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Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

ABSTRACT: Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

SUBMITTER: Franceschini N

PROVIDER: S-EPMC3484648 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Franceschini Nora N van Rooij Frank J A FJ Prins Bram P BP Feitosa Mary F MF Karakas Mahir M Eckfeldt John H JH Folsom Aaron R AR Kopp Jeffrey J Vaez Ahmad A Andrews Jeanette S JS Baumert Jens J Boraska Vesna V Broer Linda L Hayward Caroline C Ngwa Julius S JS Okada Yukinori Y Polasek Ozren O Westra Harm-Jan HJ Wang Ying A YA Del Greco M Fabiola F Glazer Nicole L NL Kapur Karen K Kema Ido P IP Lopez Lorna M LM Schillert Arne A Smith Albert V AV Winkler Cheryl A CA Zgaga Lina L Bandinelli Stefania S Bergmann Sven S Boban Mladen M Bochud Murielle M Chen Y D YD Davies Gail G Dehghan Abbas A Ding Jingzhong J Doering Angela A Durda J Peter JP Ferrucci Luigi L Franco Oscar H OH Franke Lude L Gunjaca Grog G Hofman Albert A Hsu Fang-Chi FC Kolcic Ivana I Kraja Aldi A Kubo Michiaki M Lackner Karl J KJ Launer Lenore L Loehr Laura R LR Li Guo G Meisinger Christa C Nakamura Yusuke Y Schwienbacher Christine C Starr John M JM Takahashi Atsushi A Torlak Vesela V Uitterlinden André G AG Vitart Veronique V Waldenberger Melanie M Wild Philipp S PS Kirin Mirna M Zeller Tanja T Zemunik Tatijana T Zhang Qunyuan Q Ziegler Andreas A Blankenberg Stefan S Boerwinkle Eric E Borecki Ingrid B IB Campbell Harry H Deary Ian J IJ Frayling Timothy M TM Gieger Christian C Harris Tamara B TB Hicks Andrew A AA Koenig Wolfgang W O' Donnell Christopher J CJ Fox Caroline S CS Pramstaller Peter P PP Psaty Bruce M BM Reiner Alex P AP Rotter Jerome I JI Rudan Igor I Snieder Harold H Tanaka Toshihiro T van Duijn Cornelia M CM Vollenweider Peter P Waeber Gerard G Wilson James F JF Witteman Jacqueline C M JC Wolffenbuttel Bruce H R BH Wright Alan F AF Wu Qingyu Q Liu Yongmei Y Jenny Nancy S NS North Kari E KE Felix Janine F JF Alizadeh Behrooz Z BZ Cupples L Adrienne LA Perry John R B JR Morris Andrew P AP

American journal of human genetics 20120927 4

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC ...[more]

PMID: 23022100

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Project description:Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women's Health Initiative. Loci attaining genome-wide significant evidence for association (P < 5 × 10-8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10-8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10-8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.

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Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Publications

Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

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