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. 2010 Oct 14;467(7317):832-8.
doi: 10.1038/nature09410. Epub 2010 Sep 29.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Hana Lango Allen  1 Karol EstradaGuillaume LettreSonja I BerndtMichael N WeedonFernando RivadeneiraCristen J WillerAnne U JacksonSailaja VedantamSoumya RaychaudhuriTeresa FerreiraAndrew R WoodRobert J WeyantAyellet V SegrèElizabeth K SpeliotesEleanor WheelerNicole SoranzoJu-Hyun ParkJian YangDaniel GudbjartssonNancy L Heard-CostaJoshua C RandallLu QiAlbert Vernon SmithReedik MägiTomi PastinenLiming LiangIris M HeidJian'an LuanGudmar ThorleifssonThomas W WinklerMichael E GoddardKen Sin LoCameron PalmerTsegaselassie WorkalemahuYurii S AulchenkoAsa JohanssonM Carola ZillikensMary F FeitosaTõnu EskoToby JohnsonShamika KetkarPeter KraftMassimo ManginoInga ProkopenkoDevin AbsherEva AlbrechtFlorian ErnstNicole L GlazerCaroline HaywardJouke-Jan HottengaKevin B JacobsJoshua W KnowlesZoltán KutalikKeri L MondaOzren PolasekMichael PreussNigel W RaynerNeil R RobertsonValgerdur SteinthorsdottirJonathan P TyrerBenjamin F VoightFredrik WiklundJianfeng XuJing Hua ZhaoDale R NyholtNiina PellikkaMarkus PerolaJohn R B PerryIda SurakkaMari-Liis TammesooElizabeth L AltmaierNajaf AminThor AspelundTushar BhangaleGabrielle BoucherDaniel I ChasmanConstance ChenLachlan CoinMatthew N CooperAnna L DixonQuince GibsonElin GrundbergKe HaoM Juhani JunttilaLee M KaplanJohannes KettunenInke R KönigTony KwanRobert W LawrenceDouglas F LevinsonMattias LorentzonBarbara McKnightAndrew P MorrisMartina MüllerJulius Suh NgwaShaun PurcellSuzanne RafeltRany M SalemErika SalviSerena SannaJianxin ShiUlla SovioJohn R ThompsonMichael C TurchinLiesbeth VandenputDominique J VerlaanVeronique VitartCharles C WhiteAndreas ZieglerPeter AlmgrenAnthony J BalmforthHarry CampbellLorena CitterioAlessandro De GrandiAnna DominiczakJubao DuanPaul ElliottRoberto ElosuaJohan G ErikssonNelson B FreimerEco J C GeusNicola GloriosoShen HaiqingAnna-Liisa HartikainenAki S HavulinnaAndrew A HicksJennie HuiWilmar IglThomas IlligAntti JulaEero KajantieTuomas O KilpeläinenMarkku KoiranenIvana KolcicSeppo KoskinenPeter KovacsJaana LaitinenJianjun LiuMarja-Liisa LokkiAna MarusicAndrea MaschioThomas MeitingerAntonella MulasGuillaume ParéAlex N ParkerJohn F PedenAstrid PetersmannIrene PichlerKirsi H PietiläinenAnneli PoutaMartin RidderstråleJerome I RotterJennifer G SambrookAlan R SandersCarsten Oliver SchmidtJuha SinisaloJan H SmitHeather M StringhamG Bragi WaltersElisabeth WidenSarah H WildGonneke WillemsenLaura ZagatoLina ZgagaPaavo ZittingHelene AlavereMartin FarrallWendy L McArdleMari NelisMarjolein J PetersSamuli RipattiJoyce B J van MeursKatja K AbenKristin G ArdlieJacques S BeckmannJohn P BeilbyRichard N BergmanSven BergmannFrancis S CollinsDaniele CusiMartin den HeijerGudny EiriksdottirPablo V GejmanAlistair S HallAnders HamstenHeikki V HuikuriCarlos IribarrenMika KähönenJaakko KaprioSekar KathiresanLambertus KiemeneyThomas KocherLenore J LaunerTerho LehtimäkiOlle MelanderTom H Mosley JrArthur W MuskMarkku S NieminenChristopher J O'DonnellClaes OhlssonBen OostraLyle J PalmerOlli RaitakariPaul M RidkerJohn D RiouxAila RissanenCarlo RivoltaHeribert SchunkertAlan R ShuldinerDavid S SiscovickMichael StumvollAnke TönjesJaakko TuomilehtoGert-Jan van OmmenJorma ViikariAndrew C HeathNicholas G MartinGrant W MontgomeryMichael A ProvinceManfred KayserAlice M ArnoldLarry D AtwoodEric BoerwinkleStephen J ChanockPanos DeloukasChristian GiegerHenrik GrönbergPer HallAndrew T HattersleyChristian HengstenbergWolfgang HoffmanG Mark LathropVeikko SalomaaStefan SchreiberManuela UdaDawn WaterworthAlan F WrightThemistocles L AssimesInês BarrosoAlbert HofmanKaren L MohlkeDorret I BoomsmaMark J CaulfieldL Adrienne CupplesJeanette ErdmannCaroline S FoxVilmundur GudnasonUlf GyllenstenTamara B HarrisRichard B HayesMarjo-Riitta JarvelinVincent MooserPatricia B MunroeWillem H OuwehandBrenda W PenninxPeter P PramstallerThomas QuertermousIgor RudanNilesh J SamaniTimothy D SpectorHenry VölzkeHugh WatkinsJames F WilsonLeif C GroopTalin HarituniansFrank B HuRobert C KaplanAndres MetspaluKari E NorthDavid SchlessingerNicholas J WarehamDavid J HunterJeffrey R O'ConnellDavid P StrachanH-Erich WichmannIngrid B BoreckiCornelia M van DuijnEric E SchadtUnnur ThorsteinsdottirLeena PeltonenAndré G UitterlindenPeter M VisscherNilanjan ChatterjeeRuth J F LoosMichael BoehnkeMark I McCarthyErik IngelssonCecilia M LindgrenGonçalo R AbecasisKari StefanssonTimothy M FraylingJoel N Hirschhorn
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Hundreds of variants clustered in genomic loci and biological pathways affect human height

