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Using height association studies to gain insights into human idiopathic short and syndromic stature phenotypes

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Abstract

Variation in adult height is not the most clinically relevant human quantitative trait, yet its study provides the foundation of many quantitative genetics theories and important statistical concepts (e.g. regression). Even today, the analysis of adult height by genome-wide association studies (GWAS) continues to significantly impact human genetics: these studies have led to the discovery of >200 loci associated with variation in adult height and have highlighted the very polygenic nature of human continuous traits. In this brief review, I discuss and provide examples on how such genetic associations, identified in individuals of normal height, could help understand the complex genetics behind such phenotypes as idiopathic short stature (ISS) or extreme/syndromic height phenotypes of unknown cause.

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References

  1. Galton F (1885) Regression towards mediocrity in hereditary stature. J R Anthropol Inst 5:329–348

    Google Scholar 

  2. Fisher RA (1918) The correlation between relatives on the supposition of Mendelian inheritance. Trans R Soc Edinb 52:399–433

    Article  Google Scholar 

  3. Pearson K, Lee A (1903) On the laws of inheritance in man. I. Inheritance of physical characteristics. Biometrika 2:357–462

    Google Scholar 

  4. Silventoinen K, Haukka J, Dunkel L, Tynelius P, Rasmussen F (2008) Genetics of pubertal timing and its associations with relative weight in childhood and adult height: the Swedish Young Male Twins Study. Pediatrics 121:e885–e891

    Article  PubMed  Google Scholar 

  5. Perola M, Sammalisto S, Hiekkalinna T, Martin NG, Visscher PM, Montgomery GW, Benyamin B, Harris JR, Boomsma D, Willemsen G, Hottenga JJ, Christensen K, Kyvik KO, Sorensen TI, Pedersen NL, Magnusson PK, Spector TD, Widen E, Silventoinen K, Kaprio J, Palotie A, Peltonen L (2007) Combined genome scans for body stature in 6,602 European twins: evidence for common Caucasian loci. PLoS Genet 3:e97

    Article  PubMed  Google Scholar 

  6. Visscher PM, Medland SE, Ferreira MA, Morley KI, Zhu G, Cornes BK, Montgomery GW, Martin NG (2006) Assumption-free estimation of heritability from genome-wide identity-by-descent sharing between full siblings. PLoS Genet 2:e41

    Article  PubMed  Google Scholar 

  7. Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF, Perry JR, Elliott KS, Hackett R, Guiducci C, Shields B, Zeggini E, Lango H, Lyssenko V, Timpson NJ, Burtt NP, Rayner NW, Saxena R, Ardlie K, Tobias JH, Ness AR, Ring SM, Palmer CN, Morris AD, Peltonen L, Salomaa V, Smith GD, Groop LC, Hattersley AT, McCarthy MI, Hirschhorn JN, Frayling TM (2007) A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet 39:1245–1250

    Article  PubMed  CAS  Google Scholar 

  8. Sanna S, Jackson AU, Nagaraja R, Willer CJ, Chen WM, Bonnycastle LL, Shen H, Timpson N, Lettre G, Usala G, Chines PS, Stringham HM, Scott LJ, Dei M, Lai S, Albai G, Crisponi L, Naitza S, Doheny KF, Pugh EW, Ben-Shlomo Y, Ebrahim S, Lawlor DA, Bergman RN, Watanabe RM, Uda M, Tuomilehto J, Coresh J, Hirschhorn JN, Shuldiner AR, Schlessinger D, Collins FS, Davey Smith G, Boerwinkle E, Cao A, Boehnke M, Abecasis GR, Mohlke KL (2008) Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40:198–203

