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Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 2,000, 3,700 and 9,500 SNPs explained 21%, 24% and 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate–related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

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Figure 1: Regional association plots for loci with multiple association signals.
Figure 2: Quantifying the variance explained by height-associated SNPs at different levels of significance.
Figure 3: Tissue enrichment combined with pruned gene set network synthesis.

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Acknowledgements

A full list of acknowledgments appears in the Supplementary Note.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

Steering committee overseeing the consortium: G.R.A., T.L.A., I.B., S.I.B., M. Boehnke, I.B.B., P.D., C.S.F., T.M.F., L.C.G., I.M.H., J.N.H., D.J.H., E.I., R.C.K., R.J.F.L., M.I.M., K.L. Mohlke, K.E.N., J.R.O., D. Schlessinger, D.P.S., U.T. and C.M.v.D. Writing group (wrote, edited and commented on the manuscript): S.I.B., D.I.C., A.Y.C., T.E., T.M.F., J.N.H., E.I., T.H.P., S.V., P.M.V., M.N.W., A.R.W. and J.Y. Data preparation group (checked and prepared data from contributing cohorts for meta-analyses): D.C.C.-C., F.R.D., T.E., T. Fall, T. Ferreira, S.G., I.M.H., Z.K., C.M.L., A.E.L., R.J.F.L., J. Luan, R.M., J.C.R., A. Scherag, E.K.S., S.V., T.W.W., A.R.W. and T. Workalemahu. Height meta-analyses group (GWAS and Metabochip) (analyses specific to the manuscript): T.E., T.M.F. (chair), S.V., P.M.V., A.R.W. (lead meta-analyses) and J.Y. (lead joint-effects and approximate conditional analyses). Mixed linear model analyses: J.S.B., M. Boehnke, D.I.C., A.Y.C., K.E., T.M.F. (chair), S.G., J.N.H., J.H.Z., E.I., A.U.J., Z.K., R.J.F.L., J. Luan, A. Metspalu, E.M., J.R.O., A.L.P., A.G.U., S.V., P.M.V., M.N.W., A.R.W. (lead) and J.Y. Large λ group: T.M.F., J.N.H., P.M.V., M.E. Goddard, A.L.P., M.N.W., J.Y. and G.R.A. Family transmission analyses: G.R.A., N.A., I.B.B., Y.D., C.M.v.D., J.N.H. (chair), E.I., J.R.O., E.P., S.V. (lead), P.M.V. and J.Y. Variance, heritability and prediction analyses: K.E., M.E. Goddard, M.I.M., A.A.E.V., P.M.V. (chair), M.N.W., A.R.W. and J.Y. (lead). Biological enrichment and pathway analyses: T.E. (lead biological enrichment analyses), J.N.H. (chair) and T.H.P. (lead pathway analyses). ENCODE working group: M.L.B., G.L. (chair) and K.S.L. Gene expression (eQTL) working group: J. Baron, T.E. (chair), L. Franke, J. Karjalainen, J.C.L., A. Metspalu, E.R., J.E.P. and H.-J.W. (lead). Other contributions: (DEPICT) R.F., L. Franke, J. Karjalainen and T.H.P.

