Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

TitleIntegration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.
Publication TypeJournal Article
Year of Publication2012
AuthorsChasman DI, Fuchsberger C, Pattaro C, Teumer A, Böger CA, Endlich K, Olden M, Chen M-H, Tin A, Taliun D et al.
Corporate AuthorsCARDIoGRAM consortium, ICBP Consortium, CARe Consortium, WTCCC2
JournalHum Mol Genet
Date Published2012 Dec 15
KeywordsAmino Acid Transport Systems, Basic, Antigens, CD98 Heavy Chain, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Inhibin-beta Subunits, Intracellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-2, Membrane Proteins, Polymorphism, Single Nucleotide

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.

Alternate JournalHum. Mol. Genet.
PubMed ID22962313
PubMed Central IDPMC3607468
Grant ListF32 CA165823 / CA / NCI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
R01 CA047988 / CA / NCI NIH HHS / United States
R01 HL043851 / HL / NHLBI NIH HHS / United States
R01 HL080467 / HL / NHLBI NIH HHS / United States

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