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| Open AccessGhostKnockoff inference empowers identification of putative causal variants in genome-wide association studies
The authors present GhostKnockoff, a method for genome-wide association studies which can be applied to enhance existing and future studies to identify functional variants with weaker statistical effects that might be missed by conventional association tests.
- Zihuai He
- , Linxi Liu
- & Iuliana Ionita-Laza
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Article
| Open AccessIntegrating transcription factor occupancy with transcriptome-wide association analysis identifies susceptibility genes in human cancers
Transcriptome-wide association studies can uncover genes involved in disease. Here, the authors extend the framework with a transcriptome-wide association study approach which incorporates transcription factor occupancy, adding tissue-specific mechanistic support to associations.
- Jingni He
- , Wanqing Wen
- & Xingyi Guo
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Article
| Open AccessGenome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure
Heart failure is a major cause of cardiovascular morbidity and mortality. Here, the authors report results of a genome-wide association study meta-analysis, characterizing the role of common genetic variants in heart failure, finding overlap with common cardiovascular risk factors and imaging measures of cardiac structure/function.
- Michael G. Levin
- , Noah L. Tsao
- & Scott M. Damrauer
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Article
| Open AccessPleiotropic genetic architecture and novel loci for C-reactive protein levels
Chronic inflammation and lipometabolism share many causal genes and possibly pathways. Here, the authors use a multi-trait GWAS approach to study shared genetic determinants of low-grade inflammation, measured by C-reactive protein (CRP), and closely linked lipid and metabolic pathways.
- Fotios Koskeridis
- , Evangelos Evangelou
- & Ioanna Tzoulaki
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| Open AccessCollective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology
Cognitive impairments are a key feature of psychopathology. Here, authors exploit the genetic overlap between cognitive dimensions and psychopathology to parse the biology of psychiatric illness and identify “meta-loci” genome segments characterized by specific patterns of overlap.
- Max Lam
- , Chia-Yen Chen
- & Todd Lencz
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Article
| Open AccessGenetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
Immunoglobulin A protects against infectious disease and contributes to autoimmune and inflammatory disorders. Here, the authors perform a genome-wide association study for serum IgA levels, identifying 20 genome-wide significant loci, providing new insights into the genetic regulation of IgA levels.
- Lili Liu
- , Atlas Khan
- & Krzysztof Kiryluk
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Article
| Open AccessParent-of-Origin inference for biobanks
Studies on parent-of-origin effects have been limited in terms of sample size due to lack of parental genomes or known genealogies. Here, the authors develop a method to infer the parent-of-origin of an individual alleles in biobank-scale datasets, without requiring parental genomes or prior knowledge of genealogy, allowing discovery of parent-of-origin effects with an unprecedented sample size.
- Robin J. Hofmeister
- , Simone Rubinacci
- & Olivier Delaneau
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Article
| Open AccessThe contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians
Metabolic traits are heritable intermediate phenotypes widely used in assessing the risk of various diseases. By conducting a genome-wide meta-analysis for metabolic traits in 288,137 East Asians, the authors highlight the interplay of common and rare variants on inherited risk of metabolic traits.
- Young Jin Kim
- , Sanghoon Moon
- & Bong-Jo Kim
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Article
| Open AccessShared genetic risk factors and causal association between psoriasis and coronary artery disease
Coronary artery disease (CAD) and psoriasis are established comorbidities, however their molecular relationship remains unclear. Here, the authors performed trans-disease meta-analysis, highlighting four genetic loci with evidence of colocalization, and prioritized genes based on multiomic data integration.
- Matthew T. Patrick
- , Qinmengge Li
- & Lam C. Tsoi
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Article
| Open AccessMendelian randomization accounting for complex correlated horizontal pleiotropy while elucidating shared genetic etiology
Mendelian randomization uses genetic variation to study the causal effect of exposure on outcome, but results can be biased by confounders, such as horizontal pleiotropy. Here, the authors present MR-CUE, a method to determine causal effects by accounting for correlated and uncorrelated horizontal pleiotropic effects.
- Qing Cheng
- , Xiao Zhang
- & Jin Liu
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Article
| Open AccessWhole genome sequence analysis of blood lipid levels in >66,000 individuals
Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.
