phenome-wide association study

BACKGROUND: Patients with schizophrenia have substantial comorbidity that contributes to reduced life expectancy of 10 to 20 years. Identifying modifiable comorbidities could improve rates of premature mortality. Conditions that frequently co-occur but lack shared genetic risk with schizophrenia are more likely to be products of treatment, behavior, or environmental factors and therefore are enriched for potentially modifiable associations. METHODS: Phenome-wide comorbidity was calculated from electronic health records of 250,000 patients across 2 independent health care institutions (Vanderbilt University Medical Center and Mass General Brigham); associations with schizophrenia polygenic risk scores were calculated across the same phenotypes in linked biobanks...

BACKGROUND: Numerous studies highlight the genetic underpinnings of mental disorders comorbidity, particularly in anxiety, depression, and schizophrenia. However, their shared genetic loci are not well understood. Our study employs Mendelian randomization (MR) and colocalization analyses, alongside multi-omics data, to uncover potential genetic targets for these conditions, thereby informing therapeutic and drug development strategies. METHODS: We utilized the Consortium for Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) analysis to investigate genetic correlations among anxiety, depression, and schizophrenia...

BACKGROUND: Deep learning facilitates large-scale automated imaging evaluation of body composition. However, associations of body composition biomarkers with medical phenotypes have been underexplored. Phenome-wide association study (PheWAS) techniques search for medical phenotypes associated with biomarkers. A PheWAS integrating large-scale analysis of imaging biomarkers and electronic health record (EHR) data could discover previously unreported associations and validate expected associations...

BACKGROUND: Early-onset prostate cancer (EOPC, ≤ 55 years) has a unique clinical entity harboring high genetic risk, but the majority of EOPC patients still substantial opportunity to be early-detected thus suffering an unfavorable prognosis. A refined understanding of age-based polygenic risk score (PRS) for prostate cancer (PCa) would be essential for personalized risk stratification. METHODS: We included 167,517 male participants [4882 cases including 205 EOPC and 4677 late-onset PCa (LOPC)] from UK Biobank...

BACKGROUND: Phenome-wide association studies (PheWASs) have been conducted on Asian populations, including Koreans, but many were based on chip or exome genotyping data. Such studies have limitations regarding whole genome-wide association analysis, making it crucial to have genome-to-phenome association information with the largest possible whole genome and matched phenome data to conduct further population-genome studies and develop health care services based on population genomics...

OBJECTIVE: With its size and diversity, the All of Us Research Program has the potential to power and improve representation in clinical trials through ancillary studies like Nutrition for Precision Health. We sought to characterize high-level trial opportunities for the diverse participants and sponsors of future trial investment. MATERIALS AND METHODS: We matched All of Us participants with available trials on ClinicalTrials.gov based on medical conditions, age, sex, and geographic location...

BACKGROUND: Glaucoma is a leading cause of worldwide irreversible blindness. Considerable uncertainty remains regarding the association between a variety of phenotypes and the genetic risk of glaucoma, as well as the impact they exert on the glaucoma development. METHODS: We investigated the associations of genetic liability for primary open angle glaucoma (POAG) with a wide range of potential risk factors and to assess its impact on the risk of incident glaucoma...

BACKGROUND: Mutations in the gene MTARC1 (mitochondrial amidoxime-reducing component 1) protect carriers from metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MTARC1 encodes the mARC1 enzyme, which is localized to the mitochondria and has no known MASH-relevant molecular function. Our studies aimed to expand on the published human genetic mARC1 data and to observe the molecular effects of mARC1 modulation in preclinical MASH models. METHODS AND RESULTS: We identified a novel human structural variant deletion in MTARC1, which is associated with various biomarkers of liver health, including alanine aminotransferase levels...

