Cluster effect for SNP-SNP interaction pairs for predicting complex traits.

Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP-SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP-SNP interactions.

Identification of rare genetic variants for rotator cuff tearing and repair in high-risk pedigrees.

Background: Common genetic variants with small effect sizes have been associated with rotator cuff tearing although very few rare, highly penetrant variants have been identified. The purpose of this pilot study was to identify dominant coding variants that segregated with affected individuals in pedigrees at high risk for rotator cuff tears (RCTs). We hypothesize that rare variants contribute to symptomatic RCTs and that they can be identified in related cases with a full-thickness tear requiring surgical management.

Breast Cancer is Increased in Women with Primary Ovarian Insufficiency.

Context: DNA damage/repair gene variants are associated with both primary ovarian insufficiency (POI) and cancer risk.

Objective: We hypothesized that a subset of women with POI and family members would have increased risk for cancer.

Design: Case-control population-based study using records from 1995-2022.

A Rare Variant in (rs111879470) Is Associated with Predisposition to Recurrent Breast Cancer in an Extended High-Risk Pedigree.

A significant fraction of breast cancer recurs, with lethal outcome, but specific genetic variants responsible have yet to be identified. Five cousin pairs with recurrent breast cancer from pedigrees with a statistical excess of recurrent breast cancer were sequenced to identify rare, shared candidate predisposition variants. The candidates were tested for association with breast cancer risk with UKBiobank data.

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS.

High-Risk Pedigree Study Identifies (rs62346982) as a Likely Predisposition Variant for Prostate Cancer.

There is evidence for contribution of inherited factors to prostate cancer, and more specifically to lethal prostate cancer, but few responsible genes/variants have been identified. We examined genetic sequence data for 51 affected cousin pairs who each died from prostate cancer and who were members of high-risk prostate cancer pedigrees in order to identify rare variants shared by the cousins as candidate predisposition variants. Candidate variants were tested for association with prostate cancer risk in UK Biobank data.

A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall-cell lung cancer.

A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall-cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC-affected cousin pairs belonging to high-risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank.

Comorbidity and Cancer Disease Rates among Those at High-Risk for Alzheimer's Disease: A Population Database Analysis.

(1) Importance: Alzheimer's disease (AD) is complex and only partially understood. Analyzing the relationship between other more treatable or preventable diseases and AD may help in the prevention and the eventual development of treatments for AD. Risk estimation in a high-risk population, rather than a population already affected with AD, may reduce some bias in risk estimates.

A likely HOXC4 predisposition variant for Chiari malformations.

Objective: Inherited variants predisposing patients to type 1 or 1.5 Chiari malformation (CM) have been hypothesized but have proven difficult to confirm. The authors used a unique high-risk pedigree population resource and approach to identify rare candidate variants that likely predispose individuals to CM and protein structure prediction tools to identify pathogenicity mechanisms.

Is There an Inherited Contribution to Risk for Sporadic Unilateral Vestibular Schwannoma? Evidence of Familial Clustering.

Object: Unlike the autosomal dominant inheritance of neurofibromatosis 2, there are no known inherited risk factors for sporadic, unilateral vestibular schwannoma (VS), which comprise most VS cases. The authors tested a hypothesis positing a genetic contribution to predisposition to these lesions by analyzing familial clustering of cases.

Methods: Familial clustering of individuals with unilateral VS was analyzed in two independent genealogical resources with linked diagnosis data: the Veterans Health Administration Genealogy Resource and the Utah Population Database.

The Effect of Sex Hormone Deficiency on the Incidence of Rotator Cuff Repair: Analysis of a Large Insurance Database.

Background: The purpose of the present study was to analyze the association between sex hormone deficiency and rotator cuff repair (RCR) with use of data from a large United States insurance database.

Methods: A retrospective analysis of insured subjects from the Truven Health MarketScan database was conducted, collecting data for RCR cases as well as controls matched for age, sex, and years in the database. Multivariable logistic regression models adjusted for matching variables were utilized to compare RCR status with estrogen deficiency status and testosterone deficiency status.

A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic cancer risk.

Pancreatic cancer is a deadly disease that accounts for approximately 5% of cancer deaths worldwide, with a dismal 5-year survival rate of 10%. Known genetic risk factors explain only a modest proportion of the heritable risk of pancreatic cancer. We conducted a whole-exome case-control sequencing study in 1,591 pancreatic cancer cases and 2,134 cancer-free controls of European ancestry.

Evidence for an Inherited Contribution to Sepsis Susceptibility Among a Cohort of U.S. Veterans.

Unlabelled: Analyze a unique clinical and genealogical resource for evidence of familial clustering of sepsis to test for an inherited contribution to sepsis predisposition.

Design: Observational study.

Setting: Veteran's Health Affairs (VHA) Genealogy/Phenotype resource, a U.

Evidence for excess familial clustering of Post Traumatic Stress Disorder in the US Veterans Genealogy resource.

A genealogy of the United States has been record-linked to National Veteran's Health Administration (VHA) patient data to allow non-identifiable analysis of familial clustering. This genealogy, including over 70 million individuals linked to over 1 million VHA patients, is the largest such combined resource reported. Analysis of familial clustering among VHA patients diagnosed with Post Traumatic Stress Disorder (PTSD) allowed a test of the hypothesis of an inherited contribution to PTSD.

Legal terms of use and public genealogy websites.

Public genealogy websites, to which individuals upload family history, genealogy, and sometimes individual genetic data, have been used in an increasing number of public health, epidemiological, and genetic studies. Yet there is little awareness among researchers of the legal rules that govern the use of these online resources. We analyzed the online Terms of Use (TOU) applicable to 17 popular genealogy websites and found that none of them expressly permit scientific research, while at least 13 contain restrictions that may limit or prohibit scientific research using data obtained from those sites.

Early-onset colorectal cancer risk extends to second- and third-degree relatives.

Introduction: Family history is a risk factor for colorectal cancer (CRC), however whether family history also contributes to non-syndromic early-onset CRC is unknown.

Methods: We estimated risk to first-, second-, and third-degree relatives of early-onset CRC cases in the Utah Pedigree Database.

Results: We observed elevated risks beyond RR = 2.

Analysis of high-risk pedigrees identifies 11 candidate variants for Alzheimer's disease.

Introduction: Analysis of sequence data in high-risk pedigrees is a powerful approach to detect rare predisposition variants.

Methods: Rare, shared candidate predisposition variants were identified from exome sequencing 19 Alzheimer's disease (AD)-affected cousin pairs selected from high-risk pedigrees. Variants were further prioritized by risk association in various external datasets.

Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors.

Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured.