correlation signals across multiple phenotypes.

    • Hanmin Guo
    • , James J. Li
    •  & Lin Hou
  • Article
    | Open Access

    In genome-wide association meta-analysis, it is often difficult to find an independent dataset of sufficient size to replicate associations. Here, the authors have developed MAMBA to calculate the probability of replicability based on consistency between datasets within the meta-analysis.

    • Daniel McGuire
    • , Yu Jiang
    •  & Dajiang J. Liu
  • Article
    | Open Access

    Human leukocyte antigen (HLA) genes contribute to risk of many complex traits, yet understanding inter-ethnic heterogeneity is computationally challenging. Here, the authors develop DEEP*HLA for imputation of HLA genotypes and show its ability to disentangle HLA variant risk effects in diverse populations.

    • Tatsuhiko Naito
    • , Ken Suzuki
    •  & Yukinori Okada
  • Article
    | Open Access

    The significance of translated upstream open reading frames is not well known. Here, the authors investigate genetic variants in these regions, finding that they are under high evolutionary constraint and may contribute to disease.

    • David S. M. Lee
    • , Joseph Park
    •  & Yoseph Barash
  • Article
    | Open Access

    Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments.

    • Julia Steinberg
    • , Lorraine Southam
    •  & Eleftheria Zeggini
  • Article
    | Open Access

    Blood circulating proteins reflect biological processes, thus providing insight into complex traits. Here the authors study the relationship between 1000 plasma proteins and body mass index (BMI), highlighting widespread proteome changes and causal relationships between BMI and specific proteins.

    • Shaza B. Zaghlool
    • , Sapna Sharma
    •  & Karsten Suhre
  • Article
    | Open Access

    Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

    • Puya Gharahkhani
    • , Eric Jorgenson
    •  & Janey L. Wiggs
  • Article
    | Open Access

    Studies of fruit quality traits in pears are lagging behind the other major fruit trees. Here, the authors conduct GWAS of fruit quality and phenological traits in a panel of 312 sand pear accessions using SNPs called from resequencing data, and reveal the involvement of a lignin formation-related protein in regulating stone cell development.

    • Ming-Yue Zhang
    • , Cheng Xue
    •  & Jun Wu
  • Article
    | Open Access

    Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

    • Saori Sakaue
    • , Etsuro Yamaguchi
    •  & Yukinori Okada
  • Article
    | Open Access

    Metabolites are indicators of health and disease; genetic studies can reveal variants influencing their levels. Here, the authors investigate the contribution of rare, exonic variants on the levels of urine metabolites and generate predictions on metabolic consequences underlying metabolic disease.

    • Yurong Cheng
    • , Pascal Schlosser
    •  & Anna Köttgen
  • Article
    | Open Access

    The genetic basis of daytime napping and the directional effect of daytime napping on cardiometabolic health are unknown. Here, the authors perform a genome-wide association study on self-reported daytime napping in the UK Biobank and Mendelian randomization to explore causal associations.

    • Hassan S. Dashti
    • , Iyas Daghlas
    •  & Richa Saxena
  • Article
    | Open Access

    Large BioBank studies are commonly used in GWAS, but may be biased by factors affecting participation and dropout. Here the authors show that some of the factors affecting participation may have underlying genetic components.

    • Jessica Tyrrell
    • , Jie Zheng
    •  & Kate Tilling
  • Article
    | Open Access

    Serum liver enzymes are used as markers of liver disease, their concentration influenced in part by genetic factors. Here the authors meta-analyse genome-wide association studies on the UK Biobank and BioBank Japan to evaluate the association of three liver enzymes with liver and other metabolic diseases.

    • Vincent L. Chen
    • , Xiaomeng Du
    •  & Elizabeth K. Speliotes
  • Article
    | Open Access

    Statistical colocalisation is a method to identify causal genes and shared genetic aetiology across traits. Here, the authors describe HyPrColoc, an efficient Bayesian divisive clustering algorithm which integrates summary statistics from genome-wide association studies to detect clusters of colocalised traits from large numbers of traits.

    • Christopher N. Foley
    • , James R. Staley
    •  & Joanna M. M. Howson