Discovery of novel eGFR-associated multiple independent signals using a quasi-adaptive method
A decreased estimated glomerular filtration rate (eGFR) leading to chronic kidney disease is a significant public health problem. Kidney function is a heritable trait, and recent application of genome-wide association studies (GWAS) successfully identified multiple eGFR-associated genetic loci. To i...
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| Published in: | Frontiers in genetics Vol. 13; p. 997302 |
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| Main Authors: | , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Switzerland
Frontiers Media S.A
31.10.2022
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| Subjects: | |
| ISSN: | 1664-8021, 1664-8021 |
| Online Access: | Get full text |
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| Summary: | A decreased estimated glomerular filtration rate (eGFR) leading to chronic kidney disease is a significant public health problem. Kidney function is a heritable trait, and recent application of genome-wide association studies (GWAS) successfully identified multiple eGFR-associated genetic loci. To increase statistical power for detecting independent associations in GWAS loci, we improved our recently developed quasi-adaptive method estimating SNP-specific alpha levels for the conditional analysis, and applied it to the GWAS meta-analysis results of eGFR among 783,978 European-ancestry individuals. Among known eGFR loci, we revealed 19 new independent association signals that were subsequently replicated in the United Kingdom Biobank (n = 408,608). These associations have remained undetected by conditional analysis using the established conservative genome-wide significance level of 5 × 10
–8
. Functional characterization of known index SNPs and novel independent signals using colocalization of conditional eGFR association results and gene expression in
cis
across 51 human tissues identified two potentially causal genes across kidney tissues:
TSPAN33
and
TFDP2
, and three candidate genes across other tissues:
SLC22A2, LRP2
, and
CDKN1C
. These colocalizations were not identified in the original GWAS. By applying our improved quasi-adaptive method, we successfully identified additional genetic variants associated with eGFR. Considering these signals in colocalization analyses can increase the precision of revealing potentially functional genes of GWAS loci. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Weiqiu Cheng, University of Oslo, Norway Edited by: Yaowu Liu, Southwestern University of Finance and Economics, China This article was submitted to Statistical Genetics and Methodology, a section of the journal Frontiers in Genetics Ryan Sun, University of Texas MD Anderson Cancer Center, United States Reviewed by: Elise Flynn, Columbia University, United States |
| ISSN: | 1664-8021 1664-8021 |
| DOI: | 10.3389/fgene.2022.997302 |