A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
Tekijät: Chasman DI, Fuchsberger C, Pattaro C, Teumer A, Boger CA, Endlich K, Olden M, Chen MH, Tin A, Taliun D, Li M, Gao XY, Gorski M, Yang Q, Hundertmark C, Foster MC, O'Seaghdha CM, Glazer N, Isaacs A, Liu CT, Smith AV, O'Connell JR, Struchalin M, Tanaka T, Li G, Johnson AD, Gierman HJ, Feitosa MF, Hwang SJ, Atkinson EJ, Lohman K, Cornelis MC, Johansson A, Tonjes A, Dehghan A, Lambert JC, Holliday EG, Sorice R, Kutalik Z, Lehtimaki T, Esko T, Deshmukh H, Ulivi S, Chu AY, Murgia F, Trompet S, Imboden M, Coassin S, Pistis G, Harris TB, Launer LJ, Aspelund T, Eiriksdottir G, Mitchell BD, Boerwinkle E, Schmidt H, Cavalieri M, Rao M, Hu F, Demirkan A, Oostra BA, de Andrade M, Turner ST, Ding JZ, Andrews JS, Freedman BI, Giulianini F, Koenig W, Illig T, Meisinger C, Gieger C, Zgaga L, Zemunik T, Boban M, Minelli C, Wheeler HE, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Nothlings U, Jacobs G, Biffar R, Ernst F, Homuth G, Kroemer HK, Nauck M, Stracke S, Volker U, Volzke H, Kovacs P, Stumvoll M, Magi R, Hofman A, Uitterlinden AG, Rivadeneira F, Aulchenko YS, Polasek O, Hastie N, Vitart V, Helmer C, Wang JJ, Stengel B, Ruggiero D, Bergmann S, Kahonen M, Viikari J, Nikopensius T, Province M, Ketkar S, Colhoun H, Doney A, Robino A, Kramer BK, Portas L, Ford I, Buckley BM, Adam M, Thun GA, Paulweber B, Haun M, Sala C, Mitchell P, Ciullo M, Kim SK, Vollenweider P, Raitakari O, Metspalu A, Palmer C, Gasparini P, Pirastu M, Jukema JW, Probst-Hensch NM, Kronenberg F, Toniolo D, Gudnason V, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Siscovick DS, van Duijn CM, Borecki IB, Kardia SLR, Liu YM, Curhan GC, Rudan I, Gyllensten U, Wilson JF, Franke A, Pramstaller PP, Rettig R, Prokopenko I, Witteman J, Hayward C, Ridker PM, Parsa A, Bochud M, Heid IM, Kao WHL, Fox CS, Kottgen A
Kustantaja: OXFORD UNIV PRESS
Julkaisuvuosi: 2012
Journal: Human Molecular Genetics
Tietokannassa oleva lehden nimi: HUMAN MOLECULAR GENETICS
Lehden akronyymi: HUM MOL GENET
Numero sarjassa: 24
Vuosikerta: 21
Numero: 24
Aloitussivu: 5329
Lopetussivu: 5343
Sivujen määrä: 15
ISSN: 0964-6906
DOI: https://doi.org/10.1093/hmg/dds369
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.