- Margaret Sunitha Selvaraj
- , Xihao Li
- & Pradeep Natarajan
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Article
| Open AccessVariation in the fruit development gene POINTED TIP regulates protuberance of tomato fruit tip
While auxin has been implicated in the development of tomato fruit with pointed tips, the mechanism are largely unknown. Here, the authors report variation of a C2H2-type zinc finger transcription factor affects transcription of FUL2, which consequently regulates auxin transport and distribution to determine tomato fruit shape.
- Jianwen Song
- , Lele Shang
- & Junhong Zhang
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Article
| Open AccessGWAS, MWAS and mGWAS provide insights into precision agriculture based on genotype-dependent microbial effects in foxtail millet
Plant genotype alone appears to be insufficient to explain trait variations. This study integrates GWAS, MWAS and mGWAS in 827 foxtail millet cultivars, revealing that root-associated microbiota affect plant phenotypes in a host genotype-dependent manner.
- Yayu Wang
- , Xiaolin Wang
- & Huan Liu
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Article
| Open AccessGenomic analyses of rice bean landraces reveal adaptation and yield related loci to accelerate breeding
Rice bean is an underexploited legume crop that has many desirable properties against bio and abiotic stresses. Here, the authors report the genome assembly of this species, conduct population genetics studies and reveal the genetic variations associated with adaptation and yield traits.
- Jiantao Guan
- , Jintao Zhang
- & Lixia Wang
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Article
| Open AccessMulti-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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Article
| Open AccessEfficient and accurate frailty model approach for genome-wide survival association analysis in large-scale biobanks
The proliferation of large biobanks necessitates statistical methods designed for genetic analysis on biobank data. Here, the authors have developed a frailty model-based method for GWAS analysis of time-to-event phenotypes in large biobanks that accounts for relatedness in samples and censoring of phenotypes.
- Rounak Dey
- , Wei Zhou
- & Xihong Lin
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Article
| Open AccessIdentifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes
Genetic association studies for rare variants suffer from lack of power and thus there is a need for methods to improve rare variant discovery. Here, the authors present functionally informed association tests with increased statistical power to aid discovery and interpretation of rare variants.
- Remo Monti
- , Pia Rautenstrauch
- & Christoph Lippert
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Article
| Open AccessIdentification of risk loci for primary aldosteronism in genome-wide association studies
Detection of primary aldosteronism, the most common form of secondary arterial hypertension, is essential for targeted management and prevention of cardiovascular complications. Here, the authors identify genetic loci associated with primary aldosteronism, suggesting new mechanisms of disease.
- Edith Le Floch
- , Teresa Cosentino
- & Maria-Christina Zennaro
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Article
| Open AccessGenetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.
- William J. Young
- , Najim Lahrouchi
- & Patricia B. Munroe
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| Open AccessMultiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes
Fat distribution is associated with cardiometabolic disease, although it has been less well studied than overall obesity. In a multiancestry exome-sequencing study, the authors identified predicted loss-of-function mutations in INHBE associated with favorable fat distribution and protection from type 2 diabetes.
- Parsa Akbari
- , Olukayode A. Sosina
- & Luca A. Lotta
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| Open AccessWhole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals
Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.
- Usman A. Tahir
- , Daniel H. Katz
- & Robert E. Gerszten
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Article
| Open AccessGWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.
- Peter H. Dixon
- , Adam P. Levine
- & Catherine Williamson
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Article
| Open AccessELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19
Genetic factors have been found to be associated with severe COVID-19. Here, the authors integrated genomic, proteomic, and single-cell data to identify ELF5 as a candidate risk gene with a possible role in respiratory epithelial cells, which are targeted by SARS-CoV-2.
- Maik Pietzner
- , Robert Lorenz Chua
- & Claudia Langenberg
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Article
| Open AccessA cognitive neurogenetic approach to uncovering the structure of executive functions
How complex brain functions are mapped onto the human brain is a daunting scientific challenge. Here, the authors use a cognitive neurogenetic approach to identify the structure of executive functions and their underlying neurogenetic basis.
