Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,771) and generalized our findings in 9 additional studies (HISLA Stage 2, n=10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification

Cervical Microbiome and Cytokine Profile at Various Stages of Cervical Cancer: A Pilot Study

<div><p>Cervical cancer (CC) is caused by high-risk human papillomavirus persistence due to the immunosuppressive tumor microenvironment mediated by cytokines. Vaginal microbiota determines the presence of certain cytokines locally. We assessed the association between cervical microbiota diversity and the histopathological diagnosis of each stage of CC, and we evaluated mRNA cervical expression levels of IL-4, IL-6, IL-10, TGF-β1, TNF-α and IFN-γ across the histopathological diagnosis and specific bacterial clusters. We determined the cervical microbiota by high throughput sequencing of 16S rDNA amplicons and classified it in community state types (CST). Mean difference analyses between alpha-diversity and histopathological diagnosis were carried out, as well as a β-diversity analysis within the histological diagnosis. Cervical cytokine mRNA expression was analyzed across the CSTs and the histopathological diagnoses. We found a significant difference in microbiota's diversity in NCL-HPV negative women vs those with squamous intraepithelial lesions (SIL) and CC(p = 0.006, p = 0.036).When β-diversity was evaluated, the CC samples showed the highest variation within groups (p<0.0006) and the largest distance compared to NCL-HPV negative ones (p<0.00001). The predominant bacteria in women with normal cytology were <i>L</i>. <i>crispatus</i> and <i>L</i>. <i>iners</i>, whereas for SIL, it was <i>Sneathia spp</i>. and for CC, <i>Fusobacterium spp</i>. We found higher median cervical levels of IL-4 and TGF-β1 mRNA in the CST dominated by <i>Fusobacterium spp</i>. These results suggest that the cervical microbiota may be implicated in cervical cancer pathology. Further cohort studies are needed to validate these findings.</p></div

Analysis of reproductive/sexual lifestyle-related risk factors in the study population (cervical lesion and cervical cancer patients).

<p>Analysis of reproductive/sexual lifestyle-related risk factors in the study population (cervical lesion and cervical cancer patients).</p

Estimated mean difference of bit units (Shannon diversity index) in cervix between NCL regardless of HPV status and SIL or CC.

<p>Estimated mean difference of bit units (Shannon diversity index) in cervix between NCL regardless of HPV status and SIL or CC.</p

Community compositions according to histopathological diagnosis groups.

<p>Bar chart of relative abundance of species per group.</p

Mean difference analysis between the Shannon diversity index or the phylogenetic diversity whole tree and the histopathological diagnosis.

<p>Mean difference analysis between the Shannon diversity index or the phylogenetic diversity whole tree and the histopathological diagnosis.</p

Association analysis between histopathological diagnosis and alpha diversity indexes.

<p>Association analysis between histopathological diagnosis and alpha diversity indexes.</p

Suggested mechanism of microbiome changes during immunosuppression development.

<p>The cervical epithelium is represented in each stage of CC as departing from a normal epithelium (left) and its longitudinal change when a HR-HPV infects it and it progresses to SIL and CC. Microbiome composition and diversity is depicted according to the main bacteria per stage. <i>Lactobacillus</i> are represented as purple rectangles, <i>Pseudomonas oleovorans</i> as red rectangles, <i>Fusobacterium</i> and <i>Sneathia</i> as shaped rods, <i>Streptococcus agalactie</i>as purple circles, and HPV as blue circles. After infection takes place, the microbiome changes and its diversity increases. HPV proteins E2, E6 and E7 enhance IL-10 expression and macrophages type 2 presence. The latter is also enhanced by TGFβ-1, which is in turn stimulated by the microbiota present. The diversity of the microbiota increases, through its toxins (FadA from <i>Fusobacterium spp</i>.), which disturb tight junctions and promote a metastasis similar to colon carcinoma.</p

Comparison of the Shannon diversity index and the PD whole tree logistic according to the histopathological diagnosis group.

<p>The boxplots show the distribution of the H’ (bit units) and PD values across all the samples.</p

Community composition of cervical samples at the species level as determined by massively parallel sequencing on the 454 platform.

<p>Unsupervised heatmap of the relative abundance of microbial taxa found in the cervical microbial communities of 29 subjects, based on the Bray Curtis dissimilarity metric. The species present in relative abundance of 1% in at least one sample are listed on the X axis. The first bar on the left side represents the treatment as follows: red–HPV-negative without lesion; blue–HPV-positive without lesion; orange–squamous intraepithelial cervical lesion; green–cervical cancer. CST are depicted in the second left barside; pink–CST III, dominated by <i>Pseudomonas oleovorans</i>; cyan–CST II dominated by <i>L</i>. <i>iners</i>; orange–CST I dominated by <i>L</i>. <i>crispatus</i>; green–CST IV dominated by <i>Sneathia</i>; blue–CST V dominated by <i>G</i>. <i>vaginalis</i>; yellow–CST VIII dominated by <i>Fusobacterium spp</i>.; red–CST VI dominated by <i>S</i>. <i>agalactiae</i>, and purple–CST VII dominated by <i>Fusobacterium necrophorum</i>. Sample names appear on the right side of the graph. The cladograms at the top of the species names indicate the approximate evolutionary relationships between the species. CST: Community State Type. Dx: Histopathological diagnosis.</p