New concepts on the etiology of endometriosis DOI Creative Commons
Fiona L. Cousins, Brett McKinnon, Sally Mortlock

et al.

Journal of Obstetrics and Gynaecology Research, Journal Year: 2023, Volume and Issue: 49(4), P. 1090 - 1105

Published: Feb. 6, 2023

Abstract Endometriosis is a serious, chronic disorder where endometrial tissue grows outside the uterus, causing severe pelvic pain and infertility. It affects 11% of women. multifactorial unclear etiology, although retrograde menstruation plays major role. has genetic component with over 40 risk factors mapped, their mechanism action still emerging. New evidence suggests role for stem/progenitor cells, now that identifying markers these cells are available. Recent lineage tracing clearing microscopy 3D reconstruction provided new understanding glandular structure, particularly horizontal orientation interconnection basalis glands. sequencing technologies, whole genome DNA revealing somatic mutations, including in cancer driver genes, normal eutopic endometrium patients endometriosis, as well ectopic endometriotic lesions. Methylome offering insight into regulation genes environmental factors. Single cell RNA reveals transcriptome individual shedding light on diversity range cellular subpopulations types present epithelial organoid cultures replicating epithelium providing tractable models studying endometriosis. Organoids derived from menstrual fluid offer non‐invasive source avenue testing drugs developing personalized medicine treating These approaches rapidly advancing our endometriosis etiology.

Language: Английский

Single-cell eQTL mapping identifies cell type–specific genetic control of autoimmune disease DOI
Seyhan Yazar, José Alquicira-Hernández, Kristof Wing

et al.

Science, Journal Year: 2022, Volume and Issue: 376(6589)

Published: April 7, 2022

The human immune system displays substantial variation between individuals, leading to differences in susceptibility autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from 1,267,758 peripheral blood mononuclear cells 982 healthy subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing type-specific effects on gene expression. subsequently show how eQTLs have dynamic allelic B that are transitioning naïve memory states demonstrate commonly segregating alleles lead interindividual function. Finally, using a Mendelian randomization approach, identify the causal route by which 305 risk contribute disease at cellular level. This work brings together genetic epidemiology scRNA-seq uncover drivers of system.

Language: Английский

Citations

342
Systematic differences in discovery of genetic effects on gene expression and complex traits DOI
Hakhamanesh Mostafavi, Jeffrey P. Spence,

Sahin Naqvi

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(11), P. 1866 - 1875

Published: Oct. 19, 2023

Language: Английский

Citations

157
Using genetic association data to guide drug discovery and development: Review of methods and applications DOI Creative Commons
Stephen Burgess, Amy M. Mason, Andrew J. Grant

et al.

The American Journal of Human Genetics, Journal Year: 2023, Volume and Issue: 110(2), P. 195 - 214

Published: Feb. 1, 2023

Language: Английский

Citations

101
The missing link between genetic association and regulatory function DOI Creative Commons
Noah J Connally,

Sumaiya Nazeen,

Daniel Lee

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Dec. 14, 2022

The genetic basis of most traits is highly polygenic and dominated by non-coding alleles. It widely assumed that such alleles exert small regulatory effects on the expression cis -linked genes. However, despite availability gene epigenomic datasets, few variant-to-gene links have emerged. unclear whether these sparse results are due to limitations in available data methods, or deficiencies underlying model. To better distinguish between possibilities, we identified 220 gene–trait pairs which protein-coding variants influence a complex trait its Mendelian cognate. Despite presence quantitative loci near GWAS associations, applying gene-based approach found limited evidence baseline trait-related genes explains using colocalization methods (8% implicated), transcription-wide association (2% combination annotations distance (4% implicated). These contradict hypothesis trait-associated coincide with homeostatic QTLs, suggesting models needed. field must confront this deficit pursue ‘missing regulation.’

Language: Английский

Citations

100
Limited overlap of eQTLs and GWAS hits due to systematic differences in discovery DOI Creative Commons
Hakhamanesh Mostafavi, Jeffrey P. Spence,

Sahin Naqvi

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: May 8, 2022

Abstract Most signals in genome-wide association studies (GWAS) of complex traits point to noncoding genetic variants with putative gene regulatory effects. However, currently identified expression quantitative trait loci (eQTLs) explain only a small fraction GWAS signals. By analyzing hits for the UK Biobank, and cis-eQTLs from GTEx consortium, we show that these assays systematically discover different types genes variants: eQTLs cluster strongly near transcription start sites, while do not. Genes are enriched numerous functional annotations, under strong selective constraint have landscape across tissue/cell types, depleted most relaxed constraint, simpler landscapes. We describe model understand observations, including how natural selection on hinders discovery functionally-relevant eQTLs. Our results imply eQTL biased toward variants, support use complementary approaches alongside next generation studies.

Language: Английский

Citations

91
Adipose tissue at single-cell resolution DOI Creative Commons
Babukrishna Maniyadath, Qianbin Zhang, Rana K. Gupta

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(3), P. 386 - 413

Published: March 1, 2023

Language: Английский

Citations

82
Single-cell genomics meets human genetics DOI
Anna Cuomo, Aparna Nathan, Soumya Raychaudhuri

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(8), P. 535 - 549

Published: April 21, 2023

Language: Английский

Citations

74
An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development DOI Creative Commons
Zeshuai Wang, Zhisheng Wu, Hao Wang

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4454 - 4471.e19

Published: Sept. 1, 2023

Language: Английский

Citations

65
Molecular quantitative trait loci DOI
François Aguet, Kaur Alasoo, Yang Li

et al.

Nature Reviews Methods Primers, Journal Year: 2023, Volume and Issue: 3(1)

Published: Jan. 25, 2023

Language: Английский

Citations

52
Common genetic factors among autoimmune diseases DOI
Adil Harroud, David A. Hafler

Science, Journal Year: 2023, Volume and Issue: 380(6644), P. 485 - 490

Published: May 4, 2023

Autoimmune diseases display a high degree of comorbidity within individuals and families, suggesting shared risk factors. Over the past 15 years, genome-wide association studies have established polygenic basis these common conditions revealed widespread sharing genetic effects, indicative immunopathology. Despite ongoing challenges in determining precise genes molecular consequences variants, functional experiments integration with multimodal genomic data are providing valuable insights into key immune cells pathways driving diseases, potential therapeutic implications. Moreover, ancient populations shedding light on contribution pathogen-driven selection pressures to increased prevalence autoimmune disease. This Review summarizes current understanding disease genetics, including mechanisms, evolutionary origins.

Language: Английский

Citations

47