Genome-Wide Investigation of Exogenous Female Hormones, Genetic Variation, and Venous Thromboembolism Risk.

BACKGROUND: Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT). OBJECTIVES: To investigate the potential for genetic predisposition to VTE in OC or HT users, we conducted a gene-by-environment (GxE) case-only meta-analysis of genome-wide association studies (GWAS). METHODS: Use or non-use of OCs (7 studies) or HT (8 studies) at the time of the VTE event was determined by pharmacy records or self-report. A synergy index (SI) was modeled for each variant in each study and estimated supra-multiplicative GxE interaction. The SI parameters were first meta-analyzed across OC and HT studies, and subsequently meta-analyzed to obtain an overall estimate. The primary analysis was agnostic GWAS and interrogated all imputed genotypes using a p-value threshold of <5.0x10-8; secondary analyses were candidate-based. RESULTS: The VTE case-only OC meta-analysis included 2,895 OC users and 6,607 non-users; the case-only HT meta-analysis included 2,434 HT users and 12,793 non-users. In primary GWAS meta-analyses, no variant reached genome-wide significance, but the smallest p-value approached statistical significance: rs9386463 (p = 5.03x10-8). We tested associations for 138 candidate variants and identified 2 that exceeded statistical significance (0.05/138=3.62x10-4): F5 rs6025 (p = 1.87x10-5, SI = 1.29: previously observed) and F11 rs2036914 (p = 2.0x10-4, SI = 0.91; new observation). CONCLUSIONS: The candidate-variant approach to identify supra-multiplicative associations between genetic variation and OC-HT use identified a new association with common genetic variation in F11 while the agnostic interrogations did not yield new discoveries.

Measuring high-risk parents' opinions about direct-to-consumer genetic testing for adult-onset inherited cancer syndromes in their adolescent and young adult children.

Neither direct-to-consumer (DTC) genetic testing nor predictive genetic testing for adult-onset conditions is recommended for minor children due to ethical concerns and low clinical utility. However, parents with pathogenic variants (PVs) in disease-causing genes may be interested in pursuing genetic testing that includes the familial PV for their children. The Pediatric Testing Attitudes Scale (P-TAS) was previously developed to examine high-risk parents' opinions about pediatric BRCA genetic testing for adult-onset breast/ovarian cancer. Here, the psychometric properties of the P-TAS were examined in a new sample of N = 126 parents (M age = 47.2 years) with PVs in a more complete set of cancer risk genes represented on DTC panel tests. The mean score on the P-TAS was 44 out of a maximum score of 60, indicating that a majority of parents generally held favorable opinions about testing their children for adult-onset inherited cancer syndromes. The internal consistency of the full scale was high (α = 0.91). A factor analysis identified two-component scales, labeled Attitudes and Beliefs (α = 0.93) and Decision Making and Communication (α = 0.83). In a multivariable regression model, P-TAS co-factors accounted for 34% of variance in parental opinions, including the frequency of prior family communication about cancer and the likelihood of utilizing DTC genetic testing with children (R2  = 0.34, p < 0.001). Results suggest that the P-TAS remains a reliable measure to assess high-risk parents' opinions about pediatric DTC genetic testing for adult-onset conditions, with promising validity. Applications of the P-TAS include informing genetic counseling practice, pediatric medical care, and policy guidelines surrounding DTC genetic testing.