    Article  PubMed  CAS  Google Scholar 

  9. Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segre AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa NL, Randall JC, Qi L, Vernon Smith A, Magi R, Pastinen T, Liang L, Heid IM, Luan J, Thorleifsson G, Winkler TW, Goddard ME, Sin Lo K, Palmer C, Workalemahu T, Aulchenko YS, Johansson A, Zillikens MC, Feitosa MF, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer NL, Hayward C, Hottenga JJ, Jacobs KB, Knowles JW, Kutalik Z, Monda KL, Polasek O, Preuss M, Rayner NW, Robertson NR, Steinthorsdottir V, Tyrer JP, Voight BF, Wiklund F, Xu J, Zhao JH, Nyholt DR, Pellikka N, Perola M, Perry JR, Surakka I, Tammesoo ML, Altmaier EL, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman DI, Chen C, Coin L, Cooper MN, Dixon AL, Gibson Q, Grundberg E, Hao K, Juhani Junttila M, Kaplan LM, Kettunen J, Konig IR, Kwan T, Lawrence RW, Levinson DF, Lorentzon M, McKnight B, Morris AP, Muller M, Suh Ngwa J, Purcell S, Rafelt S, Salem RM, Salvi E, Sanna S, Shi J, Sovio U, Thompson JR, Turchin MC, Vandenput L, Verlaan DJ, Vitart V, White CC, Ziegler A, Almgren P, Balmforth AJ, Campbell H, Citterio L, De Grandi A, Dominiczak A, Duan J, Elliott P, Elosua R, Eriksson JG, Freimer NB, Geus EJ, Glorioso N, Haiqing S, Hartikainen AL, Havulinna AS, Hicks AA, Hui J, Igl W, Illig T, Jula A, Kajantie E, Kilpelainen TO, Koiranen M, Kolcic I, Koskinen S, Kovacs P, Laitinen J, Liu J, Lokki ML, Marusic A, Maschio A, Meitinger T, Mulas A, Pare G, Parker AN, Peden JF, Petersmann A, Pichler I, Pietilainen KH, Pouta A, Ridderstrale M, Rotter JI, Sambrook JG, Sanders AR, Schmidt CO, Sinisalo J, Smit JH, Stringham HM, Bragi Walters G, Widen E, Wild SH, Willemsen G, Zagato L, Zgaga L, Zitting P, Alavere H, Farrall M, McArdle WL, Nelis M, Peters MJ, Ripatti S, van Meurs JB, Aben KK, Ardlie KG, Beckmann JS, Beilby JP, Bergman RN, Bergmann S, Collins FS, Cusi D, den Heijer M, Eiriksdottir G, Gejman PV, Hall AS, Hamsten A, Huikuri HV, Iribarren C, Kahonen M, Kaprio J, Kathiresan S, Kiemeney L, Kocher T, Launer LJ, Lehtimaki T, Melander O, Mosley TH Jr, Musk AW, Nieminen MS, O’Donnell CJ, Ohlsson C, Oostra B, Palmer LJ, Raitakari O, Ridker PM, Rioux JD, Rissanen A, Rivolta C, Schunkert H, Shuldiner AR, Siscovick DS, Stumvoll M, Tonjes A, Tuomilehto J, van Ommen GJ, Viikari J, Heath AC, Martin NG, Montgomery GW, Province MA, Kayser M, Arnold AM, Atwood LD, Boerwinkle E, Chanock SJ, Deloukas P, Gieger C, Gronberg H, Hall P, Hattersley AT, Hengstenberg C, Hoffman W, Lathrop GM, Salomaa V, Schreiber S, Uda M, Waterworth D, Wright AF, Assimes TL, Barroso I, Hofman A, Mohlke KL, Boomsma DI, Caulfield MJ, Cupples LA, Erdmann J, Fox CS, Gudnason V, Gyllensten U, Harris TB, Hayes RB, Jarvelin MR, Mooser V, Munroe PB, Ouwehand WH, Penninx BW, Pramstaller PP, Quertermous T, Rudan I, Samani NJ, Spector TD, Volzke H, Watkins H, Wilson JF, Groop LC, Haritunians T, Hu FB, Kaplan RC, Metspalu A, North KE, Schlessinger D, Wareham NJ, Hunter DJ, O’Connell JR, Strachan DP, Wichmann HE, Borecki IB, van Duijn CM, Schadt EE, Thorsteinsdottir U, Peltonen L, Uitterlinden AG, Visscher PM, Chatterjee N, Loos RJ, Boehnke M, McCarthy MI, Ingelsson E, Lindgren CM, Abecasis GR, Stefansson K, Frayling TM, Hirschhorn JN (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467:832–838

    Article  PubMed  CAS  Google Scholar 

  10. Perola M (2011) Genetics of human stature: Lessons from genome-wide association studies. Horm Res Paediatr 76[Suppl 3]:10–11

    Article  PubMed  CAS  Google Scholar 

  11. Lettre G (2011) Recent progress in the study of the genetics of height. Hum Genet 129:465–472

    Article  PubMed  Google Scholar 

  12. Visscher PM, McEvoy B, Yang J (2010) From Galton to GWAS: quantitative genetics of human height. Genet Res 92:371–379

    Article  Google Scholar 

  13. Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, Mikkola HK, Hirschhorn JN, Cantor AB, Orkin SH (2008) Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 322:1839–1842

