Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
- Morris, Andrew, Le, Thu, Wu, Haojia, Akbarov, Artur, van der Most, Peter, Hemani, Gibran, Smith, George, Mahajan, Anubha, Gaulton, Kyle, Nadkarni, Girish, Valladares-Salgado, Adan, Wacher-Rodarte, Niels, Mychaleckyj, Josyf, Dueker, Nicole, Guo, Xiuqing, Hai, Yang, Haessler, Jeffrey, Kamatani, Yoichiro, Stilp, Adrienne, Zhu, Gu, Cook, James, Arnlov, Johan, Blanton, Susan, de Borst, Martin, Bottinger, Erwin, Buchanan, Thomas, Cechova, Sylvia, Charchar, Fadi, Chu, Pei-Lun, Damman, Jeffrey, Eales, James, Gharavi, Ali, Giedraitis, Vilmantas, Heath, Andrew, Ipp, Eli, Kiryluk, Krzysztof, Kramer, Holly, Kubo, Michiaki, Larsson, Anders, Lindgren, Cecilia, Lu, Yingchang, Madden, Pamela, Montgomery, Grant, Papanicolaou, George, Raffel, Leslie, Sacco, Ralph, Sanchez, Elena, Stark, Holger, Sundstrom, Johan, Taylor, Kent, Xiang, Anny, Zivkovic, Aleksandra, Lind, Lars, Ingelsson, Erik, Martin, Nicholas, Whitfield, John, Cai, Jianwen, Laurie, Cathy, Okada, Yukinori, Matsuda, Koichi, Kooperberg, Charles, Chen, Yii-Der, Rundek, Tatjana, Rich, Stephen, Loos, Ruth, Parra, Esteban, Cruz, Miguel, Rotter, Jerome, Snieder, Harold, Tomaszewski, Maciej, Humphreys, Benjamin, Franceschini, Nora
- Authors: Morris, Andrew , Le, Thu , Wu, Haojia , Akbarov, Artur , van der Most, Peter , Hemani, Gibran , Smith, George , Mahajan, Anubha , Gaulton, Kyle , Nadkarni, Girish , Valladares-Salgado, Adan , Wacher-Rodarte, Niels , Mychaleckyj, Josyf , Dueker, Nicole , Guo, Xiuqing , Hai, Yang , Haessler, Jeffrey , Kamatani, Yoichiro , Stilp, Adrienne , Zhu, Gu , Cook, James , Arnlov, Johan , Blanton, Susan , de Borst, Martin , Bottinger, Erwin , Buchanan, Thomas , Cechova, Sylvia , Charchar, Fadi , Chu, Pei-Lun , Damman, Jeffrey , Eales, James , Gharavi, Ali , Giedraitis, Vilmantas , Heath, Andrew , Ipp, Eli , Kiryluk, Krzysztof , Kramer, Holly , Kubo, Michiaki , Larsson, Anders , Lindgren, Cecilia , Lu, Yingchang , Madden, Pamela , Montgomery, Grant , Papanicolaou, George , Raffel, Leslie , Sacco, Ralph , Sanchez, Elena , Stark, Holger , Sundstrom, Johan , Taylor, Kent , Xiang, Anny , Zivkovic, Aleksandra , Lind, Lars , Ingelsson, Erik , Martin, Nicholas , Whitfield, John , Cai, Jianwen , Laurie, Cathy , Okada, Yukinori , Matsuda, Koichi , Kooperberg, Charles , Chen, Yii-Der , Rundek, Tatjana , Rich, Stephen , Loos, Ruth , Parra, Esteban , Cruz, Miguel , Rotter, Jerome , Snieder, Harold , Tomaszewski, Maciej , Humphreys, Benjamin , Franceschini, Nora
- Date: 2019
- Type: Text , Journal article
- Relation: Nature Communications Vol. 10, no. 1 (2019), p. 1-14
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- Description: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
