Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits

Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta

Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type I procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type I procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the α1(I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type I procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI

Spectral characterisation of analog samples in anticipation of OSIRS-REx's arrival at Bennu: A blind test study

We present spectral measurements of a suite of mineral mixtures and meteorites that are possible analogs for asteroid (101955) Bennu, the target asteroid for NASA's Origins, Spectral Interpretation, Resource Identification, Security, Regolith Explorer (OSIRIS-REx) mission. The sample suite, which includes anhydrous and hydrated mineral mixtures and a suite of chondritic meteorites (CM, CI, CV, CR, and L5), was chosen to characterize the spectral effects due to varying amounts of aqueous alteration and minor amounts of organic material. Our results demonstrate the utility of mineral mixtures for understanding the mixing behavior of meteoritic materials and identifying spectrally dominant species across the visible to near-infrared (VNIR) and thermal infrared (TIR) spectral ranges. Our measurements demonstrate that, even with subtle signatures in the spectra of chondritic meteorites, we can identify diagnostic features related to the minerals comprising each of the samples. Also, the complementary nature of the two spectral ranges regarding their ability to detect different mixture and meteorite components can be used to characterize analog sample compositions better. However, we observe differences in the VNIR and TIR spectra between the mineral mixtures and the meteorites. These differences likely result from (1) differences in the types and physical disposition of constituents in the mixtures versus in meteorites, (2) missing phases observed in meteorites that we did not add to the mixtures, and (3) albedo differences among the samples. In addition to the initial characterization of the analog samples, we will use these spectral measurements to test phase detection and abundance determination algorithms in anticipation of mapping Bennu's surface properties and selecting a sampling site