Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia

Myopia, or nearsightedness, is the most common eye disorder, resulting primarily from excess elongation of the eye. The etiology of myopia, although known to be complex, is poorly understood. Here we report the largest ever genome-wide association study (43,360 participants) on myopia in Europeans. We performed a survival analysis on age of myopia onset and identified 19 significant associations (p < 5e-8), two of which are replications of earlier associations with refractive error. These 19 associations in total explain 2.7% of the variance in myopia age of onset, and point towards a number of different mechanisms behind the development of myopia. One association is in the gene PRSS56, which has previously been linked to abnormally small eyes; one is in a gene that forms part of the extracellular matrix (LAMA2); two are in or near genes involved in the regeneration of 11-cis-retinal (RGR and RDH5); two are near genes known to be involved in the growth and guidance of retinal ganglion cells (ZIC2, SFRP1); and five are in or near genes involved in neuronal signaling or development. These novel findings point towards multiple genetic factors involved in the development of myopia and suggest that complex interactions between extracellular matrix remodeling, neuronal development, and visual signals from the retina may underlie the development of myopia in humans

Generalized mirror symmetry and trace anomalies

We consider compactification of M-theory on X7 with betti numbers (b_0, b_1, b_2, b_3, b_3, b_2, b_1, b_0) and define a generalized mirror symmetry (b_0, b_1, b_2, b_3) goes to (b_0, b_1, b_2 -rho/2, b_3+rho/2)$ under which rho = 7b_0-5b_1+3b_2 -b_3 changes sign. Generalized self-mirror theories with rho=0 have massless sectors with vanishing trace anomaly (before dualization). Examples include pure supergravity with N \geq 4 and supergravity plus matter with N \leq 4.Comment: 19 pages late

Gamete Donor Selection Based on Genetic Calculations. U.S. Patent 8,543,339

Gamete donor selection includes receiving a specification including a phenotype of interest, receiving a genotype of a recipient and a plurality of genotypes of a respective plurality of donors, determining statistical information pertaining to the phenotype of interest based at least in part on different pairings of the genotype of the recipient and a genotype of a donor in the plurality of donors, and identifying a preferred donor among the plurality of donors, based at least in part on the statistical information determined

Dazl Functions in Maintenance of Pluripotency and Genetic and Epigenetic Programs of Differentiation in Mouse Primordial Germ Cells In Vivo and In Vitro

Mammalian germ cells progress through a unique developmental program that encompasses proliferation and migration of the nascent primordial germ cell (PGC) population, reprogramming of nuclear DNA to reset imprinted gene expression, and differentiation of mature gametes. Little is known of the genes that regulate quantitative and qualitative aspects of early mammalian germ cell development both in vivo, and during differentiation of germ cells from mouse embryonic stem cells (mESCs) in vitro.We used a transgenic mouse system that enabled isolation of small numbers of Oct4DeltaPE:GFP-positive germ cells in vivo, and following differentiation from mESCs in vitro, to uncover quantitate and qualitative phenotypes associated with the disruption of a single translational regulator, Dazl. We demonstrate that disruption of Dazl results in a post-migratory, pre-meiotic reduction in PGC number accompanied by aberrant expression of pluripotency genes and failure to erase and re-establish genomic imprints in isolated male and female PGCs, as well as subsequent defect in progression through meiosis. Moreover, the phenotypes observed in vivo were mirrored by those in vitro, with inability of isolated mutant PGCs to establish pluripotent EG (embryonic germ) cell lines and few residual Oct-4-expressing cells remaining after somatic differentiation of mESCs carrying a Dazl null mutation. Finally, we observed that even within undifferentiated mESCs, a nascent germ cell subpopulation exists that was effectively eliminated with ablation of Dazl.This report establishes the translational regulator Dazl as a component of pluripotency, genetic, and epigenetic programs at multiple time points of germ cell development in vivo and in vitro, and validates use of the ESC system to model and explore germ cell biology

Assessment of the genetic basis of rosacea by genome-wide association study.

Rosacea is a common, chronic skin disease that is currently incurable. Although environmental factors influence rosacea, the genetic basis of rosacea is not established. In this genome-wide association study, a discovery group of 22,952 individuals (2,618 rosacea cases and 20,334 controls) was analyzed, leading to identification of two significant single-nucleotide polymorphisms (SNPs) associated with rosacea, one of which replicated in a new group of 29,481 individuals (3,205 rosacea cases and 26,262 controls). The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2. Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins. In addition, three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10(-8) discovery group; P=4.4 × 10(-6) replication group), HLA-DQB1*02:01 (P=1.3 × 10(-8) discovery group; P=7.2 × 10(-6) replication group), and HLA-DQA1*05:01 (P=1.4 × 10(-8) discovery group; P=7.6 × 10(-6) replication group). Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea

Efficient Replication of Over 180 Genetic Associations with Self-Reported Medical Data

