1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

1 Scien i ic RepoR s | 7:45040 | DOI: 10.1038/s ep45040 www.na u e.com/scien i ic epo s 1000 Genomes-based me a- analysis iden i ies 10 no el loci o kidney unc ion Ma hias Go ski1,2,*, Pe e J. an de Mos 3,*, Alexande Teume 4,*, Aud ey Y. Chu5,6,*, Man Li7,8, Vladan Mija o ic9, Ilja M. Nol e3, Massimiliano Cocca10,11, Daniel Taliun12, Felicia Gomez13, Yong Li14, Bamidele Tayo15, Ad ienne Tin7, Ma y F. Fei osa13, Tho Aspelund16,17, John A ia18,19, Reine Bi a 20, Mu ielle Bochud21, E ic Boe winkle22, Ing id Bo ecki23, E win P. Bo inge 24, Ming-Huei Chen5, Vincen Chou aki25, Ma ina Ciullo26,27, Jose Co esh7, Ma ilyn C. Co nelis28, Ga y C. Cu han29,30, Adamo Pio d’Adamo31, Abbas Dehghan32, Lau a Dengle 2, Jingzhong Ding33, Gudny Ei iksdo i 16, Ka lhans Endlich34, S e an En o h35, Tõnu Esko36, Osca H. F anco32, Paolo Gaspa ini37,38, Ch is ian Giege 39,40,41, Gio gia Gi o o37,38, Om i Go esman24, Vilmundu Gudnason16,42, Ul Gyllens en35, S ephen J. Hancock18,43, Tama a B. Ha is44, Ca he ine Helme 45,46, Simon Hölle e 1, Edi h Ho e 47,48, Albe Ho man32, Elizabe h G. Holliday19, Geo g Homu h49, F ank B. Hu50, Co nelia Hu h41,51, Nina Hu i-Kähönen52, Shih-Jen Hwang5, Medea Imboden53,54, Åsa Johansson35, Mika Kähönen55,56, Wol gang König57,58,59, Holly K ame 15, Be nha d K. K äme 60, Ashish Kuma 53,54,61, Zol an Ku alik21, Jean-Cha les Lambe 25, Leno e J. Laune 44, Te ho Leh imäki62,63, Ma in H. de Bo s 64, Ge jan Na is64, Mo is Swe z64, Yongmei Liu33, Ku Lohman33, Ru h J. F. Loos24,65, Yingchang Lu24, Leo-Pekka Lyy ikäinen62,63, Ma k A. McE oy18, Ch is a Meisinge 41, Thomas Mei inge 66,67, And es Me spalu36, Ma ie Me zge 68, E elin Mihailo 36, Paul Mi chell69, Ma hias Nauck70,71, Albe ine J. Oldehinkel72, Ma hias Olden1,5, B enda WJH Penninx73, Gio gio Pis is10, Pe e P. P ams alle 12, Nicole P obs -Hensch53,54, Olli T. Rai aka i74,75, Raine Re ig76, Paul M. Ridke 6,77, Fe nando Ri adenei a78, An onie a Robino38, Syl ia E. Rosas79, Douglas Rude e 24, Daniela Ruggie o26, Yasaman Saba80, Cinzia Sala10, Helena Schmid 80, Reinhold Schmid 47, Rodney J. Sco 81,82, Sanaz Sedagha 32, Albe V. Smi h16,42, Rossella So ice26,27, Benedic e S engel68, Syl ia S acke83, Kons an in S auch39,84, Daniela Toniolo10, And e G. Ui e linden78, Sheila Uli i38, Jo ma S. Viika i85,86, Uwe Völke 49,71, Pe e Vollenweide 87, Hen y Völzke4,71,88, D agana Vucko ic37,38, Melanie Waldenbe ge 40,41, Jie Jin Wang69, Qiong Yang89, Daniel I. Chasman6,90,91, Ge a d T omp92, Ha old Sniede 3, I is M. Heid1, Ca oline S. Fox5, Anna Kö gen14,93,†, C is ian Pa a o12,†, Ca s en A. Böge 2,† & Ch is ian Fuchsbe ge 12,† 1Depa men o Gene ic Epidemiology, Uni e si y Regensbu g, Regensbu g, Ge many. 2Depa men o Neph ology, Uni e si y Hospi al Regensbu g, Regensbu g, Ge many. 3Depa men o Epidemiology, Uni e si y o G oningen, Uni e si y Medical Cen e G oningen, P.O. box 30.001, 9700 RB G oningen, The Ne he lands. 4Ins i u e o Communi y Medicine, Uni e si y Medicine G ei swald, Wal he -Ra henau-S . 48, 17475 G ei swald, Ge many. 5NHLBI’s F amingham Hea S udy, F amingham, MA 01702, USA. 6Di ision o P e en i e Medicine, B igham and Women’s Hospi al and Ha a d Medical School, Bos on, MA, 02215, USA. 7Depa men o Epidemiology, Johns Hopkins Bloombe g School o Public Heal h, 615N Wol e S , Bal imo e, MD, 21205, USA. 8Di ision o Neph ology and Depa men o Human Gene ics, Uni e si y o U ah, USA. 9Depa men o Li e and Rep oduc ion Sciences, Uni e si y o Ve ona, S ada Le G azie 8, 37134, Ve ona, I aly. 10Di ision o Gene ics and Cell Biology, San Ra aele Scien i ic Ins i u e, 20132, Milano, I aly. 11Depa men o Medical, Su gical and Heal h Sciences, Uni e si y o T ies e, 34100, T ies e, I aly. 12Cen e o Biomedicine, Eu opean Academy o Bozen/Bolzano (EURAC), a ilia ed o he Uni e si y o Lübeck, Bolzano, I aly. 13Di ision o S a is ical Genomics, Depa men o Gene ics, Washing on Uni e si y School o Medicine, S Louis, MO, 63108, USA. 14Di ision o Gene ic Epidemiology, Medical Cen e and Facul y o Medicine - Uni e si y o F eibu g, F eibu g, Ge many. 15Loyola Uni e si y Chicago, 2160 Sou h Fi s A enue, Bldg 105, Maywood, IL 60153, USA. 16Icelandic Hea Associa ion, Kopa ogu , Iceland. 17Uni e si y o Iceland, Reykja ik, Iceland. 18School o Medicine and Public Heal h, Uni e si y o Newcas le, Aus alia. 19Public Heal h P og am, Hun e Medical Resea ch Ins i u e, Newcas le, New Sou h Wales, Aus alia. 20Clinic o P os hodon ic Den is y, Ge os oma ology and Ma e ial Science, Uni e si y Medicine G ei swald, Fe dinand- Saue b uch-S ., 17475 G ei swald, Ge many. 21Ins i u e o Social and P e en i e Medicine, Lausanne Uni e si y Hospi al (CHUV), Rou e de la Co niche 10, 1010, Lausanne, Swi ze land. 22Uni e si y o Texas Heal h Science Recei ed: 14 Oc obe 2016 Accep ed: 20 Feb ua y 2017 Published: 28 Ap il 2017 OPEN www.na u e.com/scien i ic epo s/ 2 Scien i ic RepoR s | 7:45040 | DOI: 10.1038/s ep45040 Cen e a Hous on, USA. 23Regene on Gene ics Cen e , Regene on Pha maceu icals, Ta y own, NY, USA. 24The Cha les B on man Ins i u e o Pe sonalized Medicine, Ichan School o Medicine a Moun Sinai, USA. 25Inse m U1167, Lille Uni e si y, Ins i u Pas eu de Lille, Lille, F ance. 26Ins i u e o Gene ics and Biophysics, “Ad iano Buzza i-T a e so”-CNR, Via P. Cas ellino 111, 80131 Napoli, I aly. 27IRCCS Neu omed, ia dell’Ele onica, Pozzilli (Is), I aly. 28Depa men o P e en i e Medicine, No hwes e n Uni e si y Feinbe g School o Medicine, 680 N Lake Sho e D i e, Sui e 1400 Chicago, IL 60611, USA. 29Renal Di ision, B igham and Women’s Hospi al, USA. 30Channing Di ision o Ne wo k Medicine, B igham and Women’s Hospi al, Bos on, MA, USA. 31Clinical Depa men o Medical, Su gical and Heal h Science, Uni e si y o T ies e, I aly. 32Depa men o Epidemiology, E asmus Medical Cen e , Ro e dam, The Ne he lands. 33Wake Fo es School o Medicine, USA. 34Ins i u e o Ana omy and Cell Biology, Uni e si y Medicine G ei swald, F ied ich-Loe le -S . 23c, 17475 G ei swald, Ge many. 35Depa men o Immunology, Gene ics, and Pa hology, Biomedical Cen e , SciLi eLab Uppsala, Uppsala Uni e si y, SE-75108 Uppsala, Sweden. 36Es onian Genome Cen e , Uni e si y o Ta u, Ta u, Es onia. 37Depa men o Medical Sciences, Chi u gical and Heal h Depa men , Uni e si y o T ies e, T ies e, I aly. 38Ins i u e o Ma e nal and Child Heal h - IRCCS “Bu lo Ga o olo”, T ies e, I aly. 39Ins i u e o Gene ic Epidemiology, Helmhol z Zen um München, Ge man Resea ch Cen e o En i onmen al Heal h, Ingols äd e Lands . 1, 85764 Neuhe be g, Ge many. 40Resea ch Uni o Molecula Epidemiology, Helmhol z Zen um München - Ge man Resea ch Cen e o En i onmen al Heal h, Neuhe be g, Ge many. 41Ins i u e o Epidemiology II, Helmhol z Zen um München, Ge man Resea ch Cen e o En i onmen al Heal h, Ingols äd e Lands . 1, 85764 Neuhe be g, Ge many. 42Facul y o Medicine, Uni e si y o Iceland, Reykja ik, Iceland. 43Heal h Se ices Resea ch G oup, Uni e si y o Newcas le, Aus alia. 44In amu al Resea ch P og am, Labo a o y o Epidemiology and Popula ion S udies, Na ional Ins i u e on Aging, USA. 45INSERM, Cen e INSERM Resea ch Cen e U1219, Bo deaux, F ance. 46Uni e si y Bo deaux, ISPED, Bo deaux, F ance. 47Clinical Di ision o Neu oge ia ics, Depa men o Neu ology, Medical Uni e si y o G az, Aus ia. 48Ins i u e o Medical In o ma ics, S a is ics and Documen a ion, Medical Uni e si y o G az, Aus ia. 49In e acul y Ins i u e o Gene ics and Func ional Genomics, Uni e si y Medicine G ei swald, F ied ich-Ludwig-Jahn-S . 15a, 17475 G ei swald, Ge many. 50Depa men o Nu i ion, Ha a d School o Public Heal h and Channing Di ision o Ne wo k Medicine, B igham and Women’s Hospi al, USA. 51Ge man Cen e o Diabe es Resea ch (DZD), Neuhe be g, Ge many. 52Depa men o Pedia ics, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e 33014, Finland. 53Uni Ch onic Disease Epidemiology, Swiss T opical and Public Heal h Ins i u e, Basel, Swi ze land. 54Uni e si y o Basel, Swi ze land. 55Depa men o Clinical Physiology, Tampe e Uni e si y Hospi al, Tampe e 33521, Finland. 56Depa men o Clinical Physiology, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e 33014, Finland. 57Deu sches He zzen um München, Technische Uni e si ä München, Munich, Ge many. 58DZHK (Ge man Cen e o Ca dio ascula Resea ch), pa ne si e Munich Hea Alliance, Munich, Ge many. 59Depa men o In e nal Medicine II - Ca diology, Uni e si y o Ulm Medical Cen e , Ulm, Ge many. 60Uni e si y Medical Cen e Mannheim, 5 h Depa men o Medicine, Uni e si y o Heidelbe g, Theodo Ku ze U e 1–3, 68167 Mannheim, Ge many. 61Ins i u e o En i onmen al Medicine, Ka olinska Ins i u e, S ockholm, Sweden. 62Depa men o Clinical Chemis y, Fimlab Labo a o ies, Tampe e 33520, Finland. 63Depa men o Clinical Chemis y, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e 33014, Finland. 64Uni e si y Medical Cen e G oningen, Uni e si y o G oningen, The Ne he lands. 65The Mindich Child Heal h De elopmen Ins i u e, Icahn School o Medicine a Moun Sinai, USA. 66Ins i u e o Human Gene ics, Helmhol z Zen um München, Ge man Resea ch Cen e o En i onmen al Heal h, Neuhe be g, Ge many. 67Ins i u e o Human Gene ics, Technische Uni e si ä München, Munich, Ge many. 68Inse m U1018, Uni e si y Pa is-Sud, UVSQ, Uni e si y Pa is-Saclay, Villejui , F ance. 69Cen e o Vision Resea ch, Depa men o Oph halmology and Wes mead Ins i u e o Medical Resea ch, Uni e si y o Sydney C24, NSW, 2145, Aus alia. 70Ins i u e o Clinical Chemis y and Labo a o y Medicine-Uni e si y Medicine G ei swald, Fe dinand-Saue b uch-S ., 17475 G ei swald, Ge many. 71DZHK (Ge man Cen e o Ca dio ascula Resea ch), pa ne si e G ei swald, G ei swald, Ge many. 72Depa men o Psychia y, Uni e si y o G oningen, Uni e si y Medical Cen e G oningen, P.O. box 30.001, 9700 RB, G oningen, The Ne he lands. 73Depa men o Psychia y, V ije Uni e si ei , VU Uni e si y Medical Cen e , NESDA, A.J. E ns s aa 1187, 1081HL Ams e dam, The Ne he lands. 74Depa men o Clinical Physiology and Nuclea Medicine, Tu ku Uni e si y Hospi al, Tu ku 20521, Finland. 75Resea ch Cen e o Applied and P e en i e Ca dio ascula Medicine, Uni e si y o Tu ku, Tu ku 20520, Finland. 76Ins i u e o Physiology, Uni e si y Medicine G ei swald, 17475 G ei swald, Ge many. 77Di ision o Ca dio ascula Medicine, B igham and Women’s Hospi al and Ha a d Medical School, Bos on MA 02115, USA. 78Depa men o In e nal Medicine, E asmus Medical Cen e , Ro e dam, The Ne he lands. 79Joslin Diabe es Cen e . Ha a d Medical School, Bos on, MA, USA. 80Ins i u e o Molecula Biology and Biochemis y, Cen e o Molecula Medicine, Medical Uni e si y o G az, Aus ia. 81School o Biomedical Sciences and Pha macy, Uni e si y o Newcas le, Aus alia. 82Molecula Medicine, Pa hology No h Ph. 0409926764, Newcas le, Aus alia. 83Clinic o In e nal Medicine A, Uni e si y Medicine G ei swald, Fe dinand-Saue b uch-S ., 17475 G ei swald, Ge many. 84Ins i u e o Medical In o ma ics, Biome y and Epidemiology, Chai o Gene ic Epidemiology, Ludwig- Maximilians-Uni e si ä , Munich, Ge many. 85Di ision o Medicine, Tu ku Uni e si y Hospi al, Tu ku 20521, Finland. 86Depa men o Medicine, Uni e si y o Tu ku, Tu ku 20520, Finland. 87Depa men o In e nal Medicine, Lausanne Uni e si y Hospi al (CHUV), Lausanne, Swi ze land. 88DZD (Ge man Cen e o Diabe es Resea ch), Si e G ei swald, G ei swald, Ge many. 89Depa men o Bios a is ics, Bos on Uni e si y School o Public Heal h, 715 Albany S ee , Bos on, MA 02118, USA. 90Di ision o Gene ics, B igham and Women’s Hospi al and Ha a d Medical School, Bos on MA, USA. 91B oad Ins i u e o MIT and Ha a d, Camb idge MA 02142 USA. 92Weis Cen e o Resea ch, Geisinge Clinic, Dan ille, Pennsyl ania, USA. 93Depa men o Epidemiology, Johns Hopkins Bloombe g School o Public Heal h, Bal imo e, USA. *These au ho s con ibu ed equally o his wo k.†These au ho s join ly supe ised his wo k. Co espondence and eques s o ma e ials should be add essed o M.G. (email: ma hias.go ski@klinik. uni- egensbu g.de) o C.F. (email: [email p o ec ed]) o C.P. (email: [email p o ec ed]) www.na u e.com/scien i ic epo s/ 3 Scien i ic RepoR s | 7:45040 | DOI: 10.1038/s ep45040 HapMap impu ed genome-wide associa ion s udies (GWAS) ha e e ealed >50 loci a which common a ian s wi h mino allele equency >5% a e associa ed wi h kidney unc ion. GWAS using mo e comple e e e ence se s o impu a ion, such as hose om The 1000 Genomes p ojec , p omise o iden i y no el loci ha ha e been missed by p e ious e o s. To in es iga e he alue o such a mo e comple e a ian ca alog, we conduc ed a GWAS me a-analysis o kidney unc ion based on he es ima ed glome ula il a ion a e (eGFR) in 110,517 Eu opean ances y pa icipan s using 1000 Genomes impu ed da a. We iden i ied 10 no el loci wi h p- alue < 5 × 10−8 p e iously missed by HapMap-based GWAS. Six o hese loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) a e agged by common SNPs unique o he 1000 Genomes e e ence panel. Using pa hway analysis, we iden i ied 39 signi ican (FDR < 0.05) genes and 127 signi ican ly (FDR < 0.05) en iched gene se s, which we e missed by ou p e ious analyses. Among hose, he 10 iden i ied no el genes a e pa o pa hways o kidney de elopmen , ca bohyd a e me abolism, ca diac sep um de elopmen and glucose me abolism. These esul s highligh he u ili y o e-impu ing om dense e e ence panels, un il whole- genome sequencing becomes easible in la ge samples. Ch onic kidney disease (CKD) is a majo public heal h conce n a ec ing ~10% o he global adul popula ion1. CKD is de ined based on he glome ula il a ion a e es ima ed om se um c ea inine (eGFRc ea), a quan i a- i e pheno ype o which 53 loci ha e been iden i ied so a by me a-analyses o genome-wide associa ion s udies (GWAS)2–7. These GWAS me a-analyses we e based on ~2.5 million a ian s impu ed om he HapMap P ojec e e ence panel8. Simila o he gene ic a ian s iden i ied o o he pheno ypes, all a ian s associa ed wi h eGFR- c ea had a mino allele equency (MAF) o > 5%. Howe e , hough he i abili y o eGFR has been es ima ed in amily s udies o ange be ween 36–75%9,10, he iden i ied a ian s explain less han 4% o he a iance o eGFR- c ea7 and a e loca ed in egions o ex ended linkage disequilib ium (LD). So a , causal genes o a ian s ha e only been iden i ied o a ew o he associa ion signals11,12. I has been shown ha a ian s poo ly agged by GWAS a ays and HapMap impu a ion, pa icula ly low- equency a ian s (1% ≤ MAF ≤ 5%), can explain addi ional a iabili y13. Recen echnological ad ances esul ed in la ge collec ions o whole-genome sequence da a, such as hose om The 1000 Genomes p ojec 14,15. These da a p o ide be e co e age and inc eased impu a ion quali y compa ed o p e ious HapMap impu a- ion16, pa icula ly o low- equency a ian s. We unde ook a me a-analysis o GWAS om 33 s udies ha impu ed geno ypes om The 1000 Genomes e e ence panel, hypo hesizing ha his would unco e no el common a ian s associa ed wi h eGFRc ea, ex end o low- equency a ian s, e eal no el pa hways o eGFRc ea associa ed genes, and imp o e ine-mapping o known eGFRc ea loci p e iously iden i ied by ou HapMap-based GWAS3–7. Resul s S udy cha ac e is ics. In o al, 110,517 adul indi iduals o Eu opean ances y om 33 s udies pa icipa ed in GWAS me a-analysis o eGFRc ea using geno ypes impu ed wi h The 1000 Genomes Phase I e e ence panel14 (1000 Genomes me a-analysis). In addi ion, we pe o med a GWAS me a-analysis o eGFR de i ed om cys a in C (eGFRcys), an al e na i e ma ke o kidney unc ion a ailable in 11 o he 33 s udies (n = 24,063). Pa icipa ing s udies, pheno ypic cha ac e is ics, geno ype in o ma ion, and me hods o analysis a e epo ed in Supplemen a y Tables1,2,3and4, espec i ely. The 1000 Genome me a-analysis esul s on eGFRc ea a e compa ed wi h ou p e iously published HapMap impu ed da a7, which was a HapMap-based me a-analysis o 133,814 Eu opean ances y indi iduals om 50 s udies. Impu a ion quali y o a ian s impu ed wi h The 1000 Genomes e e ence panel. The 1000 Genomes me a-analysis consis ed o 10,971,307 gene ic a ian s (10,159,097 SNPs and 812,210 inse ion-dele ions) wi h impu a ion quali y IQ > 0.417 in each o he s udies and p esen in a leas 50% o he subjec s. Depending on he impu a ion me hodology used, he IQ was epo ed as RSQ18 o in o-sco e19 (Supplemen a yTable3). Compa ed o he HapMap me a-analysis, he 1000 Genomes me a-analysis included a highe numbe o well impu ed a ian s (8,103,124 e sus 2,249,027 a ian s wi h IQ > 0.8), pa icula ly among he low- equency a ian s (1,585,176 e sus 191,580, Supplemen a yTable5). While a e a ian s (MAF ≤ 1%) we e no a ailable in he p e ious HapMap me a-analysis, he e we e e en 632,526 well-impu ed a e a ian s in he 1000 Genomes me a-analysis. When limi ing he compa ison o a ian s a ailable in bo h panels, he p opo - ion o well-impu ed a ian s was highe in he 1000 Genomes compa ed o he HapMap me a-analysis (96.9% e sus 93.3% o all; 88.3% e sus 78.4% o he less equen a ian s, Supplemen a yTable5). 1000 Genomes me a-analysis esul s. The 1000 Genomes me a-analysis iden i ied 49 genome-wide signi ican loci o eGFRc ea including 10 no el loci (lead a ian p- alue < 5 × 10−8, Table1, Fig.1, and Supplemen a yFigu e1). All iden i ied lead a ian s we e SNPs, and all we e common, excep s187355703 nea HOXD8 (MAF = 0.03). None o he no el loci con ained genes known o cause monogenic o ms o kid- ney disease and o mos genes no connec ion o kidney unc ion o kidney disease has ye been desc ibed (Supplemen a yTable6). Howe e , i should be acknowledged ha gene ic a ian s iden i ied in GWAS a e no necessa ily associa ed wi h he unc ion o he physically closes gene. O he 53 known eGFRc ea loci iden- i ied p e iously based on HapMap2–7, 39 we e also genome-wide signi ican in he cu en 1000 Genomes me a-analysis (Supplemen a yTable7) and he emaining 14 showed di ec ions o associa ion consis en wi h published epo s, bu did no each signi icance (p- alues 2.2 × 10−2 o 5.2 × 10−7; Supplemen a yTable8). These www.na u e.com/scien i ic epo s/ 4 Scien i ic RepoR s | 7:45040 | DOI: 10.1038/s ep45040 esul s a e consis en wi h ou expec a ions om powe compu a ions (Fig.2). Among he 39 lead a ian s in p e iously published loci ha we e genome-wide signi ican in he 1000 Genomes me a-analysis, 6 lead a ian s we e ound o be he same as he p e iously published a ian s, 25 we e highly co ela ed ( 2 > 0.6), and 8 showed mode a e o no co ela ion ( 2 ≤ 0.6). The 1000 Genomes me a-analysis o eGFRcys con i med p e iously iden i ied loci in o nea CST3/CST9 (p- alue = 4.1 × 10−153), UMOD (p- alue = 2.9 × 10−10), and ATXN2 (p- alue = 1.6 × 10−8), bu did no e eal any no el signal. The en no el eGFRc ea loci in he con ex o he di e en e e ence panels. Fo six o he en no el loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3), he lead a ian iden i ied in he 1000 Genomes me a-analysis was no obse ed in any p e ious HapMap me a-analysis and in ac was no geno- yped as pa o he HapMap e e ence panel. Mo eo e , no a ian in LD wi h any o hese six lead a ian s ( 2 o D’ ≥ 0.4) was a ailable in he HapMap panel. These loci ha e been missed due o he limi ed co e age o he HapMap panel. Fo one u he locus, RHOC, he 1000 Genome me a-analysis lead a ian was p esen also in ou p e ious HapMap me a-analysis, bu wi h a lowe impu a ion quali y (1000 Genomes median IQ ac oss all s udies o 0.96 e sus HapMap median IQ o 0.86). The e ec size was sligh ly highe in he 1000 Genomes compa ed o he HapMap me a-analysis (0.0061 e sus 0.0051 ln ml/min/1.73 m2, Supplemen a yTable9). This locus migh ha e been missed in he HapMap me a-analysis due o he highe unce ain y in he impu ed geno ypes, which is known o diminish powe and o a enua e e ec size in linea eg ession20. Fo he emaining h ee loci (LPHN2, SLC7A6 and RNF152), he lead a ian s o he 1000 Genomes me a-analysis we e obse ed in he HapMap me a-analysis and simila ly well impu ed (IQ nea 1.0 o bo h panels). The e ec sizes we e simila o all h ee SNPs in bo h 1000 Genomes and HapMap me a-analyses (0.0057 e sus 0.0041, 0.0061 e sus 0.0049, 0.0064 e sus 0.0050 ln ml/min/1.73 m2 espec i ely) and he HapMap es ima es lie well wi hin he 98.5% con idence in e al o he 1000 Genomes es ima es. No subs an ial be ween-s udy he - e ogenei y was obse ed (I2 = 19%, 0%, o 21%, espec i ely, Supplemen a yTable9). Since he p- alues in he HapMap analysis we e jus sho o genome-wide signi icance (p- alues 8.38 × 10−6 o 2.33 × 10−7; ype II e o o 14–29%), i is concei able ha hese a ian s ha e been missed p e iously by chance. Pa hway analyses. Da a-d i en Exp ession P io i ized In eg a ion o complex T ai s (DEPICT)21 anal- ysis o eGFRc ea iden i ied 39 signi ican (FDR < 0.05) genes and 127 signi ican ly (FDR < 0.05) en iched gene se s ha we e no iden i ied p e iously7. Among hose, 23 gene se s con ained a leas one o he 10 no el index genes as a op 10 hi , unde pinning he in luence o u e e ic bud mo phogenesis on kidney de elopmen and he in luence o abno mal glucose homeos asis and glucan me abolic p ocess on ca bohyd a e me abo- lism (Supplemen a yTable10). All 127 signi ican gene se s we e u he g ouped in o me a gene se s, co e- sponding o hei co ela ion o gene exp ession. The wo mos signi ican me a gene se s we e Ca diac Sep um De elopmen (p- alue = 4.48 * 10−5) and Glucose Me abolism (p- alue = 6.11 * 10−5), con aining one o he 10 no el index genes (Supplemen a yFigu e2). We epea ed he analysis wi h a ying pa ame e s (50, 200, and 500 epe i ions and 500, 2000, and 5000 pe mu a ions, espec i ely), con i ming ou p ima y op gene se s a an FDR o < 0.05. P- alues anged om 1.32 × 10−3 o 4.48 × 10−5 and om 8.27 × 10−4 o 4.98 × 10−5 o Ca diac Sep um De elopmen and Glucose Me abolism, espec i ely. We eplica ed also he s ong in luence o emb yonic de elopmen , kidney ansmemb ane anspo e ac i i y, and kidney and u ogeni al sys em mo phology in he genesis o CKD om ou p e ious indings7: en ichmen o all 148 p e iously iden i ied gene se s was nominally signi ican (p- alue < 0.05). Va ian ID Ch Posi ion Index Gene E ec allele/ non-e ec allele E ec allele equency E ec (SE) p- alue I2 (%) IQ Numbe o subjec s in analysis s10874312 1 82,944,571 LPHN2 A/G 0.67 − 0.0057 (0.0011) 2.20 × 10−08 19 1.00 107,335 s12144044 1 113,248,791 RHOC A/C 0.28 − 0.0061 (0.0011) 2.87 × 10−08 0 0.96 110,517 s187355703 2 176,993,583 HOXD8 C/G 0.97 0.0182 (0.0030) 5.15 × 10−10 5 0.89 109,257 s111366116 5 53,295,546 ARL15 T/C 0.11 0.0094 (0.0015) 6.27 × 10−10 22 0.97 110,517 s113246091 5 67,739,274 PIK3R1 A/G 0.10 − 0.0095 (0.0016) 1.98 × 10−09 43 0.98 110,105 s7764488 6 133,812,872 EYA4 A/G 0.32 0.0061 (0.0011) 4.08 × 10−09 1 0.98 110,516 s13298297 9 119,264,108 ASTN2 A/G 0.20 − 0.0075 (0.0014) 1.53 × 10−08 0 0.81 110,514 s1111571 16 68,363,181 SLC7A6 A/G 0.71 0.0061 (0.0011) 6.20 × 10−09 0 1.00 109,275 s9962915 18 5,593,171 EPB41L3 T/C 0.48 − 0.0055 (0.0010) 7.19 × 10−09 0 0.98 110,516 s12458009 18 59,350,507 RNF152 T/G 0.78 − 0.0064 (0.0012) 2.90 × 10−08 21 1.00 107,325 Table 1. The 10 no el genome-wide signi ican loci (p < 5 × 10−8) associa ed wi h eGFRc ea in up o 110,517 subjec s om up o 33 s udies. Posi ions a e gi en on GRCh build 37. The gene closes o he a ian is lis ed (index gene). E ec sizes a e gi en on he log scale. IQ = Impu a ion quali y me ic compu ed as median o in o sco e (Impu eV2) o RSQ (minimac) ac oss s udies. SE = s anda d e o . I2 = be ween-s udy he e ogenei y s a is ic. www.na u e.com/scien i ic epo s/ 5 Scien i ic RepoR s | 7:45040 | DOI: 10.1038/s ep45040 Figu e 1. Manha an Plo o he esul s o he 1000 Genome me a-analysis o eGFRc ea. Shown a e he (− log10) p- alues by genomic posi ion (GRCh build 37). Highligh ed a e he 10 no el loci iden i ied wi h genome-wide signi icance (blue, anno a ed by nea es gene), he 39 p e iously published2–7 and con i med (genome-wide signi ican ) loci (g een) and he 14 p e iously published loci ha we e no genome-wide signi ican in his analysis (o ange). Figu e 2. E ec s o he 1000 Genomes lead a ian s o all no el and known loci. Shown a e he e ec sizes and mino allele equencies (MAF) o he 1000 Genomes lead a ian s ( a ian s wi h smalles p- alue) in each o he 10 no el (blue), he 39 known genome-wide signi ican loci (g een), and he 14 known loci ha we e no genome-wide signi ican in his analysis (o ange). Addi ionally, he 80% powe o de ec such e ec s in a sample size o 110,000 subjec s (as in his 1000 Genomes me a-analysis) is shown as a ed line. A known locus is de ined by he published lead a ian ± 1 Mb; a no el locus is de ined by he 1000 Genome lead a ian ± 1 Mb. Independen associa ion signals a no el and known loci. To iden i y independen associa ion signals wi hin a known o no el locus, we pe o med join condi ional analysis o eGFRc ea based on agg e- ga ed s udy-speci ic s a is ics using he GCTA so wa e22. Among he combined 49 loci (39 known and 10 no el) a aining genome-wide signi icance, we unco e ed eigh independen signals, all among he p e iously epo ed loci, wi h p- alues anging om 2.39 × 10−8 o 2.78 × 10−17 a e condi ioning on he lead a ian s a each locus (Supplemen a yTable11 and Supplemen a yFigu e3). We ound ha in all bu one locus (DDX1), he p e iously epo ed lead a ian was also genome-wide signi ican in ou 1000 Genomes me a-analysis. A mo e de ailed www.na u e.com/scien i ic epo s/ 6 Scien i ic RepoR s | 7:45040 | DOI: 10.1038/s ep45040 easoning o he independen associa ion signals is p oposed in Supplemen a yTable12. In o ma ion abou biological knowledge o he highligh ed genes is p esen ed in Supplemen a yTable13. P opo ion o pheno ypic a iance explained and polygenic isk sco e (PRS) analysis. The o e all p opo ion o pheno ypic a iance o eGFRc ea explained by he lead a ian s o he 1000 Genomes me a-analysis in all no el and known loci was 3.99%: 0.46% by he 10 lead a ian s in he no el loci, 3.12% by he 39 lead a ian s in he known loci, and 0.41% by he 1000 Genomes lead a ian s in he 14 known loci ha we e no genome-wide signi ican in his analysis. Nex , we es ed he p opo ion o eGFRc ea a iance ha could be explained by common gene ic a ian s in 1,071 independen adolescen s pa icipa ing in he TRAILS s udy. Gi en p io e idence ha eGFRc ea-associa ed genes a e p e e en ially exp essed in he kidney and en iched o genes impo an in kidney de elopmen 23, ex e - nal in luences on eGFRc ea such as hose o he wo main d i e s o CKD, diabe es and hype ension, may be less impo an in his se ing. In TRAILS, he maximum p opo ion o a iance explained by SNPs asso- cia ed a p e-de ined p- alue h esholds was 2.2% o a PRS composed o SNPs associa ed wi h eGFRc ea a p- alue < 1 × 10−5 (Supplemen a yTable14). SNP-based he i abili y analysis. The he i abili y es ima e using a ian s o MAF > 0.01 o eGFRc ea in he ARIC s udy was 0.21 (95% CI 0.14–0.28) and 0.31 (95% CI 0.20–0.41) o all a ian s. This is in line wi h es ima es in he li e a u e om popula ion-based amily s udies such as he F amingham Hea S udy (adjus ed h2 0.33, 95% CI 0.19–0.47)24. Exp ession quan i a i e ai loci (eQTL) lookup. To explo e po en ial unc ional implica ions o he no el loci, we in e oga ed published da abases o cis eQTL in whole blood25 o he signi ican SNPs o hei p oxy a ian s ( 2 > 0.8 wi hin a 1 MB window). A 2 no el loci, signi ican associa ion (p- alue < 0.004) wi h gene exp ession we e ound: s1111571 wi h SLC7A6, ZFP90, LYPLA3 and NFATC3, and o s12144044 wi h RHOC and ST7L (Supplemen a yTable15). We expanded ou downs eam analysis by anno a ing he signi ican a ian s wi h known and p edic ed eg- ula o y elemen s using Regulome DB26: We con i med s1111571 and s12144044 as signi ican associa ions wi h gene exp ession and ound suppo ing e idence ha hese wo a ian s show also e idence o ansc ip ion ac o binding si es and DNase peaks. Fo he locus iden i ied by s187355703 no p oxy was ound o lookup. Gene ic co ela ion. To in es iga e he gene ic co ela ion o se um c ea inine wi h ela ed pheno ypes, we que ied LD Hub27 and iden i ied modes gene ic co ela ion wi h me abolic synd ome ai s such as HDL, LDL, Type 2 diabe es, as ing glucose, BMI, and wais (LD sco e eg ession gene ic co ela ion be ween − 0.07 and 0.05). Li le e idence o kidney damage is epo ed o a isk sco e o SNPs which a e signi ican p edic o s o blood p essu e28. Discussion The main inding o ou s udy is ha impu ing om dense and la ge e e ence panels is a alid s a egy o ad ance gene mapping e en when he sample size canno be inc eased. Using geno ype impu a ion based on The 1000 Genomes panel led o he iden i ica ion o 10 no el genome-wide signi ican loci o kidney unc ion ha we e missed by ea lie HapMap-impu ed GWAS o la ge sample size, pa ly due o he enhanced co e age o genomic a ia ion. This phenomenon was obse ed in simila analyses o o he pheno ypes29. S ill, i needs o be acknowledged ha he addi ional p opo ion o ai a iance explained by hese new loci is mode a e, which is also in line wi h indings om GWAS o o he pheno ypes30. The e a e se e al me hodological insigh s ha can be gained om ou analyses. Fi s , his 1000 Genomes-based me a-analysis o 110,517 indi iduals has iden i ied 10 no el loci and 8 independen associa ion signals in known loci ha we e missed by ou la es HapMap based analysis7. Ou de ailed dissec ion shows ha 1000 Genomes impu a ion (i) p o ides a ian s missed o poo ly agged by HapMap based analysis and (ii) achie es a highe e ec i e sample size h ough inc eased impu a ion quali y. Second, al hough he 1000 Genomes impu a ion enables he analysis o low- equency a ian s, inse ions and dele ions, all iden i ied op a ian s we e SNPs, and all bu one (nea HOXD8) we e common. Mo eo e , we did no iden i y any low- equency a ian o la ge e ec . Ou esul s a e highly conco dan wi h hose o o he ecen complex diseases s udies31 showing ha low- equency a ian s a e also con ibu ing o complex disease isk, bu ha mos obse ed e ec sizes a e small o modes , and hund eds o housands o subjec s a e equi ed o de ec ion. To iden i y he con ibu ion o a e a ian s (MAF < 1%) o eGFRc ea, la ge-scale sequencing da a in addi ion o genomic chip da a ha e been shown o be a p omising app oach31. Thi d, hese no el loci, missed by ou p e ious analysis7, ex end ou knowledge o pa hways unde lying kidney unc ion, which depic s he in luence o kidney de elopmen , kidney s uc u e, and me abolic ac i i y on he de elopmen o CKD. The compa ison o ou 1000 Genomes me a-analysis wi h ou p e ious HapMap me a-analysis is limi ed by se e al ac o s: he cu en analysis consis s o a educed numbe o samples and a sligh ly di e en s udy com- posi ion. Fu he mo e, di e en 1000 Genomes e e ence panels we e used o impu e geno ypes and ad ances in impu a ion so wa e and me hodology mus be acknowledged32,33. Ne e heless, six o he en lead a ian s in he no el loci a e only co e ed by The 1000 Genomes e e ence panels, which demons a es he ad an age o me a-analyses on 1000 Genomes o e HapMap impu ed geno ypes. In conclusion, we iden i ied 10 no el loci and 8 addi ional