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Genome-wide association analyses identify 301 new loci influencing bone mineral density and 13 loci influencing fracture risk. Integrative analyses of epigenomic data and mouse knockout phenotypes provide additional insights into osteoporosis pathophysiology.
Genome-wide analysis of copy number variants in 2,824 cases across the phenotypic spectrum of CAKUT sheds light on the genomic architecture of disease and identifies TBX6 as a driver for CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.
Analysis of blood pressure data from the Million Veteran Program trans-ethnic cohort identifies common and rare variants, and genetically predicted gene expression across multiple tissues associated with systolic, diastolic and pulse pressure in over 775,000 individuals.
Analysis of ~10,000 cases of developmental delay and autism identifies 253 candidate neurodevelopmental disease genes. Network analysis highlights cell-specific enrichments of disease-related genes in the D1+ and D2+ spiny neurons of the striatum.
FitCons2 is a new framework that simultaneously clusters genomic sites by epigenomic features and evaluates the strength of natural selection on these sites. FitCons2 scores are used to generate fitness–consequence maps for 115 human cell types.
Activating HER2 mutations are shown to confer resistance to ER-directed therapies in patients with ER+ metastatic breast cancer. Drug resistance caused by HER2 mutations was overcome by combining ER-directed therapy with a HER2 kinase inhibitor.
This study leverages coding variation observed among 123,136 individuals to create a detailed map of constrained coding regions in the human genome. This map may help identify critical regions within genes that, when mutated, cause embryonic lethality or severe developmental phenotypes.
This study shows that immune-related genes are primed for transcription by proximal lncRNAs. One such lncRNA, UMLILO, directs the WDR5–MLL1 complex to CXCL chemokine promoters, facilitating H3K4me3 deposition.
Analysis of mutational asymmetry with respect to the direction of replication and transcription suggests that error-prone damage bypass on the lagging strand has a major role in human germline and cancer mutations.
The long noncoding RNA SCHLAP1 has been reported to act by depleting the SWI/SNF complex from genomic sites, but new data show that SWI/SNF remains localized to chromatin in the presence of SCHLAP1, suggesting that SCHLAP1 may act independently of SWI/SNF.
Including patient-specific information about nearby somatic and germline alterations improves the accuracy of neoantigen prediction, potentially impacting cancer vaccine design.
The improved genome assemblies of allotetraploid cotton species Gossypium hirsutum and Gossypium barbadense provide insights into cotton evolution and inform the construction of introgression lines used to identify loci associated with fiber quality.
SumHer is a software for estimating SNP heritability from summary statistics using heritability models. Applying SumHer to publicly available results for 24 GWAS provides an improved understanding of the genetic architecture of complex traits.
Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.
Multivariate adaptive shrinkage (mash) is a method for estimating and testing multiple effects in multiple conditions. When applied to GTEx data, mash can be used to analyze sharing of eQTL effects by examining variation in effect sizes.
Gain-of-function mutations altering the PWWP domain of DNMT3A are identified as a new cause of microcephalic dwarfism. These mutations abrogate DNMT3A binding to H3K36me2 and H3K36me3 and lead to aberrant DNA methylation of Polycomb-marked regions.
A Bayesian hierarchical approach identifies over 15,000 causal regulatory interactions in the human genome using ATAC-seq data from 100 individuals. The majority of detected interactions were over distances of <20 kb, a range where 3C methods perform poorly.
A genome-wide association study for attention deficit/hyperactivity disorder (ADHD) identifies 12 loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.
StructLMM is a new method to identify genotype–environment interactions (G×E) that involve multiple exposures or environments. When applied to UK Biobank and eQTL data, StructLMM discovers new G×E signals.
Individuals with biscuspid aortic valve and ascending aortic aneurysm show enrichment of rare variants in ROBO4. Functional studies suggest that ROBO4 mutations disrupt endothelial cell performance and contribute to pathological remodeling of aortic tissues.