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| Open AccessImplementing community-engaged pharmacogenomics in Indigenous communities
Innovative pharmacogenomic approaches (genetic variation related to medication response) are needed to reduce disease and disparities in Indigenous communities. We support community-based pharmacogenomics research, inclusive of Indigenous values and priorities, to improve the health and well-being of Indigenous peoples.
- Katrina G. Claw
- , Casey R. Dorr
- & Erica L. Woodahl
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Article
| Open AccessA common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators
A common East Asian-specific defect of an alcohol metabolizing enzyme (ALDH2) causes glucose abnormality, obesity, and fatty liver. Here, the authors show an ALDH2 activator can treat these metabolic disorders in mice.
- Yi-Cheng Chang
- , Hsiao-Lin Lee
- & Lee-Ming Chuang
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Article
| Open AccessEffect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease
PSEN1 E280A carriers develop dementia by midlife, but there is variability in disease trajectory. Cognitive decline is accelerated in E280A carriers who also have an APOE e4 allele. Educational attainment moderates the effect of APOE on cognition.
- Stephanie Langella
- , N. Gil Barksdale
- & Yakeel T. Quiroz
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Article
| Open AccessDeficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. Here, using genetic data for 1.52 million individuals, the authors identify 25 genes with protein-altering variants exhibiting a strong deficit of homozygosity, suggesting they are essential for successful early development.
- Asmundur Oddsson
- , Patrick Sulem
- & Daniel F. Gudbjartsson
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Article
| Open AccessMultitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis
The genetic basis of primary sclerosing cholangitis has only been partially uncovered. Here, the authors perform a multitrait genome-wide association study to provide insight into the genetic etiology of primary sclerosing cholangitis risk and possible therapeutic drug targets.
- Younghun Han
- , Jinyoung Byun
- & Christopher I. Amos
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Article
| Open AccessGermline TP53 mutations undergo copy number gain years prior to tumor diagnosis
Li-Fraumeni syndrome (LFS) is associated with pathogenic germline TP53 variants and predisposes patients to cancer; understanding the evolution and drivers of LFS-related tumours remains crucial. Here, the authors analyse 22 LFS tumours using whole-genome sequencing and reconstruct the evolution and timing of somatic driver alterations.
- Nicholas Light
- , Mehdi Layeghifard
- & Adam Shlien
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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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Article
| Open AccessRare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4
Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.
- Sarah Grosche
- , Ingo Marenholz
- & Young-Ae Lee
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Article
| Open AccessCalibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories
Identifying associations of rare variants with disease is challenging due to small effect sizes, technical artefacts and population structure heterogeneity. Here, the authors present RV-EXCALIBER, a method that uses large summary-level exome data to robustly calibrate rare variant burden.
- Ricky Lali
- , Michael Chong
- & Guillaume Paré
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Article
| Open AccessThe impact of non-additive genetic associations on age-related complex diseases
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
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Article
| Open AccessGenome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals
Genome-wide association studies (GWASs) for cigarette smoking have identified several hundred loci that account for a small proportion of the overall genetic risk. Here, the authors report a large GWAS for smoking trajectories and meta-analysis for smoking status, finding multiple plausible loci.
- Ke Xu
- , Boyang Li
- & Amy C. Justice
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Article
| Open AccessFastClone is a probabilistic tool for deconvoluting tumor heterogeneity in bulk-sequencing samples
Multiple algorithms exist for predicting heterogeneity and clonal architecture from the bulk sequencing of tumor tissue. Here, the authors report on an algorithm, FastClone, which was developed from a DREAM challenge and show that FastClone can accurately predict clonality in simulated data and data from colon cancer.
- Yao Xiao
- , Xueqing Wang
- & Yuanfang Guan
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Article
| Open AccessRare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations
Associations of copy number variations (CNVs) with complex traits are challenging to study because of their low frequency. Here, the authors analyse SNP array and array comparative genomic hybridization data of 100,028 individuals and report their associations with immune-related, cardiometabolic and neuropsychiatric diseases as well as cancer.