Project design, management and coordination of contributing studies

Previous GWAS: (AGES) V. Gudnason, T.B.H.; (AMISH) A.R.S.; (ARIC) K.E.N.; (B58C T1D CONTROLS) D.P.S.; (B58C WTCCC) D.P.S.; (BRIGHT) M.J.B., N.J.S.; (CAPS) E.I.; (CHS) J.I.R.; (COLAUS) J.S.B., S. Bergmann; (CROATIA-Vis) I.R.; (deCODE) K. Stefansson, U.T.; (DGI) L.C.G.; (EGCUT) A. Metspalu; (EPIC-Norfolk) N.J.W.; (FENLAND) N.J.W.; (Finnish Twin Cohort) J. Kaprio, K. Silventoinen; (FRAM) L.A.C.; (FUSION) R.N.B., M. Boehnke; (GerMIFS I) J.E., C. Hengstenberg; (GerMIFS II) H. Schunkert; (H2000) S. Koskinen; (HFPS) D.J.H.; (KORA S4) C.G., A.P.; (MICROS) A.A.H., P.P.P.; (NFBC66) M.-R.J., S. Sebert; (NHS) D.J.H.; (NSPHS) U.G.; (NTRNESDA) D.I.B.; (ORCADES) H.C.; (PLCO) S.I.B., S.J.C.; (RS I) C.M.v.D., A. Hofman, M. Kayser, F. Rivadeneira, A.G.U.; (RUNMC) L.A.K.; (SardiNIA) G.R.A.; (SASBAC) E.I.; (SHIP) R.B., H.V.; (WGHS) P.M.R.; (WTCCC-CAD) A.S.H., N.J.S.; (WTCCC-T2D) C.M.L., M.I.M.; (Young Finns Study (YFS)) T.L., O.T.R.

New GWAS: (ASCOT) M.J.C., P.S.; (ATCG) P.I.W.d.B., D.W.H.; (Athero-Express Biobank Studies) F.W.A., H.M.d.R., F.L.M., G.P.; (B-PROOF) R.D.-R., L.C.P.G.M.d.G., N.M.v.S., N.v.d.V.; (BLSA) L. Ferrucci; (CLHNS) K.L. Mohlke; (COROGENE) M.P., J. Sinisalo; (DESIR) S.C., P.F.; (DNBS) M. Melbye, J.C.M.; (EGCUT) A. Metspalu; (eMERGE) M.G.H.; (ERF) B.A.O., C.M.v.D.; (FamHS) I.B.B.; (FINGESTURE) J.-C.T.; (GOOD) C.O.; (HBCS) J.G.E.; (Health ABC) T.B.H., Y. Liu; (HERITAGE Family Study) C. Bouchard, D.C.R., M.A. Sarzynski; (InCHIANTI) L. Ferrucci, T.M.F.; (IPM) E.P.B., R.J.F.L.; (LLS) P.E.S.; (LOLIPOP) J.C.C., J.S.K.; (MGS) P.V.G.; (NELSON) P.I.W.d.B., P.Z.; (PLCO2) S.I.B., S.J.C.; (PREVEND) P.v.d.H.; (PROCARDIS) H.W.; (PROSPER/PHASE) I.F., J.W.J.; (QFS) C. Bouchard, A. Marette, L.P., M.-C.V.; (QIMR) A.C.H., N.G.M., G.W.M.; (RISC) E.F., T.M.F., A. Golay, M. Walker; (RS II) A. Hofman, M. Kayser, F. Rivadeneira, A.G.U.; (RS III) A. Hofman, M. Kayser, F. Rivadeneira, A.G.U.; (SHIP-TREND) R.B., H.V.; (SORBS) A. Tönjes; (TRAILS) A.J.O., H. Snieder; (TWINGENE) E.I.; (TwinsUK) T.D.S.

