Discovery of core genes for systemic lupus erythematosus via genome-wide aggregated trans-effects analysis.

The "omnigenic" hypothesis postulates that the polygenic effects of common variants on a typical complex trait coalesce on relatively few core genes through trans-effects on their expression. Our aim was to identify core genes for systemic lupus erythematosus (SLE) by testing for association with genome-wide aggregated trans-effects (GATE) scores for gene expression in a large genetic dataset (5267/4909 SLE cases/controls). SLE was strongly associated with upregulation of expression of eight interferon-stimulated genes driven by shared trans-effects.

Genome-Wide Aggregated Trans Effects Analysis for Circulating Proteins Indicates a Key Role of Immune Checkpoints in Type 1 Diabetes.

Unlabelled: The "omnigenic" hypothesis postulates that polygenic effects of common variants on typical complex traits coalesce via trans effects on the expression of a relatively sparse set of "core" effector genes and their encoded proteins in relevant tissues. The objective of this study was to identify core proteins for type 1 diabetes. We used summary statistics for single nucleotide polymorphism associations with plasma levels of 5,130 proteins in three large cohorts, including the UK Biobank, to compute genome-wide aggregated trans effects (GATE) scores for protein levels in two type 1 diabetes case-control studies (6,828 case individuals, 416,000 control individuals).

Association between methylation quantitative trait loci and colorectal cancer risk, survival and cancer recurrence.

Background: Epigenetic changes contribute to colorectal cancer (CRC) pathogenesis. We investigated whether methylation quantitative trait loci (mQTLs) are associated with CRC risk, survival and recurrence.

Methods: Using a well-characterised Scottish case-control study (6821 CRC cases, 14,692 controls), we derived 118,982 mQTLs based on the Genetics of DNA Methylation Consortium (GoDMC).

Genome-Wide Aggregated Trans Effects Analysis Identifies Genes Encoding Immune Checkpoints as Core Genes for Rheumatoid Arthritis.

Objective: The sparse effector "omnigenic" hypothesis postulates that the polygenic effects of common single nucleotide polymorphisms (SNPs) on a typical complex trait are mediated by trans effects that coalesce on expression of a relatively sparse set of core genes. The objective of this study was to identify core genes for rheumatoid arthritis by testing for association of rheumatoid arthritis with genome-wide aggregated trans effects (GATE) scores for expression of each gene as transcript in whole blood or as circulating protein levels.

Methods: GATE scores were calculated for 5,400 cases and 453,705 non-cases of primary rheumatoid arthritis in UK Biobank participants of European ancestry.

Genetics of C-Peptide and Age at Diagnosis in Type 1 Diabetes.

Identified genetic loci for C-peptide and type 1 diabetes (T1D) age at diagnosis (AAD) explain only a small proportion of their variation. We aimed to identify additional genetic loci associated with C-peptide and AAD. Some HLA allele/haplotypes associated with T1D also contributed to variability of C-peptide and AAD, whereas outside the HLA region, T1D loci were mostly not associated with C-peptide or AAD.

Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants.

The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls.

Expression quantitative trait loci analysis in rheumatoid arthritis identifies tissue specific variants associated with severity and outcome.

Objective: Genome-wide association studies have successfully identified more than 100 loci associated with susceptibility to rheumatoid arthritis (RA). However, our understanding of the functional effects of genetic variants in causing RA and their effects on disease severity and response to treatment remains limited.

Methods: In this study, we conducted expression quantitative trait locus (eQTL) analysis to dissect the link between genetic variants and gene expression comparing the disease tissue against blood using RNA-Sequencing of synovial biopsies (n=85) and blood samples (n=51) from treatment-naïve patients with RA from the Pathobiology of Early Arthritis Cohort.

Genome-wide aggregated trans-effects on risk of type 1 diabetes: A test of the "omnigenic" sparse effector hypothesis of complex trait genetics.

The "omnigenic" hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated through trans-effects on expression of a relatively sparse set of effector ("core") genes. We tested this hypothesis in a study of 4,964 cases of type 1 diabetes (T1D) and 7,497 controls by using summary statistics to calculate aggregated (excluding the HLA region) trans-scores for gene expression in blood. From associations of T1D with aggregated trans-scores, nine putative core genes were identified, of which three-STAT1, CTLA4 and FOXP3-are genes in which variants cause monogenic forms of autoimmune diabetes.

Genome-wide analysis identifies gallstone-susceptibility loci including genes regulating gastrointestinal motility.

Background And Aims: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment.