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Meta-Analysis
. 2017 Mar;28(3):981-994.
doi: 10.1681/ASN.2016020131. Epub 2016 Dec 5.

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function

Man Li  1   2 , Yong Li  3 , Olivia Weeks  4 , Vladan Mijatovic  5 , Alexander Teumer  6 , Jennifer E Huffman  7   8 , Gerard Tromp  9   10 , Christian Fuchsberger  11   12 , Mathias Gorski  13   14 , Leo-Pekka Lyytikäinen  15 , Teresa Nutile  16 , Sanaz Sedaghat  17 , Rossella Sorice  16 , Adrienne Tin  1 , Qiong Yang  18 , Tarunveer S Ahluwalia  19   20 , Dan E Arking  21 , Nathan A Bihlmeyer  21 , Carsten A Böger  14 , Robert J Carroll  22 , Daniel I Chasman  4   22   23 , Marilyn C Cornelis  24 , Abbas Dehghan  17 , Jessica D Faul  25 , Mary F Feitosa  26 , Giovanni Gambaro  27 , Paolo Gasparini  28 , Franco Giulianini  29 , Iris Heid  13   30 , Jinyan Huang  31   32 , Medea Imboden  33 , Anne U Jackson  12 , Janina Jeff  34 , Min A Jhun  35 , Ronit Katz  36 , Annette Kifley  37 , Tuomas O Kilpeläinen  19 , Ashish Kumar  33 , Markku Laakso  38 , Ruifang Li-Gao  17 , Kurt Lohman  39 , Yingchang Lu  34 , Reedik Mägi  40 , Giovanni Malerba  41 , Evelin Mihailov  40 , Karen L Mohlke  42 , Dennis O Mook-Kanamori  43   44 , Antonietta Robino  45 , Douglas Ruderfer  46 , Erika Salvi  47 , Ursula M Schick  48 , Christina-Alexandra Schulz  49 , Albert V Smith  50   51 , Jennifer A Smith  35 , Michela Traglia  52 , Laura M Yerges-Armstrong  53 , Wei Zhao  35 , Mark O Goodarzi  54   55 , Aldi T Kraja  56 , Chunyu Liu  7 , Jennifer Wessel  57   58 ; CHARGE Glycemic-T2D Working Group,; CHARGE Blood Pressure Working Group,; Eric Boerwinkle  59 , Ingrid B Borecki  26 , Jette Bork-Jensen  19 , Erwin P Bottinger  34 , Daniele Braga  47 , Ivan Brandslund  60 , Jennifer A Brody  61 , Archie Campbell  8 , David J Carey  9 , Cramer Christensen  62 , Josef Coresh  1 , Errol Crook  63 , Gary C Curhan  64 , Daniele Cusi  47   65 , Ian H de Boer  36 , Aiko P J de Vries  66 , Joshua C Denny  22 , Olivier Devuyst  67 , Albert W Dreisbach  68 , Karlhans Endlich  69 , Tõnu Esko  21   40   70   71 , Oscar H Franco  17 , Tibor Fulop  68 , Glenn S Gerhard  72 , Charlotte Glümer  73 , Omri Gottesman  34 , Niels Grarup  19 , Vilmundur Gudnason  50 , Torben Hansen  19   74 , Tamara B Harris  75 , Caroline Hayward  8   76 , Lynne Hocking  77 , Albert Hofman  17 , Frank B Hu  78 , Lise Lotte N Husemoen  73 , Rebecca D Jackson  79 , Torben Jørgensen  73 , Marit E Jørgensen  20 , Mika Kähönen  14 , Sharon L R Kardia  35 , Wolfgang König  80   81   82 , Charles Kooperberg  48 , Jennifer Kriebel  83   83 , Lenore J Launer  75 , Torsten Lauritzen  84 , Terho Lehtimäki  15 , Daniel Levy  7 , Pamela Linksted  8 , Allan Linneberg  73   85   74 , Yongmei Liu  86 , Ruth J F Loos  34 , Antonio Lupo  87 , Christine Meisinger  83 , Olle Melander  49 , Andres Metspalu  40 , Paul Mitchell  37 , Matthias Nauck  88   89 , Peter Nürnberg  90 , Marju Orho-Melander  49 , Afshin Parsa  91 , Oluf Pedersen  19 , Annette Peters  83   83   92 , Ulrike Peters  48 , Ozren Polasek  93 , David Porteous  8 , Nicole M Probst-Hensch  33 , Bruce M Psaty  61   94   95 , Lu Qi  78 , Olli T Raitakari  96 , Alex P Reiner  48 , Rainer Rettig  97 , Paul M Ridker  29   98 , Fernando Rivadeneira  99 , Jacques E Rossouw  100 , Frank Schmidt  101 , David Siscovick  61 , Nicole Soranzo  41 , Konstantin Strauch  83   102 , Daniela Toniolo  52 , Stephen T Turner  103 , André G Uitterlinden  99 , Sheila Ulivi  45 , Dinesh Velayutham  47 , Uwe Völker  89   101 , Henry Völzke  6   89   104 , Melanie Waldenberger  83   83 , Jie Jin Wang  37 , David R Weir  25 , Daniel Witte  105 , Helena Kuivaniemi  9   10 , Caroline S Fox  7 , Nora Franceschini  106 , Wolfram Goessling  4   20   107   108   109 , Anna Köttgen  110   3 , Audrey Y Chu  111   29
Collaborators, Affiliations
Meta-Analysis

