Fatal Mucormycosis in a Diabetic Patient: A Case Report and Review of Diagnostic Challenges.

Mucormycosis (zygomycosis) is a severe and often fatal mycotic infection affecting primarily immunocompromised individuals. A 61-year-old female with type 2 diabetes mellitus and end-stage renal disease developed septic shock in association with mucormycosis. Despite antifungal treatment with liposomal amphotericin B, the patient's condition rapidly deteriorated, leading to death within 48 hours.

Yield of genetic association signals from genomes, exomes and imputation in the UK Biobank.

Whole-genome sequencing (WGS), whole-exome sequencing (WES) and array genotyping with imputation (IMP) are common strategies for assessing genetic variation and its association with medically relevant phenotypes. To date, there has been no systematic empirical assessment of the yield of these approaches when applied to hundreds of thousands of samples to enable the discovery of complex trait genetic signals. Using data for 100 complex traits from 149,195 individuals in the UK Biobank, we systematically compare the relative yield of these strategies in genetic association studies.

Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus.

Context: Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides.

Objective: To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA).

Design: We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012).

Converging evidence from exome sequencing and common variants implicates target genes for osteoporosis.

In this study, we leveraged the combined evidence of rare coding variants and common alleles to identify therapeutic targets for osteoporosis. We undertook a large-scale multiancestry exome-wide association study for estimated bone mineral density, which showed that the burden of rare coding alleles in 19 genes was associated with estimated bone mineral density (P < 3.6 × 10).

A deep catalog of protein-coding variation in 985,830 individuals.

Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants.

Modeling cue-exposure therapy for alcohol use disorder in rhesus monkeys: Effects of putative cognitive enhancers.

Background: Cue-exposure therapy (CET) is an effective approach for anxiety-related disorders, but its effectiveness for substance use disorders is less clear. One potential means of improving CET outcomes is to include a cognitive-enhancing pharmacotherapy. This study evaluated d-cycloserine (DCS) and RY-023, putative cognitive enhancers targeting glutamate and GABA systems, respectively, in a monkey model of CET for alcohol use disorder.

Common and rare variant associations with clonal haematopoiesis phenotypes.

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP.

Use of Whole-Genome Sequencing to Estimate the Contribution of Immune Evasion and Waning Immunity on Decreasing COVID-19 Vaccine Effectiveness.

Background: The impact variant-specific immune evasion and waning protection have on declining coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE) remains unclear. Using whole-genome sequencing (WGS), we examined the contribution these factors had on the decline that followed the introduction of the Delta variant. Furthermore, we evaluated calendar-period-based classification as a WGS alternative.

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism.

Germline Mutations in and Protection against Liver Disease.

Background: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets.

Methods: We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.

Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects.

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes.

Methamphetamine-Induced Sleep Impairments and Subsequent Slow-Wave and Rapid Eye Movement Sleep Rebound in Male Rhesus Monkeys.

Use of amphetamine-type stimulants is associated with numerous adverse health outcomes, with disturbed sleep being one of the most prominent consequences of methamphetamine use. However, the extent to which methamphetamine alters sleep architecture, and whether methamphetamine-induced sleep impairment is associated with next-day sleep rebound effects, has received relatively little investigation. In the present study, we investigated the effects of acute morning methamphetamine administration on sleep parameters in adult male rhesus monkeys ( = 4) using a fully-implantable telemetry system.

UGT1A1 genetic variants are associated with increases in bilirubin levels in rheumatoid arthritis patients treated with sarilumab.

Sarilumab is a human monoclonal antibody against interleukin (IL)-6Rα that has been approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Mild liver function test abnormalities have been observed in patients treated with sarilumab. We describe a genome-wide association study of bilirubin elevations in RA patients treated with sarilumab.

Association of Thyroid Function with Blood Pressure and Cardiovascular Disease: A Mendelian Randomization.

Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper- or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study.

ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers.

Purpose: Birdshot chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.

Methods: We sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29-positive controls to determine genome-wide common and rare variant associations.

Exome sequencing and analysis of 454,787 UK Biobank participants.

A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing to explore protein-altering variants and their consequences in 454,787 participants in the UK Biobank study. We identified 12 million coding variants, including around 1 million loss-of-function and around 1.