Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies

Morris, Andrew P.; Le, Thu H.; Wu, Hao; Akbarov, Artur; Most, Peter J. van der; Hemani, Gibran; Smith, George Davey; Mahajan, Anubha; Gaulton, Kyle J.; Nadkarni, Girish N.; Valladares‐Salgado, Adán; Wacher, Niels H.; Mychaleckyj, Josyf C.; Dueker, Nicole; Guo, Xiuqing; Hai, Yang; Haessler, Jeffrey; Kamatani, Yoichiro; Stilp, Adrienne M.; Zhu, Gu; Cook, James P.; Ärnlöv, Johan; Blanton, Susan H.; Borst, Martin H. de; Böttinger, Erwin P.; Buchanan, Thomas A.; Cechova, Sylvia; Charchar, Fadi J.; Chu, Pei Lun; Damman, Jeffrey; Eales, James; Gharavi, Ali G.; Giedraitis, Vilmantas; Heath, Andrew C.; Ipp, Eli; Kiryluk, Krzysztof; Kramer, Holly; Kubo, Michiaki; Larsson, Anders; Lindgren, Cecilia M.; Lu, Yingchang; Madden, Pamela A. F.; Montgomery, Grant W.; Papanicolaou, George; Raffel, Leslie J.; Sacco, Ralph L.; Sánchez, Elena; Stark, Holger; Sundström, Johan; Taylor, Kent D.; Xiang, Anny H.; Živković, Aleksandra; Lind, Lars; Ingelsson, Erik; Martin, Nicholas G.; Whitfield, John B.; Cai, Jianwen; Laurie, Cathy C.; Okada, Yukinori; Matsuda, Koichi; Kooperberg, Charles; Chen, Yii Der Ida; Rundek, Tatjana; Rich, Stephen S.; Loos, Ruth J.F.; Parra, Esteban J.; Cruz, Miguel; Rotter, Jerome I.; Snieder, Harold; Tomaszewski, Maciej; Humphreys, Benjamin D.; Franceschini, Nora

doi:10.1038/s41467-018-07867-7

Cited by 130 publications

(155 citation statements)

References 90 publications

(150 reference statements)

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“…We used lead SNPs from a trans-ethnic meta-analysis [3] of eGFR to evaluate the predictive power of an unweighted GRS into unrelated individuals in the Uganda population ( Table 2).…”

Section: Transferability Of Trans-ethnic Egfr Grs Into Ugandamentioning

confidence: 99%

“…The marked genomic diversity and allelic differentiation among populations in Africa, in combination with the substantially lower linkage disequilibrium (LD) among genetic variants, provides excellent opportunities to gain new insights into disease aetiology and genetic fine-mapping that have relevance for all ancestry groups. However, despite the value of conducting such research in Africa, there is no known genome-wide association study (GWAS) of kidney function in continental Africa, with published studies of African ancestry individuals being limited to African Americans [3,4] . Whilst African Americans typically have a large proportion of African ancestry, several studies have shown that the genetic architecture of African Americans is distinct from that of Africans from continental Africa [5].…”

Section: Introductionmentioning

confidence: 99%

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Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

Fatumo

Chikowore

Kalyesubula

et al. 2020

Preprint

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Genome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288 Ugandans and replicated the findings in 8224 African Americans. We identified two loci associated with eGFR at genome-wide significance (p<5x10 -8 ). The most significantly associated variant (rs2433603, p=2.4x10 -9 ) in GATM was distinct from previously reported signals. A second association signal mapping near HBB (rs141845179, p=3.0x10 -8 ) was not significant after conditioning on a previously reported SNP (rs334) for eGFR. However, fine-mapping analyses highlighted rs141845179 to be the most likely causal variant at the HBB locus (posterior probability of 0.61). A trans-ethnic GRS of eGFR constructed from previously reported lead SNPs was not predictive into the Ugandan population, indicating that additional large-scale efforts in Africa are necessary to gain further insight into the genetic architecture of kidney disease.

