Identification of multi-omic pleiotropy factors for peripheral artery disease.

Background: Peripheral artery disease (PAD) is prevalent and frequently co-occurs with type 2 diabetes (T2D) and coronary artery disease (CAD). Although shared genetic factors may contribute to these comorbidities, few studies have examined pleiotropy at the transcriptomic and proteomic levels.

Methods: We generated summary statistics for transcriptome-wide (TWAS) and proteome-wide (PWAS) association analyses across PAD, T2D, and CAD.

Leveraging pleiotropy to improve genetic risk prediction across diseases.

Background: Polygenic scores (PGSs) have shown promise in predicting disease risk, but their predictive accuracy remains limited for many complex diseases. Leveraging the shared genetic architecture among correlated traits may improve prediction performance.

Methods: We developed a flexible framework for constructing multi-trait PGSs by integrating candidate PGSs (N=2,651) derived from publicly available GWAS summary statistics (N=51)-using single-trait, MTAG-all, and MTAG-pairwise approaches.

Leveraging Alzheimer's Disease Omics to Identify Pleiotropic Genes Contributing to Neurodegeneration in Primary Open-Angle Glaucoma.

Primary open-angle glaucoma is the most common form of glaucoma worldwide and one of the leading causes of irreversible blindness. Current therapies focus on intraocular pressure control despite substantial evidence on the importance of additional pathogenic mechanisms involved in neuronal repair and regeneration. Some of these mechanisms may be shared with and across other neurodegenerative disorders, such as Alzheimer's disease.

A framework for studying multi-omic risk factors and their interplay: application to coronary artery disease.

Background: Transcriptome-wide and proteome-wide association studies (TWAS and PWAS) have identified risk genes across complex diseases. However, the contributions of proximal risk variants and cross-omic interplay remain to be understood.

Methods: We propose an integrative framework to characterize disease-associated transcripts and proteins, and apply it to coronary artery disease (CAD).

Estimating the Effects of Hypothetical Ambient Interventions on the Risk of Dementia Using the Parametric g-Formula in the UK Biobank Cohort.

Background: Emerging evidence identifies ambient particulate matter (PM) with an aerodynamic diameter () as a modifiable risk factor for dementia, but the potential health benefits gained by enacting regulations that reduce remain unclear.

Objectives: Our aim was to estimate the total effects of hypothetical ambient interventions starting in late life on the risk of dementia in a cohort using the parametric g-formula.

Methods: We used data from 291,495 participants in the UK Biobank cohort who were free of dementia and y of age at baseline (2010).

Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis.

Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants in well-established Mendelian HL genes play an important role in ARHL etiology. In all we identified 32 Mendelian HL genes which are associated with ARHL.

The case-only design is a powerful approach to detect interactions but should be used with caution.

Background: The case-only design is a powerful approach to identify gene gene and gene environment interactions for complex traits. It has been demonstrated that for the case-only design to be valid the genetic and environmental factors must be independent in the population. Additionally, there is a rare disease assumption for the case-only design, but the impact of disease prevalence and other factors, e.

OncoSexome: the landscape of sex-based differences in oncologic diseases.

The NIH policy on sex as biological variable (SABV) emphasized the importance of sex-based differences in precision oncology. Over 50% of clinically actionable oncology genes are sex-biased, indicating differences in drug efficacy. Research has identified sex differences in non-reproductive cancers, highlighting the need for comprehensive sex-based cancer data.

LDER-GE estimates phenotypic variance component of gene-environment interactions in human complex traits accurately with GE interaction summary statistics and full LD information.

Gene-environment (GE) interactions are essential in understanding human complex traits. Identifying these interactions is necessary for deciphering the biological basis of such traits. In this study, we review state-of-art methods for estimating the proportion of phenotypic variance explained by genome-wide GE interactions and introduce a novel statistical method Linkage-Disequilibrium Eigenvalue Regression for Gene-Environment interactions (LDER-GE).

A Genome-wide Association Study of Susceptibility to Upper Urinary Tract Infections.

Background: Our goal was to identify genetic and modifiable risk factors for upper urinary tract infections (UTIs).

Methods: We used data from UK Biobank, the Trøndelag Health Study, and the Michigan Genomics Initiative to conduct genome-wide association studies and sex-stratified analyses on upper UTI. Mendelian randomization (MR) analyses were conducted to examine potential causal relationships between cardiometabolic risk factors and upper UTIs.

A mediation analysis framework based on variance component to remove genetic confounding effect.