Metabochip studies: (ADVANCE) T.L.A., T.Q.; (AMC-PAS) G.K.H., P.D.; (ARIC) E.B., K.E.N.; (B1958C) E.H., C.P.; (BHS) J. Beilby, J. Hui; (CARDIOGENICS) P.D., W.H.O., H. Schunkert; (DESIR) S.C., P.F.; (DGE DietGeneExpression) B.J.; (DIAGEN) S.R.B., P.E.H.S.; (DILGOM) P.J., A.M.J., S. Männistö, M.P., V. Salomaa; (DPS) M.U.; (DR's EXTRA) T.A.L., R. Rauramaa; (DUNDEE-GoDARTS) C.N.A.P.; (EAS) J.F.P.; (EGCUT) A. Metspalu; (EMIL (SWABIA)) B.O.B.; (FBPP) A.C., R.S.C., S.C.H.; (FIN-D2D 2007) S.M.K.-K., T.E.S.; (FUSION 2) F.S.C., J. Saramies, J.T.; (GLACIER) P.W.F.; (GxE) R.S.C., J.N.H., C.A.M.; (HNR) R.E., P. Hoffmann, S. Moebus; (HUNT 2) K.H.; (IMPROVE) U.d.F., A. Hamsten, S.E.H., E.T.; (KORA S3) T.M., H.-E.W.; (KORA S4) K. Strauch; (Leipzig) M.S.; (LURIC) W.M.; (MEC) C.A. Haiman, L.L.M.; (METSIM) J. Kuusisto, M. Laakso; (MORGAM) P.A., D. Arveiler, P. Brambilla, J.F., F.K., J.V.; (NSHD) D.K.; (PIVUS) E.I.; (PROMIS) J. Danesh, P.D., D. Saleheen; (ScarfSheep) A. Hamsten; (SPT) R.S.C., J.N.H., C.A.M.; (STR) E.I., (Tandem) M. Bochud, P. Bovet; (THISEAS) G. Dedoussis, P.D.; (Tromsø) I.N.; (ULSAM) E.I.; (WHI) T.C.M., C.K., U.P.; (Whitehall) A.D.H., M. Kivimaki, N.J.W.; (WTCCC-T2D) C.M.L., M.I.M.

Genotyping of contributing studies

Previous GWAS: (AGES) A.V. Smith; (B58C T1D CONTROLS) W.L.M.; (B58C WTCCC) W.L.M.; (CAPS) H. Grönberg; (CROATIA-Vis) C. Hayward; (EGCUT) M. Nelis; (EPIC-Norfolk) N.J.W.; (FENLAND) N.J.W.; (Finnish Twin Cohort) J. Kaprio; (KORA S3) T.I., M.M.-N.; (MICROS) A.A.H.; (NFBC66) M.-R.J.; (ORCADES) A.F.W.; (PLCO) S.J.C.; (RS I) K.E., C.M.-G., F. Rivadeneira, A.G.U.; (SASBAC) P. Hall; (SHIP) A. Hannemann, M. Nauck; (WGHS) D.I.C., L.M.R.; (WTCCC-CAD) A.S.H., N.J.S.; (WTCCC-T2D) A.T.H., M.I.M.; (Young Finns Study (YFS)) T.L., O.T.R.

New GWAS: (ASCOT) P.B.M.; (ATCG) P.I.W.d.B., D.W.H., P.J.M.; (Athero-Express Biobank Study) S.W.v.d.L.; (CLHNS) D.C.C.-C.; (DESIR) E.E., S. Lobbens; (EGCUT) T.E., L.M.; (eMERGE) D.C.C., M.G.H.; (ERF) A.I., B.A.O., C.M.v.D.; (FamHS) I.B.B., E.W.D., M.F.F., A.T.K., M.K.W., Q.Z.; (GOOD) C.O., M. Lorentzon; (Health ABC) Y. Liu; (HERITAGE Family Study) M.A. Sarzynski; (HYPERGENES) S. Lupoli.; (IPM) E.P.B.; (LifeLines) M.A. Swertz; (LLS) J. Deelen, Q.H.; (LOLIPOP) J.C.C., J.S.K.; (NELSON) J. Smolonska; (PLCO2) S.J.C., K.B.J., Z.W.; (PREVEND) P.v.d.H., I.M.L.; (PROCARDIS) M.F., A. Goel; (PROSPER/PHASE) J.W.J., D.J.S., S.T.; (QFS) C. Bellis, J. Blangero; (QIMR) A.K.H.; (SHIP-TREND) A. Hannemann, M. Nauck; (RS II) K.E., C.M.-G., F. Rivadeneira, A.G.U.; (RS III) K.E., C.M.-G., F. Rivadeneira, A.G.U.; (TRAILS) M. Bruinenberg, C.A. Hartman; (TWINGENE) A. Hamsten, N.L.P.; (TwinsUK) M. Mangino, A. Moayyeri; (WGHS) D.I.C., L.M.R.