Hana Lango Allen et al. Nature. .

Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

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Figures

Figure 1
Figure 1. Phenotypic variance explained by common variants
(a) Variance explained is higher when SNPs not reaching genome-wide significance are included in the prediction model. The y-axis represents the proportion of variance explained at different P-value thresholds from Stage 1. Results are given for five studies that were not part of Stage 1. *Proportion of variation explained by the 180 SNPs. (b) Cumulative number of susceptibility loci expected to be discovered, including already identified loci and as yet undetected loci. The projections are based on loci that achieved a significance level of P<5×10-8 in the initial scan and the distribution of their effect sizes in Stage 2. The dotted red line corresponds to expected phenotypic variance explained by the 110 loci that reached genome-wide significance in Stage 1, were replicated in Stage 2 and had at least 1% power.
Figure 1
Figure 1. Phenotypic variance explained by common variants
(a) Variance explained is higher when SNPs not reaching genome-wide significance are included in the prediction model. The y-axis represents the proportion of variance explained at different P-value thresholds from Stage 1. Results are given for five studies that were not part of Stage 1. *Proportion of variation explained by the 180 SNPs. (b) Cumulative number of susceptibility loci expected to be discovered, including already identified loci and as yet undetected loci. The projections are based on loci that achieved a significance level of P<5×10-8 in the initial scan and the distribution of their effect sizes in Stage 2. The dotted red line corresponds to expected phenotypic variance explained by the 110 loci that reached genome-wide significance in Stage 1, were replicated in Stage 2 and had at least 1% power.
Figure 2
Figure 2. Example of a locus with a secondary signal before (a) and after (b) conditioning
The plot is centered on the conditioned SNP (purple diamond) at the locus. r2 is based on the CEU HapMap II samples. The blue line and right hand Y axis represent CEU HapMap II recombination rates. Created using LocusZoom (http://csg.sph.umich.edu/locuszoom/).
Figure 2
Figure 2. Example of a locus with a secondary signal before (a) and after (b) conditioning
The plot is centered on the conditioned SNP (purple diamond) at the locus. r2 is based on the CEU HapMap II samples. The blue line and right hand Y axis represent CEU HapMap II recombination rates. Created using LocusZoom (http://csg.sph.umich.edu/locuszoom/).
Figure 3
Figure 3. Loci associated with height contain genes related to each other
(a) 180 height-associated SNPs. The y-axis plots GRAIL P-values on a log scale. The histogram corresponds to the distribution of GRAIL P-values for 1,000 sets of 180 matched SNPs. The scatter plot represents GRAIL results for the 180 height SNPs (blue dots). The black horizontal line marks the median of the GRAIL P-values (P=0.14). The top 10 keywords linking the genes were: ‘growth’, ‘kinase’, ‘factor’, ‘transcription’, ‘signaling’, ‘binding’, ‘differentiation’, ‘development’, ‘insulin’, ‘bone’. (b) Graphical representation of the connections between SNPs and corresponding genes for the 42 SNPs with GRAIL P<0.01. Thicker and redder lines imply stronger literature-based connectivity.

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