- Junjiao Feng
- , Liang Zhang
- & Gui Xue
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Article
| Open AccessGenome-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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Article
| Open AccessA common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors
Intracranial germ cell tumors (IGCTs) are rare brain tumors mainly diagnosed in children and young adults. Here, the authors conduct a genome-wide association study for IGCTs, identify a risk locus at BAK1, and characterize its functional consequences.
- Kyuto Sonehara
- , Yui Kimura
- & Keita Terashima
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Article
| Open AccessGenome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells
The genetic architecture underlying Sjögren’s syndrome is not fully understood. Here, the authors perform a genome-wide association study to identify 10 new genetic risk regions, implicating genes involved in immune and salivary gland function.
- Bhuwan Khatri
- , Kandice L. Tessneer
- & Christopher J. Lessard
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| Open AccessRare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity
Abdominal fat has been shown to increase cardiometabolic disease risk. In this study, the authors report that loss-of-function variants in the gene INHBE associate with lower BMI-adjusted waist-to-hip ratio, a surrogate measure of abdominal fat.
- Aimee M. Deaton
- , Aditi Dubey
- & Paul Nioi
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Article
| Open AccessAggregative trans-eQTL analysis detects trait-specific target gene sets in whole blood
Large-scale genetic association studies have identified many trait-associated variants that influence gene expression. Here, the authors present ARCHIE, a tool for identifying sets of genes whose regulation may be related to specific complex traits.
- Diptavo Dutta
- , Yuan He
- & Nilanjan Chatterjee
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Article
| Open AccessPopulation genomics of Group B Streptococcus reveals the genetics of neonatal disease onset and meningeal invasion
Group B Streptococcus (GBS) causes neonatal disease and mortality worldwide. Here, the authors use genome-wide association analyses to identify bacterial genetic signatures associated with disease onset time and meningeal tissue infection in acute invasive neonatal GBS disease.
- Chrispin Chaguza
- , Dorota Jamrozy
- & Stephen D. Bentley
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Article
| Open AccessVariance-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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Article
| Open AccessThe genetic architecture of pneumonia susceptibility implicates mucin biology and a relationship with psychiatric illness
Susceptibility to pneumonia has a genetic component, but specific genes involved remain poorly understood. In this study, genetic signals associated with pneumonia susceptibility are identified, providing information about disease biology and potential targets for treatment.
- William R. Reay
- , Michael P. Geaghan
- & Murray J. Cairns
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| Open AccessAdvancing our understanding of genetic risk factors and potential personalized strategies for pelvic organ prolapse
Although pelvic organ prolapse is a common gynecological condition, the genetic component of disease risk is not well known. Here the authors find common genetic variants associated with the disease and present a polygenic risk score to enhance individual risk prediction.
- Natàlia Pujol-Gualdo
- , Kristi Läll
- & Triin Laisk
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Article
| Open AccessThe impact of species-wide gene expression variation on Caenorhabditis elegans complex traits
Gene expression links genomic variation to organismal trait differences. Here, the authors identify regulatory loci underlying gene expression variation in C. elegans and demonstrate how this variation could impact other complex traits.
- Gaotian Zhang
- , Nicole M. Roberto
- & Erik C. Andersen
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Article
| Open AccessDistributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders
The hippocampus has been associated with memory traits and a variety of neurodegenerative and psychiatric disorders. Here, the authors have done a multivariate GWAS revealing 177 genetic loci, and overlap with various brain disorders may suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.
- Shahram Bahrami
- , Kaja Nordengen
- & Tobias Kaufmann
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Article
| Open AccessComprehensive genome-wide association study of different forms of hernia identifies more than 80 associated loci
Hernias involve protrusion of an organ or tissue through its surrounding cavity. Here the authors carry out GWAS for five types of hernia and find 81 variants, most of which are associated with inguinal hernia; downstream analysis suggests an important role for connective tissue morphology.
- João Fadista
- , Line Skotte
- & Frank Geller
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Article
| Open AccessIntegrating 3D genomic and epigenomic data to enhance target gene discovery and drug repurposing in transcriptome-wide association studies
Transcriptome-wide association studies can be used to test the effects of predicted gene expression in a cohort of individuals based on genetic data. Here, the authors developed a transcriptome-wide association method that integrates 3D genomic and epigenomic data with expression quantitative trait loci to improve gene expression predictions.