Identification of pleiotropy at the single nucleotide polymorphism (SNP) level provides valuable insights into shared genetic signals among phenotypes. One approach to study these signals is through mediation analysis, which dissects the total effect of a SNP on the outcome into a direct effect and an indirect effect through a mediator. However, estimated effects from mediation analysis can be confounded by the genetic correlation between phenotypes, leading to inaccurate results.

Variants in are associated with asthma, type 2 diabetes, and height in the United Kingdom biobank population.

Asthma, type 2 diabetes (T2D), and anthropometric measures are correlated complex traits that all have a major genetic component. To investigate the overlap in genetic variants associated with these complex traits. Using United Kingdom Biobank data, we performed univariate association analysis, fine-mapping, and mediation analysis to identify and dissect shared genomic regions associated with asthma, T2D, height, weight, body mass index (BMI), and waist circumference (WC).

Systematically identifying genetic signatures including novel SNP-clusters, nonsense variants, frame-shift INDELs, and long STR expansions that potentially link to unknown phenotypes existing in dog breeds.

Background: In light of previous studies that profiled breed-specific traits or used genome-wide association studies to refine loci associated with characteristic morphological features in dogs, the field has gained tremendous genetic insights for known dog traits observed among breeds. Here we aim to address the question from a reserve perspective: whether there are breed-specific genotypes that may underlie currently unknown phenotypes. This study provides a complete set of breed-specific genetic signatures (BSGS).

Paired Indoor and Outdoor Nitrogen Dioxide Associated With Childhood Asthma Outcomes in a Mixed Rural-Urban Setting: A Feasibility Study.

Introduction: Nitrogen dioxide (NO) is known to be a trigger for asthma exacerbation. However, little is known about the role of seasonal variation in indoor and outdoor NO levels in childhood asthma in a mixed rural-urban setting of North America.

Methods: This prospective cohort study, as a feasibility study, included 62 families with children (5-17 years) that had diagnosed persistent asthma residing in Olmsted County, Minnesota.

Saddlepoint approximations to score test statistics in logistic regression for analyzing genome-wide association studies.

We investigate saddlepoint approximations of tail probabilities of the score test statistic in logistic regression for genome-wide association studies. The inaccuracy in the normal approximation of the score test statistic increases with increasing imbalance in the response and with decreasing minor allele counts. Applying saddlepoint approximation methods greatly improve the accuracy, even far out in the tails of the distribution.

Inferring feature importance with uncertainties with application to large genotype data.

Estimating feature importance, which is the contribution of a prediction or several predictions due to a feature, is an essential aspect of explaining data-based models. Besides explaining the model itself, an equally relevant question is which features are important in the underlying data generating process. We present a Shapley-value-based framework for inferring the importance of individual features, including uncertainty in the estimator.

The genetic contribution of the X chromosome in age-related hearing loss.

Age-related (AR) hearing loss (HL) is the most common sensory impairment with heritability of 55%. The aim of this study was to identify genetic variants on chromosome X associated with ARHL through the analysis of data obtained from the UK Biobank. We performed association analysis between self-reported measures of HL and genotyped and imputed variants on chromosome X from ∼460,000 white Europeans.

Dyslipidemia and Risk of Preeclampsia: A Multiancestry Mendelian Randomization Study.

Background: Preeclampsia is a leading cause of maternal morbidity, and dyslipidemia has been associated with preeclampsia in observational studies. We use Mendelian randomization analyses to estimate the association between lipid levels, their pharmacological targets, and the risk of preeclampsia in 4 ancestry groups.

Methods: We extracted uncorrelated (<0.

Early-Onset Colorectal Cancer Somatic Gene Mutations by Population Subgroups.

In this issue of Cancer Discovery, Holowatyj and colleagues uncover racial/ethnic and sex heterogeneity in somatic mutations among patients with early-onset colorectal cancer. The findings shed light on a deeper understanding of complex biological and genetic mechanisms for colorectal cancer in diverse populations. See related article by Holowatyj et al.

Rare-variant association analysis reveals known and new age-related hearing loss genes.

Age-related (AR) hearing loss (HL) is a prevalent sensory deficit in the elderly population. Several studies showed that common variants increase ARHL susceptibility. Here, we demonstrate that rare-variants play a crucial role in ARHL etiology.

Type 2 cytokine genes as allergic asthma risk factors after viral bronchiolitis in early childhood.

Background: Genome-wide association studies of asthma have identified associations with variants in type-2 related genes. Also, specific interactions between genetic variants and viral bronchiolitis in the development of asthma has been suggested.

Objective: To conduct a gene-based analysis of genetic variants in type 2 cytokine related genes as risk factors for allergic asthma at school age, and further, to study their interaction with specific viral infections in early childhood.