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.
Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR013) of the Conference Program/Proceedings. Citation Format: Poorva Mudgal, Cheryl Bandoski, Zachary Opheim, Martin Mehnert, Valesca Anschau, Issa Isaac, Alan Ezrin, Todd Hembrough. Highly accurate detection of early-stage colorectal cancer using tumor and immune extracellular vesicles biomarkers [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A063.
Introduction: African Americans have the highest prevalence of obesity in the U.S. Our prior work on HapMap imputed genome-wide association studies (GWAS) from the African Ancestry Anthropometry Genetics Consortium (AAAGC) revealed seven genome-wide significant loci for body mass index (BMI). Hypothesis: In this study, we extended to use genome-wide imputation to the cosmopolitan 1000 Genomes Phase 1 reference panel to examine individuals of African ancestry for association with BMI (N=53,493), waist-to-hip ratio adjusted for BMI (WHRadjBMI) (N=23,692) and height (N=53,362) in the discovery and replication stages. Methods: In each study, traits were stratified by gender and transformed to normality and adjusted for age, study specific covariates and principal components for single variant association test under an additive model. In the discovery stage, meta-analyses using fixed-effects inverse variance weighted method were performed to combine association results in all and sex-stratified samples. Variants with P<1E-4 were selected for subsequent replications in both individuals of African ancestry and European ancestry, the latter results were obtained by imputation of summary statistics from the GIANT consortium (N=322,154 for BMI, 210,062 for WHRadjBMI, and 253,252 for height). Results: For BMI, we observed genome-wide significant associations (P<5E-8) at seven established loci (near SEC16B, TMEM18, GNPDA2, GALNT10, KLHL32, FTO and MC4R) in meta-analysis of all African ancestry individuals from the discovery and replication stages. Sex-stratified meta-analysis revealed two novel loci near IRX4-IRX2 in women, and near MLC1 in men, respectively. Meta-analysis of all individuals from African and European ancestry revealed an additional novel locus near ARAP1. For WHRadjBMI, we observed genome-wide significant associations at one established locus (ADAMTS9) in all African ancestry individuals, and three novel loci (near SSX2IP, RREB1 and PDE3B) in women. For height, we observed 29 established loci and three novel loci (near NCOA2, P4HA1 and TGFB3) in all African ancestry individuals, and three novel loci (near CRB1, MIR4268 and LINC00704) in women. Among 12 lead variants at novel loci associated with anthropometry traits, four variants are low frequencies in our African ancestry populations (0.005<MAF <0.05). On the contrary, all but one of the lead variants at established loci were common. Conclusions: We identified 12 novel loci associated with anthropometry traits in sex-combined and sex-stratified analyses of African ancestry populations and additional European populations. Our findings support that imputation to higher density reference panels such as 1000 Genomes improves the power to detect associations at low frequency variants, which is particularly useful for African ancestry populations with a low degree of linkage disequilibrium.
Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a complex disorder resulting from the combined influence of genetic and environmental factors. This study contains a comprehensive genetic analysis of putative nephropathy loci in 965 African American (AA) cases with T2D-ESKD and 1029 AA population-based controls extending prior findings. Analysis was based on 4,341 directly genotyped and imputed single nucleotide polymorphisms (SNPs) in 22 nephropathy candidate genes. After admixture adjustment and correction for multiple comparisons, 37 SNPs across eight loci were significantly associated (1.6E-05
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a dismal prognosis. We previously reported that vaccination with heat shock protein peptide complex-96 (HSPPC-96) improves survival in patients with newly diagnosed GBM (NCT02122822). Especially for patients with a strong antitumor immune response after vaccination, a durable survival benefit can be achieved. Here, we conducted T cell receptor (TCR) sequencing to retrospectively examine the TCR repertoires of tumor-infiltrating lymphocytes in long-term survivors (LTS) and short-term survivors (STS). We found that LTS exhibit lower TCR repertoire diversity compared with STS, indicating the prevalence of dominant TCR clones in LTS tumors. Accordingly, the LTS group showed increased inter-patient similarity, especially among high-frequency TCR clones, implying some of these dominant clones are shared among LTS. Indeed, we discovered four TCR clones significantly enriched in the LTS group: the presence of these clones has predictive value for stratifying patients prior to vaccination. Together, these findings uncover a group of preexisting TCR clones shared in LTS that can be utilized as candidate biomarkers to select GBM patients most likely to durably respond to HSPPC-96 treatment.
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