TY - JOUR
T1 - Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
AU - Chasman, Daniel I
AU - Fuchsberger, Christian
AU - Pattaro, Cristian
AU - Teumer, Alexander
AU - Böger, Carsten A
AU - Endlich, Karlhans
AU - Olden, Matthias
AU - Chen, Ming-Huei
AU - Tin, Adrienne
AU - Taliun, Daniel
AU - Li, Man
AU - Gao, Xiaoyi
AU - Gorski, Mathias
AU - Yang, Qiong
AU - Hundertmark, Claudia
AU - Foster, Meredith C
AU - O'Seaghdha, Conall M
AU - Glazer, Nicole
AU - Isaacs, Aaron
AU - Liu, Ching-Ti
AU - Smith, Albert V
AU - O'Connell, Jeffrey R
AU - Struchalin, Maksim
AU - Tanaka, Toshiko
AU - Li, Guo
AU - Johnson, Andrew D
AU - Gierman, Hinco J
AU - Feitosa, Mary F
AU - Hwang, Shih-Jen
AU - Atkinson, Elizabeth J
AU - Lohman, Kurt
AU - Cornelis, Marilyn C
AU - Johansson, Asa
AU - Tönjes, Anke
AU - Dehghan, Abbas
AU - Lambert, Jean-Charles
AU - Holliday, Elizabeth G
AU - Sorice, Rossella
AU - Kutalik, Zoltan
AU - Lehtimäki, Terho
AU - Esko, Tõnu
AU - Deshmukh, Harshal
AU - Ulivi, Sheila
AU - Chu, Audrey Y
AU - Murgia, Federico
AU - Trompet, Stella
AU - Imboden, Medea
AU - Coassin, Stefan
AU - Pistis, Giorgio
AU - Wang, Jie Jin
AU - CARDIoGRAM Consortium
PY - 2012/12/15
Y1 - 2012/12/15
N2 - In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
AB - In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
KW - Amino Acid Transport Systems, Basic/genetics
KW - Fusion Regulatory Protein 1, Heavy Chain/genetics
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study/methods
KW - Glomerular Filtration Rate/genetics
KW - Humans
KW - Inhibin-beta Subunits/genetics
KW - Intracellular Signaling Peptides and Proteins/genetics
KW - Low Density Lipoprotein Receptor-Related Protein-2/genetics
KW - Membrane Proteins/genetics
KW - Polymorphism, Single Nucleotide/genetics
U2 - 10.1093/hmg/dds369
DO - 10.1093/hmg/dds369
M3 - Article
C2 - 22962313
SN - 0964-6906
VL - 21
SP - 5329
EP - 5343
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 24
ER -