Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Iglesias, A.; Mishra, Aniket; Vitart, Véronique; Bykhovskaya, Yelena; Höhn, René; Springelkamp, Henriët; Cuéllar-Partida, Gabriel; Gharahkhani, Puya; Bailey, Jessica N. Cooke; Willoughby, Colin E.; Li, Xiaohui; Yazar, Seyhan; Nag, Abhishek; Khawaja, Anthony P.; Polašek, Ozren; Siscovick, David S.; Mitchell, Paul; Tham, Yih Chung; Haines, Jonathan L.; Kearns, Lisa S.; Hayward, Caroline; Shi, Yuan; Leeuwen, Elisabeth M. van; Taylor, Kent D.; Wang, Jie Jin; Rochtchina, Elena; Attia, John; Scott, Rodney J.; Holliday, Elizabeth G.; Baird, Paul N.; Xie, Jing; Inouye, Michael; Viswanathan, Ananth C.; Sim, Xueling; Bonnemaijer, Pieter W.M.; Rotter, Jerome I.; Martin, Nicholas G.; Zeller, Tanja; Mills, Richard A.; Staffieri, Sandra E; Jonas, Jost B.; Schmidtmann, Irene; Boutin, Thibaud; Kang, Jae H.; Lucas, Sionne E. M.; Wong, Tien Yin; Beutel, Manfred E.; Wilson, James F.; Allingham, R. Rand; Brilliant, Murray H.; Budenz, Donald L.; Christen, William G.; Fingert, John H.; Friedman, David S.; Gaasterland, Douglas E.; Gaasterland, Terry; Hauser, Michael A.; Kraft, Peter; Lee, Richard K.; Lichter, Paul R.; Liu, Yutao; Loomis, Stephanie; Moroi, Sayoko E.; Pericak‐Vance, Margaret A.; Realini, Anthony; Richards, Julia E.; Schuman, Joel S.; Scott, William K.; Singh, Kuldev; Sit, Arthur J.; Vollrath, Douglas; Weinreb, Robert N.; Wollstein, Gadi; Zack, Donald J.; Zhang, Kang; Donnelly, Peter; Barroso, Inês; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher; Palmer, Colin N.A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen; Trembath, Richard; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Langford, Cordelia; Hunt, Sarah; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew J.; Weston, Paul A.; Widaa, Sara; Whittaker, Pamela; Uitterlinden, André G.; Vithana, Eranga N.; Foster, Paul J.; Hysi, Pirro G.; Hewitt, Alex W.; Khor, Chiea Chuen; Pasquale, Louis R.; Montgomery, Grant W.; Klaver, Caroline C W; Aung, Tin; Pfeiffer, Norbert; Mackey, David A.; Hammond, Christopher J; Cheng, Ching‐Yu; Craig, Jamie E; Rabinowitz, Yaron S.; Wiggs, Janey L.; Burdon, Kathryn P.; Duijn, Cornelia M. van; MacGregor, Stuart

doi:10.1038/s41467-018-03646-6

Cited by 81 publications

(97 citation statements)

References 69 publications

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“…Previous work has shown a central role of bone mesenchymal stem cells in osteoblast development (47,48). In addition, SNPs for several corneal traits are also enriched in mesenchymal stem cell peaks, consistent with previously observed enrichment of corneal thickness GWAS SNPs in mesenchymal stem cell/connective tissue cell annotations (49). Results using rat peaks projected into human coordinates largely mirror the human mesenchymal stem cell enrichment findings (Fig.…”

Section: Integration Of Cell-type-specific Atac-seq Peaks With Uk Biosupporting

confidence: 89%

Human and rat skeletal muscle single-nuclei multi-omic integrative analyses nominate causal cell types, regulatory elements, and SNPs for complex traits

Orchard

Manickam

Varshney

et al. 2020

Preprint

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AbstractBackgroundSkeletal muscle accounts for the largest proportion of human body mass, on average, and is a key tissue in complex diseases, mobility, and quality of life. It is composed of several different cell and muscle fiber types.ResultsHere, we optimize single-nucleus ATAC-seq (snATAC-seq) to map skeletal muscle cell-specific chromatin accessibility landscapes in frozen human and rat samples, and single-nucleus RNA-seq (snRNA-seq) to map cell-specific transcriptomes in human. We capture type I and type II muscle fiber signatures, which are generally missed by existing single-cell RNA-seq methods. We perform cross-modality and cross-species integrative analyses on 30,531 nuclei, representing 11 libraries, profiled in this study, and identify seven distinct cell types ranging in abundance from 63% (type II fibers) to 0.9% (muscle satellite cells) of all nuclei. We introduce a regression-based approach to infer cell types by comparing transcription start site-distal ATAC-seq peaks to reference enhancer maps and show consistency with RNA-based marker gene cell type assignments. We find heterogeneity in enrichment of genetic variants linked to complex phenotypes from the UK Biobank and diabetes genome wide association studies in cell-specific ATAC-seq peaks, with the most striking enrichment patterns in muscle mesenchymal stem cells (∼3% of nuclei). Finally, we overlay these chromatin accessibility maps on GWAS data to nominate causal cell types, SNPs, and transcription factor motifs for creatinine levels and type 2 diabetes signals.ConclusionsThese chromatin accessibility profiles for human and rat skeletal muscle cell types are a useful resource for investigating specific cell types and nominating causal GWAS SNPs and cell types.

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Section: Integration Of Cell-type-specific Atac-seq Peaks With Uk Biosupporting

confidence: 89%

Human and rat skeletal muscle single-nuclei multi-omic integrative analyses nominate causal cell types, regulatory elements, and SNPs for complex traits

Orchard

Manickam

Varshney

et al. 2020

Preprint

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“…COL5A1 mutations are found in classical Ehlers-Danlos Syndrome 50 , which is associated with thinner and steeper corneas 51 . COL5A1 is also a susceptibility locus for central corneal thickness 52,53 . THBS4 encodes an extracellular calcium binding protein that is involved in cell proliferation, adhesion, and migration 54 .…”

Section: Resultsmentioning

confidence: 99%

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Fan¹,

Pozarickij²,

Nyq.³

et al. 2020

Commun Biol

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ARTICLEGenome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error Qiao Fan et al. # Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia -a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

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“…CCT has a strong genetic component, with heritability estimates ranging between 0.68 and 0.95 [11][12][13] . Recently, Iglesias et al 14 reported 44 CCT-genomic regions in a cross-ancestry meta-analysis, including 19 novel loci awaiting independent replication. These 44 CCT-loci account for~8.5% of the variance for this ocular trait.…”

mentioning

confidence: 99%

A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness

Choquet

Melles²,

Yin

et al. 2020

Commun Biol

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Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide association studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly associated with keratoconus, and one (RAPSN rs3740685) was significantly associated with glaucoma after Bonferroni correction. Two-sample Mendelian randomization analysis suggests that thinner CCT does not causally increase the risk of primary open-angle glaucoma. This large CCT study explains up to 14.2% of CCT variance and increases substantially our understanding of the etiology of CCT variation. This may open new avenues of investigation into human ocular traits and their relationship to the risk of vision disorders.

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Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Cited by 81 publications

References 69 publications

Human and rat skeletal muscle single-nuclei multi-omic integrative analyses nominate causal cell types, regulatory elements, and SNPs for complex traits

Human and rat skeletal muscle single-nuclei multi-omic integrative analyses nominate causal cell types, regulatory elements, and SNPs for complex traits

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness

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