Mapping the functional impact of non-coding regulatory elements in primary T cells through single-cell CRISPR screens.

Background: Drug targets with genetic evidence are expected to increase clinical success by at least twofold. Yet, translating disease-associated genetic variants into functional knowledge remains a fundamental challenge of drug discovery. A key issue is that the vast majority of complex disease associations cannot be cleanly mapped to a gene.

Immune disease risk variants regulate gene expression dynamics during CD4 T cell activation.

During activation, T cells undergo extensive gene expression changes that shape the properties of cells to exert their effector function. Understanding the regulation of this process could help explain how genetic variants predispose to immune diseases. Here, we mapped genetic effects on gene expression (expression quantitative trait loci (eQTLs)) using single-cell transcriptomics.

Trans-ancestry analysis reveals genetic and nongenetic associations with COVID-19 susceptibility and severity.

COVID-19 presents with a wide range of severity, from asymptomatic in some individuals to fatal in others. Based on a study of 1,051,032 23andMe research participants, we report genetic and nongenetic associations with testing positive for SARS-CoV-2, respiratory symptoms and hospitalization. Using trans-ancestry genome-wide association studies, we identified a strong association between blood type and COVID-19 diagnosis, as well as a gene-rich locus on chromosome 3p21.

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4 T cells to cytokines.

Naïve CD4 T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. Here we use quantitative proteomics, bulk RNA-seq, and single-cell RNA-seq of over 40,000 human naïve and memory CD4 T cells to show that responses to cytokines differ substantially between these cell types.

Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases.

Immune-disease-associated variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. Here we stimulated T cells and macrophages in the presence of 13 cytokines and profiled active and open chromatin regions.

Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data.

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci.

Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology.

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology.

DNA methylation within melatonin receptor 1A (MTNR1A) mediates paternally transmitted genetic variant effect on asthma plus rhinitis.

Background: Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved.

Objective: We aimed to identify novel risk loci for asthma and AR while accounting for parent-of-origin effect.

Methods: We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families.

Meta-analysis identifies seven susceptibility loci involved in the atopic march.

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci).

The genetics of the skin barrier in eczema and other allergic disorders.

Purpose Of Review: We summarize current knowledge on the genetic determinants of skin barrier deficiency in relation to eczema and disease progression to other allergic manifestations.

Recent Findings: There is increasing evidence that impairment of epidermal barrier function is not only a risk factor for the development of eczema but also for disease progression to allergic airway disease and food allergy. Support comes from recent association studies linking genetic variants in epidermal genes with eczema and food allergy, from monogenic diseases with severe skin barrier defects which display multiple allergic manifestations, and from mouse models providing a mechanism from skin inflammation to allergic reactions in the lung and intestine.

Maternal filaggrin mutations increase the risk of atopic dermatitis in children: an effect independent of mutation inheritance.

Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome's influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD).

Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.

Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual.

Shared genetic determinants between eczema and other immune-related diseases.

Purpose Of Review: Eczema and other allergic disorders are complex diseases caused by multiple genetic and environmental factors. Here, we review recent success in the identification of novel susceptibility loci for eczema.

Recent Findings: Genome-wide association studies led to marked progress in unraveling the genetic determinants of allergic disorders.

High-density genotyping study identifies four new susceptibility loci for atopic dermatitis.

Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency.

A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis.

Background: Atopic dermatitis (AD) is a common inflammatory skin disease. Previous studies have revealed shared genetic determinants among different inflammatory disorders, suggesting that markers associated with immune-related traits might also play a role in AD.

Objective: We sought to identify novel genetic risk factors for AD.

The ANO3/MUC15 locus is associated with eczema in families ascertained through asthma.

Background: A previous genome-wide linkage scan in 295 families of the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) reported strong evidence of linkage of 11p14 to eczema.

Objective: Our purpose was to conduct fine-scale mapping of the 11p14 region to identify the genetic variants associated with eczema.

Methods: Association analyses were first conducted in the family sample from the French EGEA by using 2 methods: the family-based association method and logistic regression.

Multi-locus stepwise regression: a haplotype-based algorithm for finding genetic associations applied to atopic dermatitis.

Background: Genome-wide association studies (GWAS) provide an increasing number of single nucleotide polymorphisms (SNPs) associated with diseases. Our aim is to exploit those closely spaced SNPs in candidate regions for a deeper analysis of association beyond single SNP analysis, combining the classical stepwise regression approach with haplotype analysis to identify risk haplotypes for complex diseases.

Methods: Our proposed multi-locus stepwise regression starts with an evaluation of all pair-wise SNP combinations and then extends each SNP combination stepwise by one SNP from the region, carrying out haplotype regression in each step.

Association screening in the Epidermal Differentiation Complex (EDC) identifies an SPRR3 repeat number variant as a risk factor for eczema.

The genetically determined impairment of the skin barrier is a primary cause of eczema. As numerous genes essential for an intact epidermis reside within the epidermal differentiation complex (EDC), we screened the National Center for Biotechnology Information (NCBI) database for putatively functional polymorphisms in the EDC genes and tested them for association with eczema. We identified 20 polymorphisms with predicted major impact on protein function.

The eczema risk variant on chromosome 11q13 (rs7927894) in the population-based ALSPAC cohort: a novel susceptibility factor for asthma and hay fever.

In a genome-wide association study, a common variant on chromosome 11q13.5 (rs7927894[T]) has been identified as a susceptibility locus for eczema. We aimed to analyze the effect of this risk variant on asthma and hay fever and to determine its impact on the general population level in over 9300 individuals of the prospectively evaluated Avon Longitudinal Study of Parents and Children birth cohort.

Genome-wide approaches to the etiology of eczema.

Purpose Of Review: The present review summarizes the new discoveries in the genetics of eczema, focusing on the results from the recently published first genome-wide association study.

Recent Findings: The first genome-wide association study for eczema included 10 000 individuals and provided strong evidence for a new susceptibility locus for eczema in chromosome 11q13.5 (P = 7.

A common variant on chromosome 11q13 is associated with atopic dermatitis.

We conducted a genome-wide association study in 939 individuals with atopic dermatitis and 975 controls as well as 270 complete nuclear families with two affected siblings. SNPs consistently associated with atopic dermatitis in both discovery sets were then investigated in two additional independent replication sets totalling 2,637 cases and 3,957 controls. Highly significant association was found with allele A of rs7927894 on chromosome 11q13.