Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations

Nontuberculous mycobacterial infections of the lower extremities: A 15-year experience

Objectives: Nontuberculous mycobacterial infection (NTMI), which is increasing in prevalence, is challenging to diagnose and manage despite the availability of capable laboratories because of subtle and nonspecific clinical findings and nonstandardized treatment guidelines. We aimed to present our experience with lower-extremity NTMI and to compare clinical characteristics and treatment outcomes between immunocompetent and immunocompromised patients. Methods: To determine clinical presentations and outcomes, we reviewed electronic health records of all patients with lower-extremity NTMI treated and followed up at our institution from January 2002 through December 2017. Results: Twenty-four patients were included in this study. Mean (SD) age was 58 (19) years. Eighteen patients (75%) were men; 13 (54%) were immunocompetent; and 9 (37%) had bone and joint involvement. No significant differences existed between immunocompetent and immunocompromised patients, except immunocompetent patients had significantly more infections at the hip, thigh, and toe. Bone and joint infection required significantly longer treatment time than skin and soft-tissue infection. Conclusions: Regardless of immune status, patients with lower-extremity NTMI had similar characteristics, treatments, and outcomes. However, immunosuppression can be a major risk factor in the development of disseminated NTMI and associated complications. Acid-fast bacilli culture is strongly recommended for evaluation of delayed or nonhealing lesions. Aggressive medical and surgical management can be associated with good clinical outcomes. Keywords: Bone and joint, Immunosuppression, Lower extremity, Nontuberculous mycobacterial infection, Skin and soft tissu

The DES view of the Eridanus supervoid and the CMB cold spot

ABSTRACT The Cold Spot is a puzzling large-scale feature in the Cosmic Microwave Background temperature maps and its origin has been subject to active debate. As an important foreground structure at low redshift, the Eridanus supervoid was recently detected, but it was subsequently determined that, assuming the standard ΛCDM model, only about 10–20 per cent of the observed temperature depression can be accounted for via its Integrated Sachs–Wolfe imprint. However, R ≳ 100 h−1Mpc supervoids elsewhere in the sky have shown ISW imprints AISW ≈ 5.2 ± 1.6 times stronger than expected from ΛCDM (AISW = 1), which warrants further inspection. Using the Year-3 redMaGiC catalogue of luminous red galaxies from the Dark Energy Survey, here we confirm the detection of the Eridanus supervoid as a significant underdensity in the Cold Spot’s direction at z &amp;lt; 0.2. We also show, with S/N ≳ 5 significance, that the Eridanus supervoid appears as the most prominent large-scale underdensity in the dark matter mass maps that we reconstructed from DES Year-3 gravitational lensing data. While we report no significant anomalies, an interesting aspect is that the amplitude of the lensing signal from the Eridanus supervoid at the Cold Spot centre is about 30 per cent lower than expected from similar peaks found in N-body simulations based on the standard ΛCDM model with parameters Ωm = 0.279 and σ8 = 0.82. Overall, our results confirm the causal relation between these individually rare structures in the cosmic web and in the CMB, motivating more detailed future surveys in the Cold Spot region

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) &lt; 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p &lt; 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations

Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) \u3c 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p \u3c 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations

The DESI experiment part I: science, targeting, and survey design

DESI (Dark Energy Spectroscopic Instrument) is a Stage IV ground-based dark energy experiment that will study baryon acoustic oscillations (BAO) and the growth of structure through redshift-space distortions with a wide-area galaxy and quasar redshift survey. To trace the underlying dark matter distribution, spectroscopic targets will be selected in four classes from imaging data. We will measure luminous red galaxies up to $z=1.0$. To probe the Universe out to even higher redshift, DESI will target bright [O II] emission line galaxies up to $z=1.7$. Quasars will be targeted both as direct tracers of the underlying dark matter distribution and, at higher redshifts ($2.1 < z < 3.5$), for the Ly-$\alpha$ forest absorption features in their spectra, which will be used to trace the distribution of neutral hydrogen. When moonlight prevents efficient observations of the faint targets of the baseline survey, DESI will conduct a magnitude-limited Bright Galaxy Survey comprising approximately 10 million galaxies with a median $z\approx 0.2$. In total, more than 30 million galaxy and quasar redshifts will be obtained to measure the BAO feature and determine the matter power spectrum, including redshift space distortions