An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

PACES: a Physical Activity Campus Environmental Supports Audit on University Campuses

PURPOSE: This study evaluated the policy and built and recreation environmental supports for physical activity on 13 university campuses.DESIGN: Environmental audit survey.SETTING: Thirteen U.S. universities, 2009. Subjects. University policies, recreation programs and facilities, and at least five additional buildings per campus.MEASURES: The Physical Activity Campus Environmental Supports Audit was developed for this study.ANALYSIS: Analysis of variance with post hoc Tukey\u27s B and χ(2) assessed differences by institution and building type.RESULTS: The mean obesogenic policy score was significantly lower than the desired score, ≥7 (p = .002), with only one campus scoring 10. The mean built environment audit score (5.4 ± 1.7) was low, with significant differences between institutions (p \u3c .001) and only three campuses scoring above the desired score, ≥7. Although generally stairwells were clean and well lighted, there was a lack of signage to encourage stair use (p \u3c .001). Overall, recreation programs (7.1 ± .7) and facilities (7.1 ± 1.2) scored well, but amenities scores were lower for satellite (2.8 ± 1.6) versus main (4.1 ± 1.8) recreation facilities (p = .04).CONCLUSION: On these 13 university campuses, recreation programs and facilities were supportive of healthful lifestyles for obesity prevention, but policies and the built environment were not. This physical activity environmental audit survey requires testing in a wider sample of postsecondary institutions to corroborate its utility and provide evidence to support initiatives to improve campus environments for physical activity

Preferences for Breast Cancer Risk Reduction Among BRCA1/BRCA2 Mutation Carriers: A Discrete-Choice Experiment

PURPOSE: Unaffected women who carry BRCA1 or BRCA2 mutations face difficult choices about reducing their breast cancer risk. Understanding their treatment preferences could help us improve patient counseling and inform drug trials. The objective was to explore preferences for various risk-reducing options among women with germline BRCA1/2 mutations using a discrete-choice experiment survey and to compare expressed preferences with actual behaviors. METHODS: A discrete-choice experiment survey was designed wherein women choose between hypothetical treatments to reduce breast cancer risk. The hypothetical treatments were characterized by the extent of breast cancer risk reduction, treatment duration, impact on fertility, hormone levels, risk of uterine cancer, and ease and mode of administration. Data were analyzed using a random-parameters logit model. Women were also asked to express their preference between surgical and chemoprevention options and to report on their actual risk-reduction actions. Women aged 25-55 years with germline BRCA1/2 mutations who were unaffected with breast or ovarian cancer were recruited through research registries at five clinics and a patient advocacy group. RESULTS: Between January 2015 and March 2016, 622 women completed the survey. Breast cancer risk reduction was the most important consideration expressed, followed by maintaining fertility. Among the subset of women who wished to have children in future, the ability to maintain fertility was the most important factor, followed by the extent of risk reduction. Many more women said they would take a chemoprevention drug than had actually taken chemoprevention. CONCLUSIONS: Women with BRCA1/2 mutations indicated strong preferences for breast cancer risk reduction and maintaining fertility. The expressed desire to have a safe chemoprevention drug available to them was not met by current chemoprevention options

Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (P < 3.64e-7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense (n = 41) or truncating (n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (DDX3X, MECP2, WDR45, and HDAC8). This large-scale integrative analysis identifies candidates and functional subsets of NDD genes

SPARK: A US Cohort of 50,000 Families to Accelerate Autism Research

The Simons Foundation Autism Research Initiative (SFARI) has launched SPARKForAutism. org, a dynamic platform that is engaging thousands of individuals with autism spectrum disorder (ASD) and connecting them to researchers. By making all data accessible, SPARK seeks to increase our understanding of ASD and accelerate new supports and treatments for ASD