Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection.

Clostridioides difficile (C. diff.) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. diff. do not develop any infection while others develop severe or recurrent infections. To identify common genetic variants associated with CDI, we performed a genome-wide association analysis in 19,861 participants (1349 cases; 18,512 controls) from the Electronic Medical Records and Genomics (eMERGE) Network. Using logistic regression, we found strong evidence for genetic variation in the DRB locus of the MHC (HLA) II region that predisposes individuals to CDI (P > 1.0 × 10-14; OR 1.56). Altered transcriptional regulation in the HLA region may play a role in conferring susceptibility to this opportunistic enteric pathogen.

Eat4Genes: a bioinformatic rational gene targeting app and prototype model for improving human health.

Introduction and aims: Dietary Rational Gene Targeting (DRGT) is a therapeutic dietary strategy that uses healthy dietary agents to modulate the expression of disease-causing genes back toward the normal. Here we use the DRGT approach to (1) identify human studies assessing gene expression after ingestion of healthy dietary agents with an emphasis on whole foods, and (2) use this data to construct an online dietary guide app prototype toward eventually aiding patients, healthcare providers, community and researchers in treating and preventing numerous health conditions. Methods: We used the keywords "human", "gene expression" and separately, 51 different dietary agents with reported health benefits to search GEO, PubMed, Google Scholar, Clinical trials, Cochrane library, and EMBL-EBI databases for related studies. Studies meeting qualifying criteria were assessed for gene modulations. The R-Shiny platform was utilized to construct an interactive app called "Eat4Genes". Results: Fifty-one human ingestion studies (37 whole food related) and 96 key risk genes were identified. Human gene expression studies were found for 18 of 41 searched whole foods or extracts. App construction included the option to select either specific conditions/diseases or genes followed by food guide suggestions, key target genes, data sources and links, dietary suggestion rankings, bar chart or bubble chart visualization, optional full report, and nutrient categories. We also present user scenarios from physician and researcher perspectives. Conclusion: In conclusion, an interactive dietary guide app prototype has been constructed as a first step towards eventually translating our DRGT strategy into an innovative, low-cost, healthy, and readily translatable public resource to improve health.

Importance of Diversity in Precision Medicine: Generalizability of Genetic Associations Across Ancestry Groups Toward Better Identification of Disease Susceptibility Variants.

Genome-wide association studies (GWAS) revolutionized our understanding of common genetic variation and its impact on common human disease and traits. Developed and adopted in the mid-2000s, GWAS led to searchable genotype-phenotype catalogs and genome-wide datasets available for further data mining and analysis for the eventual development of translational applications. The GWAS revolution was swift and specific, including almost exclusively populations of European descent, to the neglect of the majority of the world's genetic diversity. In this narrative review, we recount the GWAS landscape of the early years that established a genotype-phenotype catalog that is now universally understood to be inadequate for a complete understanding of complex human genetics. We then describe approaches taken to augment the genotype-phenotype catalog, including the study populations, collaborative consortia, and study design approaches aimed to generalize and then ultimately discover genome-wide associations in non-European descent populations. The collaborations and data resources established in the efforts to diversify genomic findings undoubtedly provide the foundations of the next chapters of genetic association studies with the advent of budget-friendly whole-genome sequencing.

Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity.

PURPOSE: The aim of this study was to assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD). METHODS: We developed a FECD case-control algorithm based on structured electronic health record data and confirmed accuracy by individual review of charts at 3 Veterans Affairs (VA) Medical Centers. This algorithm was applied to the Department of VA Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes, and laboratory values were extracted. Single-variable and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis. RESULTS: Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and nonocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for 4 being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications. CONCLUSIONS: Female sex, European ancestry, and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes and altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. Further studies to better understand the relationship between FECD and DM are indicated and may help identify opportunities for slowing FECD progression.

Assessment of multi-population polygenic risk scores for lipid traits in African Americans.

