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Katherine Siminovitch and colleagues report replication and fine-mapping studies for primary biliary cirrhosis. They identify three loci newly associated with susceptibility to this autoimmune liver disease.

Katherine Siminovitch and colleagues show that mice expressing the autoimmune disease–associated Ptpn22 coding variant show thymic and splenic enlargement and lymphocyte and dendritic cell hyperresponsiveness. They further show that the variant promotes degradation of the protein, suggesting that it enhances autoimmune disease risk through a loss-of-function mechanism.

Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.

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.

Multi-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable performance between populations of European and East Asian ancestries.

Genomic studies often lack representation from diverse populations, limiting equitable insights. Here, the authors show that the BIG Initiative captures extensive genetic diversity and reveals ancestry-linked health disparities in a community-based Mid-South cohort.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Technologies such as high-throughput DNA genotyping, microarray-based gene-expression profiling and mass-spectrometry-facilitated protein profiling enable DNA sequence variants to be analyzed and changes in global gene and protein expression to be assessed. By such methods, molecular pathways that link specific gene variants to cell dysfunction and disease, such as rheumatoid arthritis and systemic lupus erythematosus, can be defined.

Michael Seldin and colleagues report a genome-wide association study and meta-analyses for primary biliary cirrhosis. They identify three loci newly associated with susceptibility to this autoimmune liver disease.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

Circulating liver enzymes, like alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are highly heritable and predictive of disease. Here, the authors perform a genome-wide association study on ALT and AST, revealing a rare variant in SLC30A10 associated with elevated ALT and AST.

Genome-wide meta-analysis of SARS-CoV-2 susceptibility and severity phenotypes in up to 756,646 samples identifies a rare protective variant proximal to ACE2. A 6-SNP genetic risk score provides additional predictive power when added to known risk factors.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Complex diseases such as multiple sclerosis have both genetic and environmental components. This study demonstrates that variants of genes implicated in multiple sclerosis, and alterations in cellular metabolism and vitamin D3 levels, alterN-glycosylation, a post-translational modification causal of the disease in mice.

Eli Stahl and colleagues report results of a genome-wide association study meta-analysis and replication study for rheumatoid arthritis. Their work identifies several new risk loci and highlights genetic overlap with other autoimmune diseases.

Genome-wide analyses identify variants in B3GALT5 and ST6GAL1 associated with influenza susceptibility. Knockdown of ST6GAL1 in cell culture reduces influenza infectivity, likely by interfering with the glycoprotein modifications required for viral entry.

A dataset of coding variation, derived from exome sequencing of nearly one million individuals from a range of ancestries, provides insight into rare variants and could accelerate the discovery of disease-associated genes and advance precision medicine efforts.

Stroke is a multifactorial disease influenced by genetic and environmental factors. Here, the authors apply exome-wide association analysis to find rare coding variants associated with stroke in a Pakistani cohort, finding a significant association of a variant in NOTCH3 that is highly enriched in South Asians.

Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

A genome-wide association study meta-analysis of more than 100,000 subjects of European and Asian ancestries reveals 42 new risk loci for rheumatoid arthritis, with follow-up studies identifying 98 biological candidate genes that are either already being targeted by drugs or could be in the future.

An exome-wide association study of six smoking phenotypes in up to 749,459 individuals identifies associations of rare coding variants in CHRNB2 that may reduce the likelihood of smoking.

Protein tyrosine phosphatases (PTPs) have diverse roles as negative regulators of stimulatory signaling cascades and are widely recognized as key to maintaining immune cellular homeostasis. Recent data implicating the PTP Lyp in susceptibility to four autoimmune diseases attests to the biological importance of PTP immune regulatory roles and to the etiologic relatedness of different autoimmune conditions.

Trans-ancestry genome-wide analyses identify multiple loci associated with ascending aortic diameter. A polygenic score constructed from these loci predicted prevalent risk of thoracic aortic aneurysm in independent populations.

Analysis of whole-exome sequencing data from over 200,000 individuals in the UK Biobank provides new insights into the contribution of rare variants to cardiometabolic diseases and traits.

Peter Gregersen and colleagues report that common variants at the REL locus are associated with risk of rheumatoid arthritis. REL encodes a member of the NF-κB family of transcription factors, which play key roles in coordinating immune and inflammatory responses.

Soumya Raychaudhuri and colleagues demonstrate the utility of GRAIL, a software program used to prioritize results from genome-wide association studies for further replication, applied here to rheumatoid arthritis. The authors seek replication of their predictions in additional independent cohorts and report three new genetic loci associated with RA susceptibility.

Soumya Raychaudhuri, Paul de Bakker and colleagues report fine mapping of the rheumatoid arthritis associations within the MHC by combining genome-wide SNP data and imputation of classical HLA alleles and SNPs across the MHC. They identify five amino acid positions in HLA-DRβ1, HLA-B and HLA-DPβ1 that together can explain most of the MHC association to seropositive rheumatoid arthritis.

John Chambers and colleagues report a genome-wide association study for markers of liver function. They identify 42 loci associated with concentrations of one or more liver enzymes in plasma, and use a range of functional genomic analyses to suggest candidate genes at these loci.

Yuta Kochi and colleagues report a meta-analysis of genome-wide association studies for rheumatoid arthritis in a Japanese population. They identify nine loci newly associated with rheumatoid arthritis in this population and consider overlap of associations with previous studies in European populations.

Eli Stahl, Robert Plenge and colleagues report the application of a polygenic analysis, using a Bayesian inference framework, to rheumatoid arthritis GWAS datasets. They find that polygenic risk scores are associated with rheumatoid arthritis case-control status and estimate the total variance explained by common variants in these GWAS. They show comparable estimates for applications to GWAS for celiac disease, myocardial infarction and coronary artery disease and type 2 diabetes.

Rare variant association data from human genetics combined with in vitro and in vivo functional validation highlight ANGPTL7 as a promising therapeutic target for intraocular pressure reduction, and protection from glaucoma.

A GWAS and exome-wide association study meta-analysis identifies 53 loci affecting hearing loss risk from over half a million individuals across five cohorts. Rare variants in Mendelian hearing loss genes contribute to hearing loss risk in adults.