independen associa ion a ian s wi hin known loci associa ed wi h kidney unc ion and iden i ied 127 no el pa hways o kidney unc ion. These esul s highligh www.na u e.com/scien i ic epo s/ 7 Scien i ic RepoR s | 7:45040 | DOI: 10.1038/s ep45040 he u ili y o e-impu ing s udies om imp o ed e e ence panels as an in e media e cos -e icien app oach o scan he ull allelic equency ange o kidney unc ion associa ed a ian s, un il whole genome sequencing is easible in la ge samples. Me hods Pheno ype de ini ion. Each s udy measu ed se um c ea inine as desc ibed in Supplemen a yTable1. Be ween-labo a o y a ia ion has been accoun ed o by calib a ing c ea inine o he US na ionally ep esen a i e Na ional Heal h and Nu i ion Examina ion S udy (NHANES) da a in all s udies4,34,35. GFR based on se um c e- a inine (eGFRc ea) was es ima ed using he ou - a iable Modi ica ion o Die in Renal Disease (MDRD) S udy Equa ion36,37. In a subse o s udies, se um cys a in C was also ob ained and eGFRcys es ima ed as 76.7*(se um cys a in C)−1 19 (see also e . 38). The eGFRc ea and eGFRcys alues < 15 ml/min/1.73 m2 we e se o 15, and al- ues > 200 we e se o 200 ml/min/1.73 m2. I no s a ed o he wise, ou p esen ed da a and esul s a e o eGFRc ea, which was ou main analysis. Geno yping. Geno yping was conduc ed in each s udy as speci ied in Supplemen a yTable3. A e applying app op ia e quali y il e s, pa icipa ing s udies pe o med geno ype impu a ion wi h s anda d impu ing p o- cedu es32,33,39 using any e sion o he 1000 Genome Phase 1 e e ence panels. The ob ained impu ed gene ic a ian s we e coded as allelic dosages. De ails o s udy speci ic impu a ion p ocedu e and speci ic e e ence panel a e gi en in Supplemen a yTable3. Genome-wide associa ion analysis. Each s udy pe o med GWAS acco ding o a uni o m analysis plan by eg essing sex- and age-adjus ed esiduals o he na u al loga i hm o eGFRc ea and eGFRcys on he allelic dosage le els. When app op ia e, adjus men o s udy-speci ic ea u es such as s udy si e o gene ic p incipal componen s was included in he model. Family-based s udies accoun ed o ela edness using mixed e ec mod- els. De ails on he s udy-speci ic me hods a e epo ed in Supplemen a yTable4. GWAS me a-analysis. All GWAS iles unde wen quali y con ol using he GWA oolbox package40. GWAS me a-analyses o eGFRc ea and eGFRcys we e pe o med using he so wa e METAL41 assuming ixed e ec s ac oss s udies and using in e se- a iance weigh ing, excluding a ian s wi h impu a ion quali y IQ ≤ 0.4 o a i- an s p esen in less han 50% o he 110,517 subjec s (yielding 10,971,307 a ian s). The genomic in la ion ac o λ was es ima ed o each s udy as he a io be ween he median o all obse ed es s a is ics (b/SE)2 and he expec ed median o a chi-squa ed wi h 1 deg ee o eedom, wi h b and SE ep esen ing he e ec o each SNP on ln eGFRc ea o ln eGFRcys and i s s anda d e o , espec i ely. Genomic-con ol (GC) co ec ion42 was applied o p- alues and SEs in case o λ > 1 (1s GC co ec ion). To limi he possibili y o alse posi i es, a second GC co - ec ion on he agg ega ed esul s was applied a e he me a-analysis. Be ween-s udy he e ogenei y was assessed wi h he I2 s a is ic43. De ini ion o known and no el loci. Known loci we e de ined by a p e iously published lead a i- an ha had shown genome-wide signi ican associa ion wi h eGFRc ea (p- alue < 5 × 10−8) and he gene ic segmen a ound i (lead SNP ± 1 Mb)2–7. Va ian s ou side such segmen s and associa ed wi h eGFRc ea a a p- alue < 5 × 10−8 in he 1000 Genomes me a-analysis de ined he no el loci. Each no el locus was pinpoin ed by he lead a ian wi h he smalles p- alue ± 1 Mb. Compa ison o 1000 Genomes and HapMap esul s. Fo he a ian s a ailable in bo h he 1000 Genomes and HapMap me a-analyses, we compa ed lead a ian s, e ec sizes, impu a ion quali y as well as he powe ha we had in he da a o de ec he espec i e e ec s. Fo his compa ison, we also u ilized he associa ion esul s o ou p e ious HapMap me a-analysis7 in 50 s udies including a maximum o 133,814 subjec s. Powe was calcula ed in R (www. -p ojec .o g) o he app oxima e maximum numbe o subjec s in he 1000 Genomes me a-analyses (n = 110,000) o iden i y he lead a ian s wi h an alpha o 5 × 10−8. Fu he , e ec i e powe , which akes in o accoun he impu a ion quali y o he a ian , was calcula ed based on he e ec i e numbe o subjec s, which is he numbe o subjec s pe a ian mul iplied by he median o he impu a ion quali y ac oss s udies. Pa hway Analyses. Pa hway analyses, comp ised o pa hway/gene se en ichmen and issue/cell ype analyses, we e pe o med by applying a so wa e package called Da a-D i en Exp ession P io i ized In eg a ion o Complex T ai s (DEPICT)21. DEPICT pe o ms gene se en ichmen analyses by es ing whe he genes in GWAS-associa ed loci a e en iched o econs i u ed e sions o known molecula pa hways (join ly e e ed o as econs i u ed gene se s). The econs i u ion is accomplished by iden i ying genes ha a e co- egula ed wi h o he genes in a gi en gene se based on a panel o 77,840 gene exp ession mic oa ays44. Genes ha a e ound o be ansc ip ionally co- egula ed wi h genes om he o iginal gene se a e added o he gene se , which esul s