Polygenic risk scores (PRS) based on genome-wide discoveries are promising predictors or classifiers of disease development, severity, and/or progression for common clinical outcomes. A major limitation of most risk scores is the paucity of genome-wide discoveries in diverse populations, prompting an emphasis to generate these needed data for trans-population and population-specific PRS construction. Given diverse genome-wide discoveries are just now being completed, there has been little opportunity for PRS to be evaluated in diverse populations independent from the discovery efforts. To fill this gap, we leverage here summary data from a recent genome-wide discovery study of lipid traits (HDL-C, LDL-C, triglycerides, and total cholesterol) conducted in diverse populations represented by African Americans, Hispanics, Asians, Native Hawaiians, Native Americans, and others by the Population Architecture using Genomics and Epidemiology (PAGE) Study. We constructed lipid trait PRS using PAGE Study published genetic variants and weights in an independent African American adult patient population linked to de-identified electronic health records and genotypes from the Illumina Metabochip (n = 3,254). Using multi-population lipid trait PRS, we assessed levels of association for their respective lipid traits, clinical outcomes (cardiovascular disease and type 2 diabetes), and common clinical labs. While none of the multi-population PRS were strongly associated with the tested trait or outcome, PRSLDL-Cwas nominally associated with cardiovascular disease. These data demonstrate the complexity in applying PRS to real-world clinical data even when data from multiple populations are available.

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.

BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility. OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. RESULTS AND LIMITATIONS: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4). CONCLUSIONS: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. PATIENT SUMMARY: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Session Introduction: Precision Medicine: Using Artificial Intelligence to Improve Diagnostics and Healthcare.

Precision medicine requires a deep understanding of complex biomedical and healthcare data, which is being generated at exponential rates and increasingly made available through public biobanks, electronic medical record systems and biomedical databases and knowledgebases. The complexity and sheer amount of data prohibit manual manipulation. Instead, the field depends on artificial intelligence approaches to parse, annotate, evaluate and interpret the data to enable applications to patient healthcare At the 2023 Pacific Symposium on Biocomputing (PSB) session entitled "Precision Medicine: Using Artificial Intelligence (AI) to improve diagnostics and healthcare", we spotlight research that develops and applies computational methodologies to solve biomedical problems.

Diversity is key for cross-ancestry transferability of glaucoma genetic risk scores in Hispanic Veterans in the Million Veteran Program.

A major goal of precision medicine is to stratify patients based on their genetic risk for a disease to inform future screening and intervention strategies. For conditions like primary open-angle glaucoma (POAG), the genetic risk architecture is complicated with multiple variants contributing small effects on risk. Following the tepid success of genome-wide association studies for high-effect disease risk variant discovery, genetic risk scores (GRS), which collate effects from multiple genetic variants into a single measure, have shown promise for disease risk stratification. We assessed the application of GRS for POAG risk stratification in Hispanic-descent (HIS) and European-descent (EUR) Veterans in the Million Veteran Program. Unweighted and cross-ancestry meta-weighted GRS were calculated based on 127 genomic variants identified in the most recent report of cross-ancestry POAG meta-analyses. We found that both GRS types were associated with POAG case-control status and performed similarly in HIS and EUR Veterans. This trend was also seen in our subset analysis of HIS Veterans with less than 50% EUR global genetic ancestry. Our findings highlight the importance of evaluating GRS based on known POAG risk variants in different ancestry groups and emphasize the need for more multi-ancestry POAG genetic studies.

T-cell receptor diversity in minimal change disease in the NEPTUNE study.