    Article  PubMed  CAS  Google Scholar 

  14. Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, Li X, Li H, Kuperwasser N, Ruda VM, Pirruccello JP, Muchmore B, Prokunina-Olsson L, Hall JL, Schadt EE, Morales CR, Lund-Katz S, Phillips MC, Wong J, Cantley W, Racie T, Ejebe KG, Orho-Melander M, Melander O, Koteliansky V, Fitzgerald K, Krauss RM, Cowan CA, Kathiresan S, Rader DJ (2010) From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466:714–719

    Article  PubMed  CAS  Google Scholar 

  15. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329:841–845

    Article  PubMed  CAS  Google Scholar 

  16. Zhu H, Shah S, Shyh-Chang N, Shinoda G, Einhorn WS, Viswanathan SR, Takeuchi A, Grasemann C, Rinn JL, Lopez MF, Hirschhorn JN, Palmert MR, Daley GQ (2010) Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat Genet 42:626–630

    Article  PubMed  CAS  Google Scholar 

  17. Kim JJ, Lee HI, Park T, Kim K, Lee JE, Cho NH, Shin C, Cho YS, Lee JY, Han BG, Yoo HW, Lee JK (2010) Identification of 15 loci influencing height in a Korean population. J Hum Genet 55:27–31

    Article  PubMed  Google Scholar 

  18. Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, Yoon D, Lee MH, Kim DJ, Park M, Cha SH, Kim JW, Han BG, Min H, Ahn Y, Park MS, Han HR, Jang HY, Cho EY, Lee JE, Cho NH, Shin C, Park T, Park JW, Lee JK, Cardon L, Clarke G, McCarthy MI, Lee JY, Oh B, Kim HL (2009) A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41:527–534

    Article  PubMed  CAS  Google Scholar 

  19. N’Diaye A, Chen GK, Palmer CD, Ge B, Tayo B, Mathias RA, Ding J, Nalls MA, Adeyemo A, Adoue V, Ambrosone CB, Atwood L, Bandera EV, Becker LC, Berndt SI, Bernstein L, Blot WJ, Boerwinkle E, Britton A, Casey G, Chanock SJ, Demerath E, Deming SL, Diver WR, Fox C, Harris TB, Hernandez DG, Hu JJ, Ingles SA, John EM, Johnson C, Keating B, Kittles RA, Kolonel LN, Kritchevsky SB, Le Marchand L, Lohman K, Liu J, Millikan RC, Murphy A, Musani S, Neslund-Dudas C, North KE, Nyante S, Ogunniyi A, Ostrander EA, Papanicolaou G, Patel S, Pettaway CA, Press MF, Redline S, Rodriguez-Gil JL, Rotimi C, Rybicki BA, Salako B, Schreiner PJ, Signorello LB, Singleton AB, Stanford JL, Stram AH, Stram DO, Strom SS, Suktitipat B, Thun MJ, Witte JS, Yanek LR, Ziegler RG, Zheng W, Zhu X, Zmuda JM, Zonderman AB, Evans MK, Liu Y, Becker DM, Cooper RS, Pastinen T, Henderson BE, Hirschhorn JN, Lettre G, Haiman CA (2011) Identification, replication, and fine-mapping of Loci associated with adult height in individuals of African ancestry. PLoS Genet 7:e1002298

    Article  PubMed  Google Scholar 

  20. Carty CL, Johnson NA, Hutter CM, Reiner AP, Peters U, Tang H, Kooperberg C (2012) Genome-wide association study of body height in African Americans: the Women’s Health Initiative SNP Health Association Resource (SHARe). Hum Mol Genet 21:711–720

    Article  PubMed  CAS  Google Scholar 

  21. Silventoinen K, Pietilainen KH, Tynelius P, Sorensen TI, Kaprio J, Rasmussen F (2008) Genetic regulation of growth from birth to 18 years of age: the Swedish young male twins study. Am J Hum Biol 20:292–298

    Article  PubMed  Google Scholar 

  22. Widen E, Ripatti S, Cousminer DL, Surakka I, Lappalainen T, Jarvelin MR, Eriksson JG, Raitakari O, Salomaa V, Sovio U, Hartikainen AL, Pouta A, McCarthy MI, Osmond C, Kajantie E, Lehtimaki T, Viikari J, Kahonen M, Tyler-Smith C, Freimer N, Hirschhorn JN, Peltonen L, Palotie A (2010) Distinct variants at LIN28B influence growth in height from birth to adulthood. Am J Hum Genet 86:773–782

