Polygenic scores and social determinants of health: Their correlations and potential biases.

The use of polygenic scores (PGS) for personalized medicine has gained momentum, along with caution to avoid accentuating health disparities. Greater ancestral diversity in genetic studies is needed, as well as close attention to the social determinants of health (SDoH).We measured the correlations between 3,030 PGS from the PGS Catalog and SDoH among participants in the Personalized Environment and Genes Study (PEGS).

Association between Kidney Stones and CKD: A Bidirectional Mendelian Randomization Study.

Key Points: Common kidney stones are unlikely to be an independent and direct cause of CKD in the general population. CKD may protect against kidney stones because of changes in key urinary factors critical for stone formation.

Background: Kidney stones and CKD are common disorders with a substantial interaction.

Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm as the strongest overall FTLD-TDP risk factor and identify as a novel FTLD-TDP risk factor.

A microRNA Transcriptome-wide Association Study of Prostate Cancer Risk.

Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with increased risk of prostate cancer (PrCa), and many of these risk loci is presumed to confer regulatory effects on gene expression. While eQTL studies of long RNAs has yielded many potential risk genes, the relationship between PrCa risk genetics and microRNA expression dysregulation is understudied. We performed an microRNA transcriptome-wide association study of PrCa risk using small RNA sequencing and genome-wide genotyping data from N = 441 normal prostate epithelium tissue samples along with N = 411 prostate adenocarcinoma tumor samples from the Cancer Genome Atlas (TCGA).

Polygenic risk for prostate cancer: Decreasing relative risk with age but little impact on absolute risk.

Polygenic risk scores (PRSs) for a variety of diseases have recently been shown to have relative risks that depend on age, and genetic relative risks decrease with increasing age. A refined understanding of the age dependency of PRSs for a disease is important for personalized risk predictions and risk stratification. To further evaluate how the PRS relative risk for prostate cancer depends on age, we refined analyses for a validated PRS for prostate cancer by using 64,274 prostate cancer cases and 46,432 controls of diverse ancestry (82.

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

Background: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.

Objective: To precisely estimate the contribution of germline ATM mutations to PrCa risk.

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.

Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer.

Background: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.

Objective: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa.

Design, Setting, And Participants: A two-stage design was used.

A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data.

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.

Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases).

The effect of sample size on polygenic hazard models for prostate cancer.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets.

An expanded variant list and assembly annotation identifies multiple novel coding and noncoding genes for prostate cancer risk using a normal prostate tissue eQTL data set.

Prostate cancer (PrCa) is highly heritable; 284 variants have been identified to date that are associated with increased prostate cancer risk, yet few genes contributing to its development are known. Expression quantitative trait loci (eQTL) studies link variants with affected genes, helping to determine how these variants might regulate gene expression and may influence prostate cancer risk. In the current study, we performed eQTL analysis on 471 normal prostate epithelium samples and 249 PrCa-risk variants in 196 risk loci, utilizing RNA sequencing transcriptome data based on ENSEMBL gene definition and genome-wide variant data.

Familial recurrence risk with varying amount of family history.

The familial recurrence risk is the probability a person will have disease, given a reported family history. When family histories are obtained as simple counts of disease among family members, as often obtained in cancer registries or surveys, we propose methods to estimate recurrence risks based on truncated binomial distributions. By this approach, we are able to obtain unbiased estimates of risk for a person with at least k-affected relatives, where k can be specified to determine how risk varies with k.

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.

Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.

Association of mitochondrial DNA copy number with self-rated health status.

Purpose: In aging adults, mitochondrial dysfunction may be an important contributor. We evaluated the association between mitochondrial DNA (mtDNA) copy number, which is a biomarker for mitochondrial function, and self-rated health status.

Patients And Methods: We conducted a cross-sectional study of patients enrolled within the Mayo Clinic Biobank.

Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19.

The prostate cancer (PCa) risk-associated SNP rs11672691 is positively associated with aggressive disease at diagnosis. We showed that rs11672691 maps to the promoter of a short isoform of long noncoding RNA PCAT19 (PCAT19-short), which is in the third intron of the long isoform (PCAT19-long). The risk variant is associated with decreased and increased levels of PCAT19-short and PCAT19-long, respectively.

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis.

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.

Identification of missing variants by combining multiple analytic pipelines.

Background: After decades of identifying risk factors using array-based genome-wide association studies (GWAS), genetic research of complex diseases has shifted to sequencing-based rare variants discovery. This requires large sample sizes for statistical power and has brought up questions about whether the current variant calling practices are adequate for large cohorts. It is well-known that there are discrepancies between variants called by different pipelines, and that using a single pipeline always misses true variants exclusively identifiable by other pipelines.

Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci.

Large-scale genome-wide association studies have identified multiple single-nucleotide polymorphisms associated with risk of prostate cancer. Many of these genetic variants are presumed to be regulatory in nature; however, follow-up expression quantitative trait loci (eQTL) association studies have to-date been restricted largely to -acting associations due to study limitations. While -eQTL scans suffer from high testing dimensionality, recent evidence indicates most -eQTL associations are mediated by -regulated genes, such as transcription factors.

FIRE: functional inference of genetic variants that regulate gene expression.

Motivation: Interpreting genetic variation in noncoding regions of the genome is an important challenge for personal genome analysis. One mechanism by which noncoding single nucleotide variants (SNVs) influence downstream phenotypes is through the regulation of gene expression. Methods to predict whether or not individual SNVs are likely to regulate gene expression would aid interpretation of variants of unknown significance identified in whole-genome sequencing studies.

Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer.

It is unclear how standing genetic variation affects the prognosis of prostate cancer patients. To provide one controlled answer to this problem, we crossed a dominant, penetrant mouse model of prostate cancer to Diversity Outbred mice, a collection of animals that carries over 40 million SNPs. Integration of disease phenotype and SNP variation data in 493 F1 males identified a metastasis modifier locus on Chromosome 8 (LOD = 8.