Less than half of human zygotes survive to birth, primarily due to aneuploidies of meiotic or mitotic origin. Mitotic errors generate chromosomal mosaicism, defined by multiple cell lineages with ...distinct chromosome complements. The incidence and impacts of mosaicism in human embryos remain controversial, with most previous studies based on bulk DNA assays or comparisons of multiple biopsies of few embryonic cells. Single-cell genomic data provide an opportunity to quantify mosaicism on an embryo-wide scale. To this end, we extended an approach to infer aneuploidies based on dosage-associated changes in gene expression by integrating signatures of allelic imbalance. We applied this method to published single-cell RNA sequencing data from 74 human embryos, spanning the morula to blastocyst stages. Our analysis revealed widespread mosaic aneuploidies, with 59 of 74 (80%) embryos harboring at least one putative aneuploid cell (1% FDR). By clustering copy number calls, we reconstructed histories of chromosome segregation, inferring that 55 (74%) embryos possessed mitotic aneuploidies and 23 (31%) embryos possessed meiotic aneuploidies. We found no significant enrichment of aneuploid cells in the trophectoderm compared to the inner cell mass, although we do detect such enrichment in data from later postimplantation stages. Finally, we observed that aneuploid cells up-regulate immune response genes and down-regulate genes involved in proliferation, metabolism, and protein processing, consistent with stress responses documented in other stages and systems. Together, our work provides a high-resolution view of aneuploidy in preimplantation embryos, and supports the conclusion that low-level mosaicism is a common feature of early human development.
Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to age-related macular degeneration (AMD)
. We generated transcriptional profiles of postmortem retinas ...from 453 controls and cases at distinct stages of AMD and integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at more than 9 million common SNPs for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets
. Cis-eQTL analysis identified 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. Integrated analysis of AMD-GWAS with eQTLs ascertained likely target genes at six reported loci. Using transcriptome-wide association analysis (TWAS), we identified three additional genes, RLBP1, HIC1 and PARP12, after Bonferroni correction. Our studies expand the genetic landscape of AMD and establish the Eye Genotype Expression (EyeGEx) database as a resource for post-GWAS interpretation of multifactorial ocular traits.
We evaluated whether markers of economic empowerment are associated with a tolerant attitude toward spousal physical violence (SPV) among employed married women in Nigeria. Cross-sectional analyses ...of responses to the 2013 Nigeria Demographic Health Survey by a nationally representative sample of 3,999 women aged 15 to 49 years who reported being employed and married. Tolerance for SPV was defined as supporting statements with justifications for wife-beating. Logistic regression assessed the associations of reporting tolerance for SPV with educational attainment and interspousal equivalency in income, controlling for previous exposure to domestic abuse. The prevalence of tolerance for SPV among the sample was 37%. Women with tertiary education had lower odds of tolerance for SPV relative to their counterparts without formal education (adjusted odds ratio aOR = 0.22, 95% confidence interval CI = 0.12, 0.40, p < .0001). Compared with women with similar income levels as their partners, women who either earned more (aOR = 2.77, 95% CI = 1.36, 5.62, p = .005) or earned less income relative to their spouses (aOR = 1.93, 95% CI = 1.14, 3.26, p = .02) had higher odds of tolerance for SPV. Odds of tolerance for SPV were also higher among women reporting previous spousal abuse than among their counterparts without such a history (aOR = 1.55, 95% CI = 1.14, 2.12, p = .006). A history of nonspousal abuse was associated with lower odds of tolerance for SPV (aOR = 0.56, 95% CI = 0.37, 0.84, p = .005). Lower educational attainment and interspousal differences in income may contribute to tolerance of SPV. Efforts to increase economic empowerment should be combined with education to recognize cultural norms that foster SPV and build skills to exit violent relationships.
In this study, we leveraged the combined evidence of rare coding variants and common alleles to identify therapeutic targets for osteoporosis. We undertook a large-scale multiancestry exome-wide ...association study for estimated bone mineral density, which showed that the burden of rare coding alleles in 19 genes was associated with estimated bone mineral density (P < 3.6 × 10
). These genes were highly enriched for a set of known causal genes for osteoporosis (65-fold; P = 2.5 × 10
). Exome-wide significant genes had 96-fold increased odds of being the top ranked effector gene at a given GWAS locus (P = 1.8 × 10
). By integrating proteomics Mendelian randomization evidence, we prioritized CD109 (cluster of differentiation 109) as a gene for which heterozygous loss of function is associated with higher bone density. CRISPR-Cas9 editing of CD109 in SaOS-2 osteoblast-like cell lines showed that partial CD109 knockdown led to increased mineralization. This study demonstrates that the convergence of common and rare variants, proteomics and CRISPR can highlight new bone biology to guide therapeutic development.
Rare mutations in
CIDEB
protect against liver disease, making the gene a candidate target for treatment. Suppression of CIDEB interferes with the formation of fat droplets in cells.
Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) ...from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10
), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.
Background: Statistical deconvolution strategies have emerged over the past decade to estimate the proportion of various cell populations in homogenate tissue sources like brain using gene expression ...data. However, no study has been undertaken to assess the extent to which expression-based and DNAm-based cell type composition estimates agree.
Results: Using estimated neuronal fractions from DNAm data, from the same brain region (i.e., matched) as our bulk RNA-Seq dataset, as proxies for the true unobserved cell-type fractions (i.e., as the gold standard), we assessed the accuracy (RMSE) and concordance (R
2) of four reference-based deconvolution algorithms: Houseman, CIBERSORT, non-negative least squares (NNLS)/MIND, and MuSiC. We did this for two cell-type populations - neurons and non-neurons/glia - using matched single nuclei RNA-Seq and mismatched single cell RNA-Seq reference datasets. With the mismatched single cell RNA-Seq reference dataset, Houseman, MuSiC, and NNLS produced concordant (high correlation; Houseman R
2 = 0.51, 95% CI 0.39, 0.65; MuSiC R
2 = 0.56, 95% CI 0.43, 0.69; NNLS R
2 = 0.54, 95% CI 0.32, 0.68) but biased (high RMSE,
>0.35) neuronal fraction estimates. CIBERSORT produced more discordant (moderate correlation; R
2 = 0.25, 95% CI 0.15, 0.38) neuronal fraction estimates, but with less bias (low RSME, 0.09). Using the matched single nuclei RNA-Seq reference dataset did not eliminate bias (MuSiC RMSE = 0.17).
Conclusions: Our results together suggest that many existing RNA deconvolution algorithms estimate the RNA composition of homogenate tissue, e.g. the amount of RNA attributable to each cell type, and not the cellular composition, which relates to the underlying fraction of cells.
Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 ...independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.
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•A multicohort study identifies 52 previously unknown osteoarthritis genetic risk variants•Similarities and differences in osteoarthritis genetic risk depend on joint sites•Osteoarthritis genetic components are associated with pain-related phenotypes•High-confidence effector genes highlight potential targets for drug intervention
A multicohort genome-wide association meta-analysis of osteoarthritis highlights the impact of joint site types on the features of genetic risk variants and the link between osteoarthritis genetics and pain-related phenotypes, pointing toward potential targets for therapeutic intervention.
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