- Chachrit Khunsriraksakul
- , Daniel McGuire
- & Dajiang J. Liu
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| Open AccessComprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease
Dysregulation of lipid metabolism is associated with coronary artery disease (CAD). Here, the authors perform GWAS of the serum lipidome to identify variants associated with lipid species that are putatively in the mechanistic pathway to CAD.
- Gemma Cadby
- , Corey Giles
- & Eric K. Moses
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Article
| Open AccessGenome-wide association analysis and replication in 810,625 individuals with varicose veins
Although varicose veins are a common condition, the genetic basis is not well understood. Here, the authors find genetic variants associated with varicose veins and show that a higher polygenic risk score for varicose veins correlates with a greater likelihood of patients undergoing surgical treatment.
- Waheed-Ul-Rahman Ahmed
- , Sam Kleeman
- & Dominic Furniss
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Article
| Open AccessIdentification of positive and negative regulators of antiviral RNA interference in Arabidopsis thaliana
Whether natural variations of plant virus resistance are enriched in genes of RNA interference pathway is unknown. Here, via genome-wide association studies, the authors identify regulators of the RDR6 and DCL2 antiviral pathways are involved in quantitative resistance to cucumber mosaic virus in Arabidopsis.
- Si Liu
- , Meijuan Chen
- & Shou-Wei Ding
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Article
| Open AccessA rare variant analysis framework using public genotype summary counts to prioritize disease-predisposition genes
Sequencing studies in clinical and cancer genomics often utilize public data sets to identify genes enriched with pathogenic variants. Here, the authors propose a framework which controls for confounding factors that can bias the results in these studies.
- Wenan Chen
- , Shuoguo Wang
- & Gang Wu
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Article
| Open AccessGenetic analyses identify pleiotropy and causality for blood proteins and highlight Wnt/β-catenin signalling in migraine
Understanding of the causes and treatment of migraine is incomplete. Here, the authors detect pleiotropic genetic effects and causal relationships between migraine and 58 proteins that are largely distinct from migraine-associated loci identified by GWAS.
- Hamzeh M. Tanha
- , Dale R. Nyholt
- & Dale R. Nyholt
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Article
| Open AccessMeta-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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Article
| Open AccessContribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability
Despite the success of genome-wide association studies, much of the genetic contribution to complex traits remains unexplained. Here, the authors identify effects by rare variants on plasma proteins, and estimate the contribution of rare variants to the heritability.
- Marcin Kierczak
- , Nima Rafati
- & Åsa Johansson
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Article
| Open AccessMultivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain
How the tissue composition of the human brain is determined remains unclear. Here, the authors apply advanced analyses to two large imaging genetic datasets to identify and validate genetic loci that simultaneously influence multiple brain regions.
- Chun Chieh Fan
- , Robert Loughnan
- & Anders M. Dale
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Article
| Open AccessGenetic analysis of over half a million people characterises C-reactive protein loci
Inflammation is associated with a variety of diseases. Here, the authors identify 266 genetic loci associated with C-reactive protein levels, a marker of inflammation, in >500,000 Europeans, along with associated pathways, clinical outcomes and potential causal associations with disease.
- Saredo Said
- , Raha Pazoki
- & Abbas Dehghan
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Article
| Open AccessGenome-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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Article
| Open AccessGenetic regulation of post-translational modification of two distinct proteins
Post-translational modifications are known to diversify protein functions, but the effect of genetic variation on the modifications is not well known. Here, the authors find both shared and protein-specific genetic mechanisms regulating the glycosylation of two different proteins.
- Arianna Landini
- , Irena Trbojević-Akmačić
- & Lucija Klarić
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Article
| Open AccessA genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome
The underlying genetics of carpal tunnel syndrome is not well understood. Here, the authors perform a GWAS meta-analysis for carpal tunnel syndrome finding variants at 50 loci with connections to the extracellular matrix discovered through various functional analyses.
- Astros Th. Skuladottir
- , Gyda Bjornsdottir
- & Kari Stefansson