Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.
Adrienne TinJonathan MartenVictoria L Halperin KuhnsYong LiMatthias WuttkeHolger KirstenKarsten B SieberChengxiang QiuMathias GorskiZhi YuAyush GiriGardar SveinbjornssonMan LiAudrey Y ChuAnselm HoppmannLuke O' ConnorBram PrinsTeresa NutileDamia NoceMasato AkiyamaMassimiliano CoccaSahar GhasemiPeter J van der MostKatrin HornYizhe XuChristian FuchsbergerSanaz SedaghatSaima AfaqNajaf AminJohan ÄrnlövStephan J L BakkerNisha BansalDaniela BaptistaSven BergmannMary L BiggsGinevra BiinoEric BoerwinkleErwin P BottingerThibaud S BoutinMarco BrumatRalph BurkhardtEric CampanaArchie I CampbellHarry CampbellRobert J CarrollEulalia CatamoJohn C ChambersMarina CiulloMaria Pina ConcasJosef CoreshTanguy CorreDaniele CusiCinzia Felicita SalaMartin H de BorstAlessandro De GrandiRenée de MutsertAiko P J de VriesGraciela DelgadoAyşe DemirkanOlivier DevuystKatalin DittrichKai-Uwe EckardtGeorg B EhretKarlhans EndlichMichele K EvansRon T GansevoortPaolo GaspariniVilmantas GiedraitisChristian GiegerGiorgia GirottoMartin GögeleScott D GordonDaníel F GuðbjartssonVilmundur G Gudnasonnull nullToomas HallerPavel HametTamara B HarrisCaroline HaywardAndrew A HicksEdith HoferHilma HolmWei HuangNina Hutri-KähönenShih-Jen HwangMohammad Arfan IkramRaychel M LewisErik IngelssonJohanna JakobsdottirIngileif JónsdóttirHelgi JonssonPeter K JoshiNavya Shilpa JosyulaBettina JungMika KähönenYoichiro KamataniMasahiro KanaiShona M KerrWieland KiessMarcus Edi KleberWolfgang KoenigJaspal S KoonerAntje KörnerPeter KovacsBernhard K KrämerFlorian KronenbergMichiaki KuboBrigitte KühnelMartina La BiancaLeslie A LangeBenjamin LehneTerho Lehtimäkinull nullJun LiuMarkus LoefflerRuth J F LoosLeo-Pekka LyytikainenReedik MagiAnubha MahajanNicholas G MartinWinfried MärzDeborah MascalzoniKoichi MatsudaChrista MeisingerThomas MeitingerAndres MetspaluYuri Milaneschinull nullChristopher J O'DonnellOtis D WilsonJ Michael GazianoPashupati P MishraKaren L MohlkeNina MononenGrant W MontgomeryDennis O Mook-KanamoriMartina Müller-NuraysidGirish N NadkarniMike A NallsMatthias NauckKjell NikusBoting NingIlja Maria NolteRaymond NoordamJeffrey R O'ConnellIsleifur OlafssonSandosh PadmanabhanBrenda W J H PenninxThomas PerlsAnnette PetersMario PirastuNicola PirastuGiorgio PistisOzren PolasekBelen PonteDavid J PorteousTanja PoulainMichael H PreussTon J RabelinkLaura M RaffieldOlli T RaitakariRainer RettigMyriam RheinbergerKenneth M RiceFederica RizziAntonietta RobinoIgor RudanAlena KrajcoviechovaRenata CifkovaRico RueediDaniela RuggieroKathleen A RyanYasaman SabaErika SalviHelena SchmidtReinhold SchmidtChristian M ShafferAlbert Vernon SmithBlair H SmithCassandra N SpracklenKonstantin StrauchMichael StumvollPatrick SulemSalman M TajuddinAndrej TerenJoachim ThieryChris H L ThioUnnur ThorsteinsdottirDaniela TonioloAnke TönjesJohanne TremblayAndre G UitterlindenSimona VaccargiuPim van der HarstCornelia M van DuijnNiek VerweijLinus VölkerPeter VollenweiderGerard WaeberMelanie WaldenbergerJohn B WhitfieldSarah D WildJames F WilsonQiong YangWeihua ZhangAlan B ZondermanMurielle BochudJames G WilsonSarah A PendergrassKevin HoAfshin ParsaPeter P PramstallerBruce M PsatyCarsten A BögerHarold SniederAdam S ButterworthYukinori OkadaTodd L EdwardsKári StefánssonKatalin SusztakMarkus ScholzIris M HeidAdriana M HungAlexander TeumerCristian PattaroOwen M WoodwardVeronique VitartAnna KottgenPublished in: Nature genetics (2019)
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
Keyphrases
- gene expression
- genome wide
- dna methylation
- genome wide association study
- copy number
- transcription factor
- nuclear factor
- induced apoptosis
- uric acid
- high resolution
- emergency department
- cell proliferation
- oxidative stress
- air pollution
- inflammatory response
- endoplasmic reticulum stress
- genome wide identification
- genome wide association