Metabochip studies: (ADVANCE) D. Absher, T.L.A., T.Q.; (AMCPAS) K. Stirrups; (ARIC) E.B., K.E.N.; (B1958C) N.R.R., C.J.G., T.J.; (BHS) G.M.A., J. Hui; (CARDIOGENICS) K. Stirrups; (DESIR) E.E., S. Lobbens; (DGE DietGeneExpression) B.J.; (DIAGEN) M.A.M.; (DUNDEE-GoDARTS) A.J.B., C.N.A.P., N.W.R.; (EAS) J.F.W.; (EGCUT) T.E., L.M.; (ELY) N.G.F., C.L., R.J.F.L., K.K.O., R.A.S., N.J.W.; (EMIL (SWABIA)) B.O.B.; (EPIC-Norfolk) N.G.F., C.L., R.J.F.L., K.K.O., R.A.S., N.J.W.; (FBPP) A.C.; (FENLAND) N.G.F., C.L., R.J.F.L., K.K.O., R.A.S., N.J.W.; (FIN-D2D 2007) P.S.C.; (FUSION 2) L.K.; (GLACIER) I.B.; (HNR) M.M.N.; (HUNT 2) N.N.; (KORA S3) N.K., M. Waldenberger; (KORA S4) H. Grallert, P.L.; (Leipzig) Y.B., P.K.; (LURIC) M.E.K.; (MEC) C.A. Haiman, L.A.H.; (NSHD) D.K., K.K.O., A.W.; (PIVUS) E.I., C. Berne, L.L., J. Sundström; (PROMIS) K. Stirrups; (STR) N.L.P.; (Tandem) G.B.E., M. Maillard; (THISEAS) K. Stirrups; (Tromsø) P.S.C.; (ULSAM) J.Ä., E.I., A.-C.S.; (WHI) C.K., U.P.; (Whitehall) C.L.; (WTCCC-T2D) A.T.H., M.I.M.

Phenotype coordination of contributing studies

Previous GWAS: (AMISH) A.R.S.; (B58C T1D CONTROLS) D.P.S.; (B58C WTCCC) D.P.S.; (BRIGHT) M.J.B., N.J.S.; (CAPS) H. Grönberg; (CHS) R.C.K.; (CROATIA-Vis) I.R.; (DGI) V. Lyssenko; (EGCUT) A. Metspalu; (EPIC-Norfolk) N.J.W.; (FENLAND) N.J.W.; (Finnish Twin Cohort) J. Kaprio; (KORA S4) A.P.; (NFBC66) M.-R.J.; (NTRNESDA) J.H.S.; (ORCADES) A.F.W.; (PLCO) S.I.B.; (RS I) A. Hofman, F. Rivadeneira, A.G.U.; (SASBAC) P. Hall; (SHIP) M. Dörr, W.H., T.K.; (UKBS-CC) J. Jolley; (WGHS) D.I.C., L.M.R., A.Y.C.; (WTCCC-CAD) A.S.H., N.J.S.; (WTCCC-T2D) A.B., A.T.H.; (Young Finns Study (YFS)) T.L., O.T.R.

New GWAS: (ASCOT) M.J.C., P.S., A.V. Stanton; (ATCG) D.W.H.; (Athero-Express Biobank Study) F.L.M.; (BLSA) S. Bandinelli; (DESIR) R. Roussel; (DNBC) H.A.B., B.F., F.G.; (EGCUT) T.E., A. Metspalu; (eMERGE) J.C.D., A.N.K.; (ERF) B.A.O., C.M.v.D.; (FamHS) I.B.B., M.F.F.; (FINGESTURE) J. Junttila; (GOOD) C.O., M. Lorentzon; (HBCS) J.G.E.; (Health ABC) M.E. Garcia, T.B.H., M.A.N.; (HERITAGE Family Study) C. Bouchard; (HYPERGENES) P.M.; (InCHIANTI) S. Bandinelli, L. Ferrucci; (IPM) O.G.; (LifeLines) S. Scholtens, M.A. Swertz, J.M.V.; (LLS) D.v.H.; (LOLIPOP) J.C.C., J.S.K., U.A., L.O., J. Sehmi; (NELSON) P.A.D.J.; (PLCO2) S.I.B.; (PREVEND) S.J.L.B., R.T.G., H.L.H.; (PROCARDIS) R. Clarke, R. Collins, M.F., A. Hamsten; (PROSPER/PHASE) J.W.J., I.F., B.M.B.; (QFS) A. Tremblay; (QIMR) A.K.H., A.C.H., P.A.F.M., N.G.M., G.W.M.; (RS II) A. Hofman, F. Rivadeneira, A.G.U.; (RS III) A. Hofman, F. Rivadeneira, A.G.U.; (SORBS) A. Tönjes; (SHIP-TREND) M. Dörr, W.H., T.K.; (TRAILS) C.A. Hartman, R.P.S., F.V.A.v.O.; (TWINGENE) P.K.E.M., N.L.P.; (TwinsUK) M. Mangino, C.M.; (WGHS) D.I.C., L.M.R.

Metabochip studies: (ADVANCE) A.S.G., M.A.H.; (AMCPAS) J.J.P.K.; (ARIC) E.B.; (B1958C) E.H., C.P.; (BHS) A.L.J., A.W.M.; (DESIR) R. Roussel; (DGE DietGeneExpression) B.J., I.H.C.; (DIAGEN) J. Gräßler, G.M.; (DPS) J. Lindström; (DR's EXTRA) M.H.; (DUNDEE-GoDARTS) A.S.F.D., A.D.M., C.N.A.P.; (EAS) S. McLachlan; (EGCUT) T.E., A. Metspalu; (EMIL (SWABIA)) B.O.B., S.C.-B., W.K., S. Merger, T.S., R.W.; (FBPP) R.S.C., S.C.H.; (GLACIER) G. Hallmans; (GxE) T. Forrester, B.O.T.; (HNR) R.E., S. Moebus; (HUNT 2) O.H.; (KORA S3) H.-E.W.; (Leipzig) M. Blüher; (MEC) L.R.W.; (METSIM) H.M.S.; (NSHD) D.K.; (PIVUS) C. Berne, E.I., L.L., J. Sundström; (PROMIS) D. Saleheen; (SPT) T. Forrester, B.O.T.; (STR) N.L.P.; (Tandem) M. Bochud, P. Bovet; (THISEAS) S. Kanoni; (Tromsø) T. Wilsgaard; (ULSAM) J.Ä., V. Giedraitis, E.I.; (WHI) C.K., U.P.; (Whitehall) M. Kumari; (WTCCC-T2D) A.B., A.T.H.

Data analysis

Previous GWAS: (AGES) A.V. Smith; (ARIC) K.L. Monda, K.E.N.; (B58C T1D CONTROLS) D.P.S.; (B58C WTCCC) D.P.S.; (CAPS) E.I.; (CHS) R.C.K., B.M.; (COLAUS) S. Bergmann, Z.K.; (CROATIA-Vis) C. Hayward; (deCODE) V. Steinthorsdottir, G.T.; (EGCUT) M. Nelis; (EPIC-Norfolk) J.H.Z.; (FENLAND) J. Luan; (FRAM) L.A.C., N.L.H.-C.; (FUSION) C.J.W.; (GerMIFS II) C.W.; (H2000) N.E.; (HPFS) L.Q.; (NHS) L.Q.; (NSPHS) Å.J.; (PLCO) S.I.B.; (RS I) K.E., C.M.-G., F. Rivadeneira, A.G.U.; (RUNMC) S.H.V.; (SardiNIA) S. Sanna; (SASBAC) E.I.; (SEARCH) J.P.T.; (SHIP) A. Teumer; (WGHS) D.I.C., L.M.R., A.Y.C.; (WTCCC-T2D) A.P.M., T. Ferreira, A. Mahajan, R.M.