- Authors: Morris, Andrew , Le, Thu , Wu, Haojia , Akbarov, Artur , van der Most, Peter , Hemani, Gibran , Smith, George , Mahajan, Anubha , Gaulton, Kyle , Nadkarni, Girish , Valladares-Salgado, Adan , Wacher-Rodarte, Niels , Mychaleckyj, Josyf , Dueker, Nicole , Guo, Xiuqing , Hai, Yang , Haessler, Jeffrey , Kamatani, Yoichiro , Stilp, Adrienne , Zhu, Gu , Cook, James , Arnlov, Johan , Blanton, Susan , de Borst, Martin , Bottinger, Erwin , Buchanan, Thomas , Cechova, Sylvia , Charchar, Fadi , Chu, Pei-Lun , Damman, Jeffrey , Eales, James , Gharavi, Ali , Giedraitis, Vilmantas , Heath, Andrew , Ipp, Eli , Kiryluk, Krzysztof , Kramer, Holly , Kubo, Michiaki , Larsson, Anders , Lindgren, Cecilia , Lu, Yingchang , Madden, Pamela , Montgomery, Grant , Papanicolaou, George , Raffel, Leslie , Sacco, Ralph , Sanchez, Elena , Stark, Holger , Sundstrom, Johan , Taylor, Kent , Xiang, Anny , Zivkovic, Aleksandra , Lind, Lars , Ingelsson, Erik , Martin, Nicholas , Whitfield, John , Cai, Jianwen , Laurie, Cathy , Okada, Yukinori , Matsuda, Koichi , Kooperberg, Charles , Chen, Yii-Der , Rundek, Tatjana , Rich, Stephen , Loos, Ruth , Parra, Esteban , Cruz, Miguel , Rotter, Jerome , Snieder, Harold , Tomaszewski, Maciej , Humphreys, Benjamin , Franceschini, Nora
- Date: 2019
- Type: Text , Journal article
- Relation: Nature Communications Vol. 10, no. 1 (2019), p. 1-14
- Full Text:
- Reviewed:
- Description: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
Molecular insights into genome-wide association studies of chronic kidney disease-defining traits
- Xu, Xiaoguang, Eales, James, Akbarov, Artur, Guo, Hui, Becker, Lorenz, Talavera, David, Ashraf, Fehzan, Nawaz, Jabran, Pramanik, Sanjeev, Bowes, John, Jiang, Xiao, Dormer, John, Denniff, Matthew, Antczak, Andrzej, Szulinska, Monika, Wise, Ingrid, Prestes, Priscilla, Glyda, Maciej, Bogdanski, Pawel, Zukowska-Szczechowska, Ewa, Berzuini, Carlo, Woolf, Adrian, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Xu, Xiaoguang , Eales, James , Akbarov, Artur , Guo, Hui , Becker, Lorenz , Talavera, David , Ashraf, Fehzan , Nawaz, Jabran , Pramanik, Sanjeev , Bowes, John , Jiang, Xiao , Dormer, John , Denniff, Matthew , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Prestes, Priscilla , Glyda, Maciej , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Berzuini, Carlo , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2018
- Type: Text , Journal article
- Relation: Nature communications Vol. 9, no. 1 (2018), p. 1-12
- Full Text:
- Reviewed:
- Description: Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.
- Authors: Xu, Xiaoguang , Eales, James , Akbarov, Artur , Guo, Hui , Becker, Lorenz , Talavera, David , Ashraf, Fehzan , Nawaz, Jabran , Pramanik, Sanjeev , Bowes, John , Jiang, Xiao , Dormer, John , Denniff, Matthew , Antczak, Andrzej , Szulinska, Monika , Wise, Ingrid , Prestes, Priscilla , Glyda, Maciej , Bogdanski, Pawel , Zukowska-Szczechowska, Ewa , Berzuini, Carlo , Woolf, Adrian , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2018
- Type: Text , Journal article
- Relation: Nature communications Vol. 9, no. 1 (2018), p. 1-12
- Full Text:
- Reviewed:
- Description: Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.
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