BACKGROUND AND HYPOTHESIS: The synaptic pruning hypothesis posits that schizophrenia (SCZ) and autism spectrum disorder (ASD) may represent opposite ends of neurodevelopmental disorders: individuals with ASD exhibit an overabundance of synapses and connections while SCZ was characterized by excessive pruning of synapses and a reduction. Given the strong genetic predisposition of both disorders, we propose a shared genetic component, with certain loci having differential regulatory impacts...

Biological sex is a key variable influencing many physiological systems. Disease prevalence as well as treatment success can be modified by sex. Differences emerge already early in life and include pregnancy complications and adverse birth outcomes. The placenta is a critical organ for fetal development and shows sex-based differences in the expression of hormones and cytokines. Epigenetic regulation, such as DNA methylation (DNAm), may underlie the previously reported placental sexual dimorphism. We associated placental DNAm with fetal sex in three cohorts...

Breast cancer (BC) remains a major disease posing a threat to women's health, but the underlying biological interpretation remains largely unknown. Here, we aimed to identify genes associated with breast cancer and analyze their pathophysiological mechanisms based on multi-omics Mendelian randomization (MR). Summary-data-based MR (SMR) was performed to estimate the causal effects of blood and breast mammary tissue expression quantitative trait loci (eQTLs) on BC. External validation analysis was used to validate the identified genes...

Cell death mediated by genetically defined signaling pathways influences the health and dynamics of all tissues, however the tissue specificity of cell death pathways and the relationships between these pathways and human disease are not well understood. We analyzed the expression profiles of an array of 44 cell death genes involved in apoptosis, necroptosis, and pyroptosis cell death pathways across 49 human tissues from GTEx, to elucidate the landscape of cell death gene expression across human tissues, and the relationship between tissue-specific genetically determined expression and the human phenome...

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function and a cure for this devastating disease remains elusive. Early detection and risk stratification are crucial for timely intervention and improving patient outcomes. This study aimed to identify predisposing genetic, phenotypic, and exposure-related factors for Amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential. METHODS: Utilizing data from the UK Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent...

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases...

IMPORTANCE: Aortic stenosis (AS) is a major public health challenge with a growing therapeutic landscape, but current biomarkers do not inform personalized screening and follow-up. A video-based artificial intelligence (AI) biomarker (Digital AS Severity index [DASSi]) can detect severe AS using single-view long-axis echocardiography without Doppler characterization. OBJECTIVE: To deploy DASSi to patients with no AS or with mild or moderate AS at baseline to identify AS development and progression...

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype-phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries...

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e...

BACKGROUND: Thyroid cancer represents the most prevalent malignant endocrine tumour, with rising incidence worldwide and high mortality rates among patients exhibiting dedifferentiation and metastasis. Effective biomarkers and therapeutic interventions are warranted in aggressive thyroid malignancies. The transcription factor 19 (TCF19) gene has been implicated in conferring a malignant phenotype in cancers. However, its contribution to thyroid neoplasms remains unclear. RESULTS: In this study, we performed genome-wide and phenome-wide association studies to identify a potential causal relationship between TCF19 and thyroid cancer...

BACKGROUND: Ankylosing Spondylitis (AS) is a chronic inflammatory disorder which can lead to considerable pain and disability. Mendelian randomization (MR) has been extensively applied for repurposing licensed drugs and uncovering new therapeutic targets. Our objective is to pinpoint innovative therapeutic protein targets for AS and assess the potential adverse effects of druggable proteins. METHODS: We conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of AS...

BACKGROUND: Male-pattern baldness (MPB) is the most common cause of hair loss in men. It can be categorized into three types: type 2 (T2), type 3 (T3), and type 4 (T4), with type 1 (T1) being considered normal. Although various MPB-associated genetic variants have been suggested, a comprehensive study for linking these variants to gene expression regulation has not been performed to the best of our knowledge. RESULTS: In this study, we prioritized MPB-related tissue panels using tissue-specific enrichment analysis and utilized single-tissue panels from genotype-tissue expression version 8, as well as cross-tissue panels from context-specific genetics...