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function

Man Li et al. J Am Soc Nephrol. 2017 Mar.

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 (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), 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, SOS2 (P=5.4×10-8 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 acp1- and sos2-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: human genetics; kidney development; renal function.

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Figures

Figure 1.
Figure 1.
Manhattan plot for single-variant analysis in eGFRcrea among 111,666 EA participants. Newly identified variants are in dark orange. The gene, ORC4, not successfully replicated, is in orange. Known loci are in blue.
Figure 2.
Figure 2.
sos2 and acp1 knockdowns result in defective kidney development. (A–D) Whole mount in situ hybridization in control embryos demonstrates normal expression of kidney markers, including pax2a (global kidney, A), slc20a1a (proximal tubules, B), and slc12a3 (distal tubules, C) at 48 hpf, and wt1a (podocytes, D) at 24 hpf. (E–L) sos2 and acp1 ATG morpholino (MO) knockdown embryos develop glomerular gene expression defects (E, I, arrowheads) and display elongated proximal tubules (F, J). Knockdown of acp1 shortened the distal tubules, whereas sos2 knockdown left distal tubule slc12a3 expression unaffected (G, K). No abnormalities in podocyte marker wt1a were observed for sos2 ATG- and acp1 ATG-MOs (H, L). (M) Quantitative assessment of proximal tubule length (slc20a1a expression) shows that proximal tubules are elongated in sos2 ATG- and acp1 ATG-MO injected embryos. t test used to calculate P values. (N) Table of observed abnormal embryos and total number examined by kidney markers pax2a, wt1a, and slc12a3, and MO-injected or control status. Fisher exact test used to calculate P values.
Figure 3.
Figure 3.
sos2 and acp1 knockdowns result in altered kidney function. (A) sos2 and acp1 morphants develop edema, which is a sign of kidney failure in zebrafish. sos2 morphants display severe global edema at 120 hpf, with fluid accumulation in the pericardium (black arrow) and intestinal tract (black star). At 96 hpf, acp1 morphants have severe pericardial edema (black arrow). (B–C) Incidence of edema and embryonic lethality in acp1 and sos2 morphants with Fisher exact test. *Indicates P value <0.05; **indicates P value <0.01; ***indicates P value <0.001. (D–I) Embryos were injected with control, sos2, or acp1 morpholino at the single cell stage and subsequently injected with 70 kDa molecular mass fluorescent rhodamine dextran at 72 hpf. Dextran fluorescence intensity was measured over 48 hpi. Dextran-injected embryos show equal loading at 2 hpi. Compared with control embryos, sos2 and acp1 MO injected embryos have reduced dextran clearance in the cardiovascular region over time. (J–L) Morphant embryos have altered convoluted tubule morphology at 120 hpf (48 hpi) (white arrows). (M) Dextran fluorescence intensity over time as normalized to starting fluorescence intensity.
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