in he econs i u ion. Se e al ypes o gene se s we e econs i u ed in DEPICT: 5,984 p o ein molecula pa hways de i ed om 169,810 high-con idence expe imen ally de i ed p o ein-p o ein in e ac ions45, 2,473 pheno ypic gene se s de i ed om 211,882 gene-pheno ype pai s om he Mouse Gene ics Ini ia i e46, 737 Reac ome da a- base pa hways47, 184 Kyo o Encyclopedia o Genes and Genomes (KEGG) da abase pa hways48 and 5,083 Gene On ology da abase e ms49. In o al, 14,461 gene se s we e assessed o en ichmen in genes in associa ed egions. DEPICT also acili a es issue and cell ype en ichmen analyses by es ing whe he he genes in associa ed egions a e highly exp essed in any o he 209 MeSH anno a ions o 37,427 mic oa ays on he A yme ix U133 Plus 2.0 A ay pla o m. In ou analysis, we used DEPICT e sion 1 el194 and o be compa able o ou p e ious analysis, included all a ian s eaching eGFRc ea associa ion p- alues < 1 × 10−5 om HapMap and 1000 Genomes impu ed da a wi h genomic coo dina es de ined by genome build GRCh38 (h ps://genome.ucsc.edu/cgi-bin/hgLi O e ). www.na u e.com/scien i ic epo s/ 8 Scien i ic RepoR s | 7:45040 | DOI: 10.1038/s ep45040 Since 1000 Genomes impu ed loci in he DEPICT analysis di e ed sligh ly om he HapMap impu ed loci, ou HapMap and 1000 Genomes inpu was c ea ed by adding all signi ican 1000 Genomes a ian s o all signi ican HapMap a ian s. This p ocess esul ed in a o al o 3,659 a ian s o HapMap, 7,894 a ian s o 1000 Genomes, and 9,270 a ian s o HapMap and 1000 Genomes analyses. Nex , independen lead a ian s we e iden i ied wi h Plink50 using ± 500 kb lanking egions and 2 > 0.01 wi h he 1000 Genomes da a14 as e e ence. Genomic in e als a e gene a ed consis ing o all a ian s wi hin 2 > 0.5 o each lead a ian . I any o he 19,987 genes in he analysis o e laps o esides wi hin a genomic in e al, i is mapped o ha in e al. A e me ging o o e lap- ping egions and excluding egions wi hin he majo his ocompa ibili y complex on ch omosome 6, base pai s 25,000,000–35,000,000, DEPICT analyses we e conduc ed using he ollowing pa ame e s: 200 epe i ions o compu e FDR and 2,000 pe mu a ions o compu e p- alues adjus ed o gene leng h by using 500 null GWAS. Fo he en ichmen analysis we used 10,968 econs i u ed gene se s. Fo isualiza ion, all no el signi ican gene se s we e u he me ged in o me a gene se s by unning an a ini y p opaga ion51 om Py hons sciki -lea n package (h p://sciki -lea n.o g/). The ne wo k was isualized wi h Cy oscape (h p://cy oscape.o g/). Iden i ica ion o independen associa ion signals wi h GCTA. We sea ched o independen associ- a ion signals in he known and no el loci wi h a join condi ional analysis on he agg ega ed me a-analysis esul s using he GCTA-COJO me hod (condi ional and join genome-wide associa ion analysis)22,52. The KORA-F4 GWAS da a53 we e used o es ima e he LD ( 2) in he join condi ional analysis, and o quan i y he ex en o coinhe i ance (D’)50. A po en ial independen associa ion signal wi hin a gi en locus was epo ed i he a ian wi h he smalles condi ional p- alue was genome-wide signi ican (p- alue < 5 × 10−8) a e condi ioning on he p e iously epo ed a ian in a locus. SNP-based he i abili y analysis. The he i abili y o eGFRc ea was es ima ed using GCTA GREML-LDMS me hods54 ( e sion 1.25) wi h impu ed geno ype accoun ing o linkage disequilib ium. The impu ed geno ype was based on dosage (p obabili y > 0.9) impu ed using he 1000 Genomes Phase I e e ence panel and il e ed by he ollowing c i e ia: HWE < 1 × 10−6, indi idual missingness > 5%, SNP missingness > 5%, and MAF < 0.0005 (~3 copies). P opo ion o pheno ypic a iance explained. To quan i y he impac o he iden i ied gene ic loci on enal unc ion, he pe cen o pheno ypic a iance explained by all lead a ian s in he no el and known loci was es ima ed as ∗ Be a a a ian a eGFRc ea () ( esid(ln( ))) 2 , whe e a ( a ian ) = 2 * MAF * (1− MAF)and be a is he es ima ed e ec o he a ian in he 1000 Genomes me a-analysis55. The a iance o he esiduals o ln (eGFRc ea) is compu ed in he ARIC s udy (n = 9,038). All a ian s we e assumed o ha e independen e ec s on he pheno ype. Polygenic isk sco e analysis. P io i yP une (h p://p io i yp une .sou ce o ge.ne ) was used o selec independen SNPs om The 1000 Genomes e e ence panel using an algo i hm ha p e e en ially selec s SNPs ha a e mo e signi ican in he cu en 1000 Genomes me a-analysis compa ed o he p e ious HapMap me a-analysis. Polygenic isk sco es (PRSs), using a ious h esholds o signi icance, as ob ained om he 1000 Genomes me a-analysis esul s and weigh ed o he e ec s sizes wi hin s udy we e gene a ed in TRAILS56 (n = 1,071), an independen s udy o adolescen s, which was no pa o he me a-analysis. These PRSs we e es ed o associa ion wi h eGFRc ea using linea eg ession in R and he a iance explained by he PRSs was calcula ed. Re e ences 1. Ecka d , K. U. e al. E ol ing impo ance o kidney disease: om subspecial y o global heal h bu den. Lance 382, 158–69 (2013). 2. Chambe s, J. C. e al. Gene ic loci in luencing kidney unc ion and ch onic kidney disease. Na Gene 42, 373–5 (2010). 3. Chasman, D. I. e al. 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