@article {12133, title = {SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {Journal of the American Society of Nephrology }, volume = {28}, year = {2017}, pages = {981-994}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7{\texttimes}10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4{\texttimes}10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, keywords = {Animals, Exome, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, kidney, Protein Tyrosine Phosphatases, Proto-Oncogene Proteins, Son of Sevenless Proteins, Zebrafish}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Dan E Arking and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Daniel I Chasman and Marilyn C Cornelis and Dehghan, Abbas and Jessica Faul and Feitosa, Mary F and Gambaro, Giovanni and Paolo P. Gasparini and Giulianini, Franco and Iris M Heid and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Janina Jeff and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Kurt Lohman and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Dennis O Mook-Kanamori and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Laura M Yerges-Armstrong and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Ingrid B Borecki and Bork-Jensen, Jette and Erwin P Bottinger and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Cramer Christensen and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and T{\~o}nu Esko and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Hansen, Torben and Tamara B Harris and Caroline Hayward and Lynne J Hocking and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Sharon L R Kardia and K{\"o}nig, Wolfgang and Charles Kooperberg and Kriebel, Jennifer and Lenore J Launer and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Ruth J F Loos and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Andres Metspalu and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and David J Porteous and Nicole M Probst-Hensch and Psaty, Bruce M and Qi, Lu and Olli T Raitakari and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Fernando Rivadeneira and Rossouw, Jacques E and Schmidt, Frank and David S Siscovick and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Stephen T Turner and Andr{\'e} G Uitterlinden and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and David R Weir and Daniel Witte and Kuivaniemi, Helena and Caroline S Fox and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {8604, title = {Genetic diversity is a predictor of mortality in humans.}, journal = {BMC Genet}, volume = {15}, year = {2014}, month = {2014 Dec 29}, pages = {159}, abstract = {

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person{\textquoteright}s risk of death by 1.57\%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

}, keywords = {Genome-Wide Association Study, Heterozygote, Humans, Mortality, Polymorphism, Single Nucleotide, Proportional Hazards Models}, issn = {1471-2156}, doi = {10.1186/s12863-014-0159-7}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301661/}, author = {Bihlmeyer, Nathan A and Brody, Jennifer A and Albert Vernon Smith and Kathryn L Lunetta and Michael A Nalls and Jennifer A Smith and Toshiko Tanaka and Gail Davies and Lei Yu and Saira S Mirza and Teumer, Alexander and Coresh, Josef and Pankow, James S and Franceschini, Nora and Scaria, Anish and Oshima, Junko and Psaty, Bruce M and Gudnason, Vilmundur and Gu{\dh}ny Eir{\'\i}ksd{\'o}ttir and Tamara B Harris and Li, Hanyue and Karasik, David and Douglas P Kiel and Melissa E Garcia and Yongmei Liu and Jessica Faul and Sharon L R Kardia and Wei Zhao and Luigi Ferrucci and Allerhand, Michael and David C Liewald and Redmond, Paul and John M Starr and Philip L de Jager and Nese Direk and Mohammed Arfan Ikram and Andr{\'e} G Uitterlinden and Homuth, Georg and Lorbeer, Roberto and Hans-J{\"o}rgen Grabe and Lenore J Launer and Joanne M Murabito and Andrew B Singleton and David R Weir and Bandinelli, Stefania and Ian J Deary and David A Bennett and Henning Tiemeier and Kocher, Thomas and Lumley, Thomas and Dan E Arking} }