While the cost and speed of generating genomic data have come down dramatically in recent years, the slow pace of collecting medical data for large cohorts continues to hamper genetic research. Here we evaluate a novel online framework for amassing large amounts of medical information in a recontactable cohort by assessing our ability to replicate genetic associations using these data. Using web-based questionnaires, we gathered self-reported data on 50 medical phenotypes from a generally unselected cohort of over 20,000 genotyped individuals. Of a list of genetic associations curated by NHGRI, we successfully replicated about 75% of the associations that we expected to (based on the number of cases in our cohort and reported odds ratios, and excluding a set of associations with contradictory published evidence). Altogether we replicated over 180 previously reported associations, including many for type 2 diabetes, prostate cancer, cholesterol levels, and multiple sclerosis. We found significant variation across categories of conditions in the percentage of expected associations that we were able to replicate, which may reflect systematic inflation of the effects in some initial reports, or differences across diseases in the likelihood of misdiagnosis or misreport. We also demonstrated that we could improve replication success by taking advantage of our recontactable cohort, offering more in-depth questions to refine self-reported diagnoses. Our data suggests that online collection of self-reported data in a recontactable cohort may be a viable method for both broad and deep phenotyping in large populations

Race/Ethnicity and Geographic Access to Urban Trauma Care

Importance Little is known about the distribution of life-saving trauma resources by racial/ethnic composition in US cities, and if racial/ethnic minority populations disproportionately live in US urban trauma deserts. Objective To examine racial/ethnic differences in geographic access to trauma care in the 3 largest US cities, considering the role of residential segregation and neighborhood poverty. Design, Setting, and Participants A cross-sectional, multiple-methods study evaluated census tract data from the 2015 American Community Survey in Chicago, Illinois; Los Angeles (LA), California; and New York City (NYC), New York (N = 3932). These data were paired to geographic coordinates of all adult level I and II trauma centers within an 8.0-km buffer of each city. Between February and September 2018, small-area analyses were conducted to assess trauma desert status as a function of neighborhood racial/ethnic composition, and geospatial analyses were conducted to examine statistically significant trauma desert hot spots. Main Outcomes and Measures In small-area analyses, a trauma desert was defined as travel distance greater than 8.0 km to the nearest adult level I or level II trauma center. In geospatial analyses, relative trauma deserts were identified using travel distance as a continuous measure. Census tracts were classified into (1) racial/ethnic composition categories, based on patterns of residential segregation, including white majority, black majority, Hispanic/Latino majority, and other or integrated; and (2) poverty categories, including nonpoor and poor. Results Chicago, LA, and NYC contained 798, 1006, and 2128 census tracts, respectively. A large proportion comprised a black majority population in Chicago (35.1%) and NYC (21.4%), compared with LA (2.7%). In primary analyses, black majority census tracts were more likely than white majority census tracts to be located in a trauma desert in Chicago (odds ratio [OR], 8.48; 95% CI, 5.71-12.59) and LA (OR, 5.11; 95% CI, 1.50-17.39). In NYC, racial/ethnic disparities were not significant in unadjusted models, but were significant in models adjusting for poverty and race-poverty interaction effects (adjusted OR, 1.87; 95% CI, 1.27-2.74). In comparison, Hispanic/Latino majority census tracts were less likely to be located in a trauma desert in NYC (OR, 0.03; 95% CI, 0.01-0.11) and LA (OR, 0.30; 95% CI, 0.22-0.40), but slightly more likely in Chicago (OR, 2.38; 95% CI, 1.56-3.64). Conclusions and Relevance In this study, black majority census tracts were the only racial/ethnic group that appeared to be associated with disparities in geographic access to trauma centers

Live Imaging of Cysteine-Cathepsin Activity Reveals Dynamics of Focal Inflammation, Angiogenesis, and Polyp Growth

It has been estimated that up to 30% of detectable polyps in patients regress spontaneously. One major challenge in the evaluation of effective therapy of cancer is the readout for tumor regression and favorable biological response to therapy. Inducible near infra-red (NIR) fluorescent probes were utilized to visualize intestinal polyps of mice hemizygous for a novel truncation of the Adenomatous Polyposis coli (APC) gene. Laser Scanning Confocal Microscopy in live mice allowed visualization of cathepsin activity in richly vascularized benign dysplastic lesions. Using biotinylated suicide inhibitors we quantified increased activities of the Cathepsin B &amp; Z in the polyps. More than ¾ of the probe signal was localized in CD11b+Gr1+ myeloid derived suppressor cells (MDSC) and CD11b+F4/80+ macrophages infiltrating the lesions. Polyposis was attenuated through genetic ablation of cathepsin B, and suppressed by neutralization of TNFα in mice. In both cases, diminished probe signal was accounted for by loss of MDSC. Thus, in vivo NIR imaging of focal cathepsin activity reveals inflammatory reactions etiologically linked with cancer progression and is a suitable approach for monitoring response to therapy.Stem Cell and Regenerative Biolog

Novel missense mutations of the Deleted-in-AZoospermia-Like (DAZL) gene in infertile women and men

BACKGROUND: The Deleted-in-AZoospermia-Like (DAZL) gene has homologs required for germ cell development in many organisms. Recently, we showed that there are several common polymorphisms within the DAZL gene that are associated with age at ovarian failure/menopause and sperm count. METHODS: Here we sought to identify rare mutations in DAZL and examine their phenotypes in men and women. We sequenced the DAZL gene in 519 individuals; sequences spanned the entire coding region of the gene. RESULTS: We report the identification of four putative missense mutations in DAZL. Three individuals that were heterozygous for a DAZL mutation reported having children, while two individuals that were homozygous reported no children. These mutations were found only in infertile men and women. CONCLUSION: Given the strong data associating DAZL polymorphisms and deletions with fertility in humans and model organisms, we suggest that these mutations may be associated with age at menopause and/or sperm count and warrant further biochemical and genetic investigation