BACKGROUND: Minimal change disease (MCD) is the major cause of childhood idiopathic nephrotic syndrome, which is characterized by massive proteinuria and debilitating edema. Proteinuria in MCD is typically rapidly reversible with corticosteroid therapy, but relapses are common, and children often have many adverse events from the repeated courses of immunosuppressive therapy. The pathobiology of MCD remains poorly understood. Prior clinical observations suggest that abnormal T-cell function may play a central role in MCD pathogenesis. Based on these observations, we hypothesized that T-cell responses to specific exposures or antigens lead to a clonal expansion of T-cell subsets, a restriction in the T-cell repertoire, and an elaboration of specific circulating factors that trigger disease onset and relapses. METHODS: To test these hypotheses, we sequenced T-cell receptors in fourteen MCD, four focal segmental glomerulosclerosis (FSGS), and four membranous nephropathy (MN) patients with clinical data and blood samples drawn during active disease and during remission collected by the Nephrotic Syndrome Study Network (NEPTUNE). We calculated several T-cell receptor diversity metrics to assess possible differences between active disease and remission states in paired samples. RESULTS: Median productive clonality did not differ between MCD active disease (0.0083; range: 0.0042, 0.0397) and remission (0.0088; range: 0.0038, 0.0369). We did not identify dominant clonotypes in MCD active disease, and few clonotypes were shared with FSGS and MN patients. CONCLUSIONS: While these data do not support an obvious role of the adaptive immune system T-cells in MCD pathogenesis, further study is warranted given the limited sample size. A higher resolution version of the Graphical abstract is available as Supplementary information.

Thyroid Hormone Induces Oral Cancer Growth via the PD-L1-Dependent Signaling Pathway.

Oral cancer is a fatal disease, and its incidence in Taiwan is increasing. Thyroid hormone as L-thyroxine (T4) stimulates cancer cell proliferation via a receptor on integrin αvß3 of plasma membranes. It also induces the expression of programmed death-ligand 1 (PD-L1) and cell proliferation in cancer cells. Thyroid hormone also activates ß-catenin-dependent cell proliferation in cancer cells. However, the relationship between PD-L1 and cancer proliferation is not fully understood. In the current study, we investigated the role of inducible thyroid hormone-induced PD-L1-regulated gene expression and proliferation in oral cancer cells. Thyroxine bound to integrin αvß3 to induce PD-L1 expressions via activation of ERK1/2 and signal transducer and activator of transcription 3 (STAT3). Inactivated STAT3 inhibited PD-L1 expression and nuclear PD-L1 accumulation. Inhibition of PD-L1 expression reduced ß-catenin accumulation. Furthermore, nuclear PD-L1 formed a complex with nuclear proteins such as p300. Suppression PD-L1 expression by shRNA blocked not only expression of PD-L1 and ß-catenin but also signal transduction, proliferative gene expressions, and cancer cell growth. In summary, thyroxine via integrin αvß3 activated ERK1/2 and STAT3 to stimulate the PD-L1-dependent and ß-catenin-related growth in oral cancer cells.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-Glucoside improves female ovarian aging.

Reduced fertility associated with normal aging may reflect the over-maturity of oocytes. It is increasingly important to reduce aging-induced infertility since recent trends show people marrying at later ages. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), a polyphenol extracted from Polygonum multiflorum, has been reported to have anti-inflammatory and anti-aging properties. To evaluate whether THSG can reduce aging-related ovarian damage in a female mouse model of aging, THSG was administered by gavage at a dose of 10 mg/kg twice weekly, starting at 4 weeks of age in a group of young mice. In addition, the effect of THSG in a group of aged mice was also studied in mice starting at 24 weeks of age. The number of oocytes in the THSG-fed group was higher than in the untreated control group. Although the percentage of secondary polar bodies (PB2) decreased during aging in the THSG-fed group, it decreased much more slowly than in the age-matched control group. THSG administration increased the quality of ovaries in young mice becoming aged. Western blotting analyses also indicated that CYP19, PR-B, and ER-ß expressions were significantly increased in 36-week-old mice. THSG also increased oocyte numbers in aged mice compared to mice without THSG fed. Studies of qPCR and immunohistochemistry (IHC) analyses of ovaries in the aged mice groups were conducted. THSG increased gene expression of anti-Müllerian hormone (AMH), a biomarker of oocyte number, and protein accumulation in 40-week-old mice. THSG increased the expression of pgc1α and atp6, mitochondrial biogenesis-related genes, and their protein expression. THSG also attenuated the fading rate of CYP11a and CYP19 associated with sex hormone synthesis. And THSG maintains a high level of ER-ß expression, thereby enhancing the sensitivity of estrogen. Our findings indicated that THSG increased or extended gene expression involved in ovarian maintenance and rejuvenation in young and aged mice. On the other hand, THSG treatments significantly maintained oocyte quantity and quality in both groups of young and aged mice compared to each age-matched control group. In conclusion, THSG can delay aging-related menopause, and the antioxidant properties of THSG may make it suitable for preventing aging-induced infertility.

