The Ulcerative Colitis-Associated Gene NXPE1 Catalyzes Glycan Modifications on Colonic Mucin.

Colonic mucus forms a first line of defense against bacterial invasion while providing nutrition to support coinhabiting microbes in the gut. Mucus is composed of polymeric networks of mucin proteins, which are heavily modified post-translationally. The full compendium of enzymes responsible for these modifications and their roles in health and disease remain incompletely understood.

Prevalence and disease risks for male and female sex chromosome trisomies: a registry-based phenome-wide association study in 1.5 million participants of MVP, FinnGen, and UK Biobank.

Sex chromosome trisomies (SCT) are the most common whole chromosome aneuploidy in humans. Yet, our understanding of the prevalence and associated health outcomes is largely driven by observational studies of clinically diagnosed cases, resulting in a disproportionate focus on 47,XXY and associated hypogonadism. We analyzed microarray intensity data of sex chromosomes for 1.

Whole Genome Sequencing of Pedigrees With High Density of Substance Use and Psychiatric Disorders: A Meeting Report.

The National Institute of Drug Abuse convened a panel of scientists with expertise in substance use disorders (SUD) and genetic methodologies primarily to determine the feasibility of performing whole genome sequencing utilizing existing pedigree collections with a high density of SUD and psychiatric disorders. A major focus was on determining if there had been any successes in identifying genetic variants for complex traits in family-based designs. Such information could provide assurance that whole genome sequencing might provide significant pay-offs particularly in the pursuit of rare variants and copy number variants.

Deleterious coding variation associated with autism is consistent across populations, as exemplified by admixed Latin American populations.

The past decade has seen remarkable progress in identifying genes that, when impacted by deleterious coding variation, confer high risk for autism spectrum disorder (ASD), intellectual disability, and other developmental disorders. However, most underlying gene discovery efforts have focused on individuals of European ancestry, limiting insights into genetic risks across diverse populations. To help address this, the Genomics of Autism in Latin American Ancestries Consortium (GALA) was formed, presenting here the largest sequencing study of ASD in Latin American individuals (n>15,000).

Cystic fibrosis risk variants confer protection against inflammatory bowel disease.

Genetic mutations that yield defective cystic fibrosis transmembrane regulator () protein cause cystic fibrosis, a life-limiting autosomal recessive Mendelian disorder. A protective role of loss-of-function mutations in inflammatory bowel disease (IBD) has been suggested, but its evidence has been inconclusive and contradictory. Here, leveraging the largest IBD exome sequencing dataset to date, comprising 38,558 cases and 66,945 controls in the discovery stage, and 35,797 cases and 179,942 controls in the replication stage, we established a protective role of CF-risk variants against IBD based on evidence from the association test of delF508 (p-value=8.

Analysis of Variants Induced by Combined Ex Vivo Irradiation and In Vivo Tumorigenesis Suggests a Role for the ZNF831 p.R1393Q Variant in Cutaneous Melanoma Development.

UVR is known to be the most important environmental carcinogen for cutaneous melanoma. Whereas genomic analyses of melanoma tumors implicate a high rate of UV damage, the experimental induction and recovery of bona fide UV-signature changes have not been directly observed. To replicate recurrent UV variants from The Cancer Genome Atlas_SKCM specimens, we UV irradiated cultured immortalized human melanocytes and subjected them to in vivo tumorigenesis assays.

Inherited infertility: Mapping loci associated with impaired female reproduction.

Female infertility is a common and complex health problem affecting millions of women worldwide. While multiple factors can contribute to this condition, the underlying cause remains elusive in up to 15%-30% of affected individuals. In our large genome-wide association study (GWAS) of 22,849 women with infertility and 198,989 control individuals from the Finnish population cohort FinnGen, we unveil a landscape of genetic factors associated with the disorder.

The Exponential Shapeshifting Response of N-Vinylcaprolactam Hydrogel Bilayers Due to Temperature Change for Potential Minimally Invasive Surgery.

Poly (N-vinylcaprolactam) (PNVCL) and poly (N-isopropylacrylamide) (PNIPAm) are two popular negatively temperature-responsive hydrogels, due to their biocompatibility, softness, hydrophilicity, superabsorbency, viscoelasticity, and near-physiological lower critical solution temperature (LCST). These characteristics make them ideal for biomedical applications. When combined with other materials, hydrogel expansion induces the morphing of the assembly due to internal stress differences.

Autochthonous Human Babesia divergens Infection, England.

We describe a case of autochthonous human Babesia divergens infection in an immunocompetent woman in England. The patient had fever, hemolysis, multiorgan failure, and 18% parasitemia. We confirmed B.

Semi-supervised machine learning method for predicting homogeneous ancestry groups to assess Hardy-Weinberg equilibrium in diverse whole-genome sequencing studies.

Large-scale, multi-ethnic whole-genome sequencing (WGS) studies, such as the National Human Genome Research Institute Genome Sequencing Program's Centers for Common Disease Genomics (CCDG), play an important role in increasing diversity for genetic research. Before performing association analyses, assessing Hardy-Weinberg equilibrium (HWE) is a crucial step in quality control procedures to remove low quality variants and ensure valid downstream analyses. Diverse WGS studies contain ancestrally heterogeneous samples; however, commonly used HWE methods assume that the samples are homogeneous.

High Burden of Ileus and Pneumonia in Clozapine-Treated Individuals With Schizophrenia: A Finnish 25-Year Follow-Up Register Study.

Objective: The authors used longitudinal biobank data with up to 25 years of follow-up on over 2,600 clozapine users to derive reliable estimates of the real-world burden of clozapine adverse drug events (ADEs).

Methods: A total of 2,659 participants in the FinnGen biobank project had a schizophrenia diagnosis and clozapine purchases with longitudinal electronic health record follow-up for up to 25 years after clozapine initiation. Diseases and health-related events enriched during clozapine use were identified, adjusting for disease severity.

Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases.

Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestry has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping.

Genetic variants affect diurnal glucose levels throughout the day.

Circadian rhythms not only coordinate the timing of wake and sleep but also regulate homeostasis within the body, including glucose metabolism. However, the genetic variants that contribute to temporal control of glucose levels have not been previously examined. Using data from 420,000 individuals from the UK Biobank and replicating our findings in 100,000 individuals from the Estonian Biobank, we show that diurnal serum glucose is under genetic control.

Polygenic risk scores as a marker for epilepsy risk across lifetime and after unspecified seizure events.

A diagnosis of epilepsy has significant consequences for an individual but is often challenging in clinical practice. Novel biomarkers are thus greatly needed. Here, we investigated how common genetic factors (epilepsy polygenic risk scores, [PRSs]) influence epilepsy risk in detailed longitudinal electronic health records (EHRs) of > 700k Finns and Estonians.

Complex trait susceptibilities and population diversity in a sample of 4,145 Russians.

The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ancestries. We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia.

Autoimmune hypothyroidism GWAS reveals independent autoimmune and thyroid-specific contributions and an inverse relation with cancer risk.

The high prevalence of autoimmune hypothyroidism (AIHT) - more than 5% in human populations - provides a unique opportunity to unlock the most complete picture to date of genetic loci that underlie systemic and organ-specific autoimmunity. Using a meta-analysis of 81,718 AIHT cases in FinnGen and the UK Biobank, we dissect associations along axes of thyroid dysfunction and autoimmunity. This largest-to-date scan of hypothyroidism identifies 418 independent associations (p < 5×10), more than half of which have not previously been documented in thyroid disease.