    Article  PubMed  CAS  Google Scholar 

  23. Sovio U, Bennett AJ, Millwood IY, Molitor J, O’Reilly PF, Timpson NJ, Kaakinen M, Laitinen J, Haukka J, Pillas D, Tzoulaki I, Hoggart C, Coin LJ, Whittaker J, Pouta A, Hartikainen AL, Freimer NB, Widen E, Peltonen L, Elliott P, McCarthy MI, Jarvelin MR (2009) Genetic determinants of height growth assessed longitudinally from infancy to adulthood in the northern Finland birth cohort 1966. PLoS Genet 5:e1000409

    Article  PubMed  Google Scholar 

  24. Vrieze SI, McGue M, Miller MB, Legrand LN, Schork NJ, Iacono WG (2011) An assessment of the individual and collective effects of variants on height using twins and a developmentally informative study design. PLoS Genet 7:e1002413

    Article  PubMed  CAS  Google Scholar 

  25. Paternoster L, Howe LD, Tilling K, Weedon MN, Freathy RM, Frayling TM, Kemp JP, Smith GD, Timpson NJ, Ring SM, Evans DM, Lawlor DA (2011) Adult height variants affect birth length and growth rate in children. Hum Mol Genet 20:4069–4075

    Article  PubMed  CAS  Google Scholar 

  26. Ranke MB (2011) Chairman’s summary: definition of idiopathic short stature. Horm Res Paediatr 76[Suppl 3]:2

    Article  PubMed  CAS  Google Scholar 

  27. Cuttler L, Marinova D, Mercer MB, Connors A, Meehan R, Silvers JB (2009) Patient, physician, and consumer drivers: referrals for short stature and access to specialty drugs. Med Care 47:858–865

    Article  PubMed  Google Scholar 

  28. Chan Y, Holmen OL, Dauber A, Vatten L, Havulinna AS, Skorpen F, Kvaloy K, Silander K, Nguyen TT, Willer C, Boehnke M, Perola M, Palotie A, Salomaa V, Hveem K, Frayling TM, Hirschhorn JN, Weedon MN (2011) Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals. PLoS Genet 7:e1002439

    Article  PubMed  CAS  Google Scholar 

  29. Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C, Illig T, Hackett R, Heid IM, Jacobs KB, Lyssenko V, Uda M, Boehnke M, Chanock SJ, Groop LC, Hu FB, Isomaa B, Kraft P, Peltonen L, Salomaa V, Schlessinger D, Hunter DJ, Hayes RB, Abecasis GR, Wichmann HE, Mohlke KL, Hirschhorn JN (2008) Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40:584–591

    Article  PubMed  CAS  Google Scholar 

  30. Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Pedersen O, Aben KK, Witjes JA, Swinkels DW, den Heijer M, Franke B, Verbeek AL, Becker DM, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Gulcher J, Kiemeney LA, Kong A, Thorsteinsdottir U, Stefansson K (2008) Many sequence variants affecting diversity of adult human height. Nat Genet 40:609–615

    Article  PubMed  CAS  Google Scholar 

  31. Smits P, Bolton AD, Funari V, Hong M, Boyden ED, Lu L, Manning DK, Dwyer ND, Moran JL, Prysak M, Merriman B, Nelson SF, Bonafe L, Superti-Furga A, Ikegawa S, Krakow D, Cohn DH, Kirchhausen T, Warman ML, Beier DR (2010) Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210. N Engl J Med 362:206–216

    Article  PubMed  CAS  Google Scholar 

  32. de Pontual L, Yao E, Callier P, Faivre L, Drouin V, Cariou S, Van Haeringen A, Genevieve D, Goldenberg A, Oufadem M, Manouvrier S, Munnich A, Vidigal JA, Vekemans M, Lyonnet S, Henrion-Caude A, Ventura A, Amiel J (2011) Germline deletion of the miR-17 approximately 92 cluster causes skeletal and growth defects in humans. Nat Genet 43:1026–1030

    Article  PubMed  Google Scholar 

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Acknowledgments

I would like to thank Aikaterini Kritikou and members of my laboratory for comments on earlier versions of this manuscript. Work on the genetics of height and other anthropometric traits in my laboratory is funded by the Montreal Heart Institute Foundation and the “Fonds de Recherche du Québec en Santé (FRQS).”

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  1. Montreal Heart Institute and Université de Montréal, 5000 Bélanger Street, Montreal, Quebec, H1T 1C8, Canada

    Guillaume Lettre

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Lettre, G. Using height association studies to gain insights into human idiopathic short and syndromic stature phenotypes. Pediatr Nephrol 28, 557–562 (2013). https://doi.org/10.1007/s00467-012-2301-y

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