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“…We used lead SNPs from a trans-ethnic meta-analysis [3] of eGFR to evaluate the predictive power of an unweighted GRS into unrelated individuals in the Uganda population ( Table 2).…”

Section: Transferability Of Trans-ethnic Egfr Grs Into Ugandamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

Fatumo

Chikowore

Kalyesubula

et al. 2020

Preprint

Self Cite

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“…We also leveraged summary statistics manually downloaded from recent large association studies for Chronic Kidney Disease 39 , blood lipids 40 , Atrial Fibrillation, Type-II Diabetes, Coronary Artery Disease, estimated glomerular filtration rate 41 , albuminuria 42 , and anthropometric traits 43 . Two proteins, PDL2 and TNFRSF10C, had both cis and trans associations where the trans did not fall in a highly pleiotropic gene.…”

Section: Two-sample Mrmentioning

confidence: 99%

Whole genome sequencing analysis of the cardiometabolic proteome

Gilly

Park

Png

et al. 2019

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The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we comprehensively assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance through high-depth (22.5x) whole-genome sequencing (WGS) in 1,328 individuals. We discover 131 independent sequence variant associations (P<7.45×10−11) across the allele frequency spectrum, all of which replicate in an independent cohort (n=1,605, 18.4x WGS). We identify for the first time replicating evidence for rare-variant cis-acting protein quantitative trait loci for five genes, involving both coding and non-coding variation. We construct and validate polygenic scores that explain up to 45% of protein level variation. We find causal links between protein levels and disease risk, identifying high-value biomarkers and drug development targets.

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“…Reports on the association between kidney function decline and incident hypertension have been more limited 11 12 . Analysis of the causal effects of lower kidney function on higher blood pressure has inconsistent results 13 . Evaluating the causal relations between kidney function and blood pressure can inform disease prevention and treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

“…Haas et al showed evidence supporting the existence of a feed-forward loop between albuminuria, a marker of kidney damage, and hypertension 16 . Morris et al reported significant causal effect of lower kidney function on higher diastolic blood pressure (DBP) and not on systolic blood pressure (SBP) 13 . Two-sample Mendelian randomisation analysis is an extension of the Mendelian randomisation method that allows the use of summary statistics of genome-wide association studies (GWAS) for conducting Mendelian randomisation studies.…”

Section: Introductionmentioning

confidence: 99%

Kidney Function and Blood Pressure: A Bi-directional Mendelian Randomisation Study

Coresh

et al. 2019

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ObjectiveTo evaluate the bi-directional causal relation between kidney function and blood pressure. DesignMendelian randomisation study. SettingWe performed two-sample Mendelian randomisation analyses. Genetic instruments of kidney function traits were selected from summary statistics of genome-wide association studies (GWAS) of glomerular filtration rate estimated from serum creatinine (eGFRcr) and blood urea nitrogen (BUN) and were required to be associated with both eGFRcr and BUN to ensure that the instruments were more likely to represent the underlying kidney function. Genetic instruments of blood pressure were selected from summary statistics of GWAS of systolic and diastolic blood pressure. We investigated Mendelian randomisation hypothesis using several alternative approaches, including methods that are most robust to the presence of horizontal pleiotropy. ParticipantsThe summary statistics of eGFRcr included 567,460 participants from 54 cohorts, and the summary statistics of BUN included 243,031 participants from 48 cohorts from the Chronic Kidney Disease Genetics (CKDGen) Consortium. The summary statistics of systolic and diastolic blood pressure included 757,601 participants from the UK Biobank and 78 cohorts from the International Consortium for Blood Pressure (ICBP). ResultsSignificant evidence supported the causal effects of higher kidney function on lower blood pressure with multiple methods. Based on the mode-based Mendelian randomisation analysis approach, known for its robustness to the presence of pleiotropic effect, the effect estimate for 1 SD higher in eGFRcr was -0.17 SD unit (95 % CI: -0.09 to -0.24) in systolic blood pressure (SBP) and -0.15 SD unit (95% CI: -0.07 to -0.22) in diastolic blood pressure (DBP). In contrast, the causal effects of blood pressure on kidney function were not statistically significant. ConclusionsMendelian randomisation analyses support causal effects of higher kidney function on lower blood pressure. These results suggest preventing kidney function decline can reduce the public health burden of hypertension.

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Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies

Cited by 130 publications

References 90 publications

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans

Whole genome sequencing analysis of the cardiometabolic proteome

Kidney Function and Blood Pressure: A Bi-directional Mendelian Randomisation Study

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