Atopic dermatitis (AD) is a common inflammatory skin disease highly attributable to genetic factors. In this study, we report results from a genome-wide meta-analysis of AD in 37,541 cases and ...1,056,519 controls with data from the FinnGen project, the Estonian Biobank, the UK Biobank, the EAGLE Consortium, and the BioBank Japan. We detected 77 independent AD-associated loci, of which 10 were, to our knowledge, previously unreported. The associated loci showed enrichment in various immune regulatory processes. We further performed subgroup analyses of mild and severe AD and of early- and late-onset AD, with data from the FinnGen project. Fifty-five of the 79 tested variants in the associated loci showed larger effect estimates for severe than for mild AD as determined through administered treatment. The age of onset, as determined by the first hospital visit with AD diagnosis, was lower in patients with particular AD-risk alleles. Our findings add to the knowledge of the genetic background of AD and may underlie the development of new therapeutic strategies.
Sarcoidosis is a complex systemic disease with clinical heterogeneity based on varying phenotypes and natural history. The detailed etiology of sarcoidosis remains unknown, but genetic predisposition ...as well as environmental exposures play a significant role in disease pathogenesis. We performed a comprehensive review of germline genetic (DNA) and transcriptomic (RNA) studies of sarcoidosis, including both previous studies and more recent findings. In this review, we provide an assessment of the following: genetic variants in sarcoidosis susceptibility and phenotypes, ancestry- and sex-specific genetic variants in sarcoidosis, shared genetic architecture between sarcoidosis and other diseases, and gene-environment interactions in sarcoidosis. We also highlight the unmet needs in sarcoidosis genetic studies, including the pressing requirement to include diverse populations and have consistent definitions of phenotypes in the sarcoidosis research community to help advance the application of genetic predisposition to sarcoidosis disease risk and manifestations.
Quinolone resistance presents a growing global health threat. We employed word-based GWAS to explore genomic data, aiming to enhance our understanding of this phenomenon. Unlike traditional ...variant-based GWAS analyses, this approach simultaneously captures multiple genomic factors, including single and interacting resistance mutations and genes. Analyzing a dataset of 92 genomic
samples from a wastewater treatment plant in Dresden, we identified 54 DNA unitigs significantly associated with quinolone resistance. Remarkably, our analysis not only validated known mutations in
and
genes and the results of our variant-based GWAS but also revealed new (mutated) genes such as
, the AcrEF-TolC multidrug efflux system,
, and
, implicated in antibiotic resistance. Furthermore, our study identified joint mutations in 14 genes including the known
gene, providing insights into potential synergistic effects contributing to quinolone resistance. These findings showcase the exceptional capabilities of word-based GWAS in unraveling the intricate genomic foundations of quinolone resistance.
Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than ...1 year.
We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants.
We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume.
Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.
In this paper, we present a comprehensive study of gestation length (GL) in 16 cattle breeds by using large genotype and animal record databases. Data included over 20 million gestations since 2000 ...and genotypes from one million calves. The study addressed the GL variability within and between breeds, estimation of its direct and maternal heritability coefficients, association with fitness and several economic traits, and QTL detection. The breed average GL varied from 279.7 to 294.4 d, in Holstein and Blonde d'Aquitaine breeds, respectively. Standard deviations per breed were similar and ranged from 5.2 to 5.8 d. Direct heritability (i.e., for GL defined as a trait of the calf) was moderate to high (h2 = 0.40 to 0.67), whereas the maternal heritability was low (0.04 to 0.06). Extreme breeding values for GL were strongly associated with a higher mortality during the first 2 d of life and were associated with milk production of dams for dairy breeds and precocity of females. Finally, several QTL were detected affecting GL with cumulated effects up to a few days, and at least 2 QTL were found to be shared between different breeds. Our study highlights the risks that would be associated with selection toward a reduced gestation length. Further genomic studies are needed to identify the causal variants, and their association with juvenile mortality and other economic traits.
This study aimed to evaluate the impact of copy number variants (CNVs) on 13 reproduction and 12 disease traits in Holstein cattle. Intensity signal files containing Log R ratio and B allele ...frequency information from 13,730 Holstein animals genotyped with a 95K SNP panel, and 8,467 Holstein animals genotyped with a 50K SNP panel were used to identify the CNVs. Subsequently, the identified CNVs were validated using whole genome sequence data from 126 animals, resulting in 870 high-confidence CNV regions (CNVRs) on 12,131 animals. Out of these, 54 CNVRs had frequencies higher than or equal to 1% in the population and were used in the genome-wide association analysis (one CNVR at a time, including the G matrix). Results revealed that 4 CNVRs were significantly (p-value < 3.7 × 10−5) associated with at least one of the traits analyzed in this study. Specifically, 2 CNVRs were associated with 3 reproduction traits (i.e., calf survival, first service to conception, and non-return rate), and 2 CNVRs were associated with 2 disease traits (i.e., metritis and retained placenta). These CNVRs harbored genes implicated in immune response, cellular signaling, and neuronal development, supporting their potential involvement in these traits. Further investigations to unravel the mechanistic and functional implications of these CNVRs on the mentioned traits are warranted.
Understanding the mechanisms of hip disease, such as osteoarthritis (OA), is crucial to advance their treatment. Such hip diseases often involve specific morphological changes. Genetic variations, ...called single nucleotide polymorphisms (SNPs), influence various hip morphological parameters. This study investigated the biological relevance of SNPs correlated to hip morphology in genome-wide association studies (GWAS). The SNP-associated genes were compared to genes associated with OA in other joints, aiming to see if the same genes play a role in both hip development and the risk of OA in other lower limb joints.
A systematic literature review was conducted to identify SNPs correlated with hip morphology, based on the Population, Intervention, Comparison, Outcome, and Study (PICOS) framework. Afterwards, Gene Ontology (GO) analysis was performed, using EnrichR, on the SNP-associated genes and compared with non-hip OA-associated genes, across different databases.
Reviewing 49 GWAS identified 436 SNPs associated with hip joint morphology, encompassing variance in bone size, structure and shape. Among the SNP-associated genes, SOX9 plays a pivotal role in size, GDF5 impacts bone structure, and BMP7 affects shape. Overall, skeletal system development, regulation of cell differentiation, and chondrocyte differentiation emerged as crucial processes influencing hip morphology. Eighteen percent of GWAS-identified genes related to hip morphology were also associated with non-hip OA.
Our findings indicate the existence of multiple shared genetic mechanisms across hip morphology and OA, highlighting the necessity for more extensive research in this area, as in contrast to the hip, the genetic background on knee or foot morphology remains largely understudied.
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