Heteronemin and Tetrac Induce Anti-Proliferation by Blocking EGFR-Mediated Signaling in Colorectal Cancer Cells.

Overexpressed EGFR and mutant K-Ras play vital roles in therapeutic resistance in colorectal cancer patients. To search for an effective therapeutic protocol is an urgent task. A secondary metabolite in the sponge Hippospongia sp., Heteronemin, has been shown to induce anti-proliferation in several types of cancers. A thyroxine-deaminated analogue, tetrac, binds to integrin αvß3 to induce anti-proliferation in different cancers. Heteronemin- and in combination with tetrac-induced antiproliferative effects were evaluated. Tetrac enhanced heteronemin-induced anti-proliferation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC). Heteronemin and tetrac arrested cell cycle in different phases. Combined treatment increased the cell accumulation in sub-G1 and S phases. The combined treatment also induced the inactivation of EGFR signaling and downregulated the phosphorylated ERK1/2 protein in both cell lines. Heteronemin and the combination showed the downregulation of the phosphorylated and total PI3K protein in HT-29 cells (KRAS WT CRC). Results by NanoString technology and RT-qPCR revealed that heteronemin and combined treatment suppressed the expression of EGFR and downstream genes in HCT-116 cells (KRAS MT CRC). Heteronemin or combined treatment downregulated genes associated with cancer progression and decreased cell motility. Heteronemin or the combined treatment suppressed PD-L1 expression in both cancer cell lines. However, only tetrac and the combined treatment inhibited PD-L1 protein accumulation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC), respectively. In summary, heteronemin induced anti-proliferation in colorectal cancer cells by blocking the EGFR-dependent signal transduction pathway. The combined treatment further enhanced the anti-proliferative effect via PD-L1 suppression. It can be an alternative strategy to suppress mutant KRAS resistance for anti-EGFR therapy.

Glaucoma Genetic Risk Scores in the Million Veteran Program.

PURPOSE: Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS). DESIGN: Cross-sectional study. PARTICIPANTS: MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls. METHODS: We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS. MAIN OUTCOME MEASURES: Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS. RESULTS: GRS were significantly associated with POAG (P < 5 × 10-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases. CONCLUSIONS: Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns.

More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure-based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes (TREM2, SORL1, and EXOC3L4) and another suggestive gene from the ADSP WES data. For TREM2 and SORL1, two known Alzheimer's disease (AD) genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low-frequency risk variants within these genes. EXOC3L4 is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.

A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry.

A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10-4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10-5; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10-4; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.

Maturation and application of phenome-wide association studies.

In the past 10 years since its introduction, phenome-wide association studies (PheWAS) have uncovered novel genotype-phenotype relationships. Along the way, PheWAS have evolved in many aspects as a study design with the expanded availability of large data repositories with genome-wide data linked to detailed phenotypic data. Advancement in methods, including algorithms, software, and publicly available integrated resources, makes it feasible to more fully realize the potential of PheWAS, overcoming the previous computational and analytical limitations. We review here the most recent improvements and notable applications of PheWAS since the second half of the decade from its inception. We also note the challenges that remain embedded along the entire PheWAS analytical pipeline that necessitate further development of tools and resources to further advance the understanding of the complex genetic architecture underlying human diseases and traits.

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.