New GWAS: (ATCG) P.I.W.d.B., P.J.M., S.R.; (Athero-Express Biobank Studies) S.W.v.d.L.; (B-PROOF) S.v.D.; (BHS) M.C.; (BLSA) T.T.; (CLHNS) D.C.C.-C.; (DESIR) S.C., L.Y.; (DNBC) B.F., F.G.; (EGCUT) T.E., K.F., T.H., R.M.; (eMERGE) M.G.H.; (ERF) N.A., A.D.; (FamHS) M.F.F.; (GOOD) C.O., M. Lorentzon; (HBCS) N.E.; (Health ABC) M.A.N.; (HERITAGE Family Study) C. Bouchard, M.A. Sarzynski, D.C.R., T.R., T.K.R., Y.J.S.; (HYPERGENES) S. Lupoli; (InCHIANTI) D.P., T.T., A.R.W.; (IPM) J. Jeff, V. Lotay, Y. Lu; (LifeLines) I.M.N., J.V.V.V.-O.; (LLS) M. Beekman, J.J.H.-D.; (LOLIPOP) W.Z.; (MGS) J. Shi, (NELSON) S.R., J.v.S.; (PLCO2) S.I.B., Z.W.; (PREVEND) P.v.d.H., I.M.L., N.V.; (PROCARDIS) A. Goel; (PROSPER/PHASE) I.F., B.M.B., S.T.; (QFS) J. Blangero, L.P.; (QIMR) G. Hemani, D.R.N., J.E.P.; (RISC) D.P., A.R.W.; (RS II) K.E., C.M.-G., F. Rivadeneira, A.G.U.; (RS III) K.E., C.M.-G., F. Rivadeneira, A.G.U.; (SHIP-TREND) A. Teumer; (SORBS) R.M.; (TRAILS) H. Snieder; (TWINGENE) E.I., S.G.; (TwinsUK) M. Mangino; (WGHS) D.I.C., L.M.R.

Metabochip studies: (ADVANCE) D. Absher, T.L.A., L.L.W.; (AMCPAS) S. Kanoni; (ARIC) S. Buyske, A.E.J., K.E.N.; (B1958C) T. Ferreira; (BHS) D. Anderson; (CARDIOGENICS) S. Kanoni; (DESIR) S.C., L.Y.; (DGE DietGeneExpression) I.H.C.; (DIAGEN) A.U.J., G.M.; (DILGOM) K.K.; (DUNDEE) T. Ferreira; (EAS) J.L.B., R.M.F.; (EGCUT) T.E., K.F., E.M.; (ELY) J. Luan; (EMIL (SWABIA)) B.O.B.; (EPIC-Norfolk) J. Luan; (FBPP) A.C., G.B.E.; (FENLAND) J. Luan; (GLACIER) F. Renstrom, D. Shungin; (GxE) C.D.P.; (HNR) S. Pechlivanis, A. Scherag; (IMPROVE) L. Folkersen, R.J.S.; (KORA S3) J.S.R.; (KORA S4) E.A.; (Leipzig) A. Mahajan, I.P.; (LURIC) G. Delgado, T.B.G., M.E.K., S. Pilz, H. Scharnag; (MEC) U.L., F.R.S.; (METSIM) A. Stancáková; (NSHD) A.W., J. Luan; (PIVUS) S.G., E.I.; (PROMIS) S. Kanoni; (ScarfSheep) R.J.S.; (SPT) C.D.P.; (STR) E.I., S.G.; (TANDEM) G.B.E.; (THISEAS) M. Dimitriou; (ULSAM) S.G., E.I.; (WHI) J. Gong, J. Haessler, M.R.; (Whitehall) J. Luan; (WTCCC-T2D) A.P.M., T. Ferreira, A. Mahajan, R.M.

Corresponding authors

Correspondence to Peter M Visscher, Joel N Hirschhorn or Timothy M Frayling.

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Competing interests

The authors declare no competing financial interests.

Additional information

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

Integrated supplementary information

Supplementary Figure 1 Overview of the analysis strategy implemented.