- Yun Rose Li
- , Joseph T. Glessner
- & Hakon Hakonarson
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Article
| Open AccessFunctional disease architectures reveal unique biological role of transposable elements
Transposable elements (TE) make up a large component of the human genome and have been shown to contribute to human diseases. Here, Hormozdiari
et al . estimate the contribution of TEs to the heritability of 41 complex traits and diseases and find enrichment of SINEs in blood traits.- Farhad Hormozdiari
- , Bryce van de Geijn
- & Alkes L. Price
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Article
| Open AccessChromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities
Multimorbidities of common diseases often have shared underlying predisposing factors. Here Fadason et al. study the pleiotropy of SNPs and their effects on target genes by integrating chromatin interaction and expression quantitative trait loci data to identify target genes shared between phenotypes.
- Tayaza Fadason
- , William Schierding
- & Justin M. O’Sullivan
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Article
| Open AccessPhenome-wide association studies across large population cohorts support drug target validation
Testing the association between genetic variants and a range of phenotypes can assist drug development. Here, in a phenome-wide association study in up to 697,815 individuals, Diogo et al. identify genotype–phenotype associations predicting efficacy, alternative indications or adverse drug effects.
- Dorothée Diogo
- , Chao Tian
- & Heiko Runz
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Article
| Open AccessGermline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls
Association between variants in 11 different genes and breast cancer risk has been established and sequencing of these genes is recommended to provide personalized diagnosis, therapy, and surveillance for the high-risk patients and their relatives. Here the authors analyse the frequency of germline pathogenic mutations in these genes specifically in a Japanese population.
- Yukihide Momozawa
- , Yusuke Iwasaki
- & Michiaki Kubo
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Correspondence
| Open AccessReply to ‘Misestimation of heritability and prediction accuracy of male-pattern baldness’
- Nicola Pirastu
- , Peter K. Joshi
- & James F. Wilson
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Article
| Open AccessAnalysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease
Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.
- Connor A. Emdin
- , Amit V. Khera
- & Sekar Kathiresan
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Article
| Open AccessMedical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study
Protein-truncating variants (PTVs) are predicted to significantly affect a gene’s function and, thus, human traits. Here, DeBoever et al. systematically analyze PTVs in more than 300,000 individuals across 135 phenotypes and identify 27 associations between PTVs and medical conditions.
- Christopher DeBoever
- , Yosuke Tanigawa
- & Manuel A. Rivas
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Article
| Open AccessGWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk
Male pattern baldness (MBP) is a complex trait that has genetic associations. Here, Pirastu and colleagues perform a genome-wide association study to show 71 susceptibility loci associated with MBP — 30 of which are novel — and that these loci can explain 38% of heritability.
- Nicola Pirastu
- , Peter K. Joshi
- & James F. Wilson
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Article
| Open AccessPrevalence of sexual dimorphism in mammalian phenotypic traits
Systemic dissection of sexually dimorphic phenotypes in mice is lacking. Here, Karp and the International Mouse Phenotype Consortium show that approximately 10% of qualitative traits and 56% of quantitative traits in mice as measured in laboratory setting are sexually dimorphic.
- Natasha A. Karp
- , Jeremy Mason
- & Jacqueline K. White
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Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci
About 2% of the population are affected by psoriasis, a chronic skin disease with complex genetics. Here Tsoi et al.conduct a meta-analysis of several genome-wide association studies and identify five novel loci, helping to further our understanding of the biology behind this condition.
- Lam C. Tsoi
- , Sarah L. Spain
- & James T. Elder
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Article
| Open AccessGipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human
Progressive sensorineural hearing loss affects many people, but the underlying genetics remain largely undefined. Here, the authors identify mutations inGIPC3in mice and two consanguineous families that lead to hearing loss and in mice cause defects in the structure of stereocilia bundles and audiogenic seizures.
- Nikoletta Charizopoulou
- , Andrea Lelli
- & Konrad Noben-Trauth