Supplementary Figure 2 Quantile-quantile plot showing the P-value distribution of GWAS meta-analysis results after applying a single genomic control.

Supplementary Figure 3 Manhattan plots.

Plots of (a) results obtained from meta-analysis after applying a single genomic control correction and (b) results obtained from performing an approximate conditional and joint multiple-SNP analysis on the meta-analysis results. The red horizontal line in both plots represents the genome-wide significance threshold of P = 5 × 10–8.

Supplementary Figure 4 Examples of loci with multiple signals that cluster around the same gene or are in close proximity to others.

Supplementary Figure 5 Partitioning the variance in the SNP-derived genetic predictor using a within-family analysis.

The variance of the SNP-based genetic predictor was partitioned into components due to real SNP effects (Vg), errors in estimating SNP effects (Ve) and population stratification (Cg + Ce) (Online Methods). The SNPs were selected from the approximate conditional and joint multiple-SNP association analysis with the target cohort being excluded from the meta-analysis. In b, d and f, the SNP-based predictor was adjusted by the first 20 principal components (PCs). The comparison between the results with and without PC adjustment demonstrates clearly the portioning of the variance component due to population stratification (Cg + Ce).

Supplementary Figure 6 Variance explained by the SNPs at known loci.

Details of data and analyses can be found in the Online Methods. (a) Variance explained by all the SNPs within a certain physical distance of the top associated SNPs (including the top SNPs). (b) Variance explained by the SNPs at the known loci excluding the top SNPs divided by the number of these SNPs. Estimates in b are without LD adjustment. Error bars are the standard errors of the estimates.

Supplementary Figure 7 Results from GRAIL analysis.

A subset of the 697 lead height SNPs are arranged along the outer circle alternating with colors. The inner circle represents the individual prioritized (P < 1 × 10–6) genes. Gene names shown in black have literature connections, and the ones in gray do not. The redness and thickness of the lines connecting pairs of genes represent the strength of the connections. Top-ranking keywords prioritized by GRAIL were ‘transcription’, ‘growth’, ‘nuclear’, ‘factor’, ‘binding’, ‘collagen’, ‘differentiation’, ‘promoter’, ‘development’, ‘ribosomal’, ‘bone’, ‘mice’, ‘expression’ and ‘cartilage’.

Supplementary Figure 8 DEPICT cell type enrichment analysis.

Genes in associated height loci tended to be highly expressed in, among other cell types, chondrocytes and mesenchymal stem cells. The analysis was conducted based on the DEPICT method and 37,427 human microarray samples. Significantly enriched (FDR < 0.05) cell types are color coded in violet. The figure also includes tissue enrichment results, which were not shown in Figure 3 of the main text.

Supplementary Figure 9 Partitioning the variance explained by chromosome length.

(a) The proportion of variance explained by the genome-wide significant SNPs on a chromosome plotted against chromosome length. (b) The correlation of the variance explained by the top GWAS SNPs on each chromosome against the estimate from Yang et al. (2011) for that chromosome. Note: the numbers in red circles indicate chromosome number.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Supplementary Tables 2, 4–6, 9–12, 15 and 17–22, and Supplementary Note. (PDF 6671 kb)

Supplementary Table 1

SNPs representing signals identified through meta-analysis and approximate conditional analysis. (XLSX 171 kb)

Supplementary Table 3

Results from Metabochip replication analysis. (XLSX 138 kb)

Supplementary Table 7

Nonsynonymous variant enrichment analysis. (XLSX 79 kb)

Supplementary Table 8

Cis-regulatory variant enrichment analysis. (XLSX 185 kb)

Supplementary Table 13

Results from GRAIL text-mining analysis. (XLSX 59 kb)

Supplementary Table 14

Pathways and protein complexes prioritized by DEPICT. (XLSX 67 kb)

Supplementary Table 16

Results from DEPICT gene prioritization analysis. (XLSX 133 kb)

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Wood, A., Esko, T., Yang, J. et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 46, 1173–1186 (2014). https://doi.org/10.1038/ng.3097

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