Distinct variants at LIN28B influence growth in height from birth to adulthood.
We have studied the largely unknown genetic underpinnings of height growth by using a unique resource of longitudinal childhood height data available in Finnish population cohorts. After applying GWAS mapping of potential genes influencing pubertal height growth followed by further characterization of the genetic effects on complete postnatal growth trajectories, we have identified strong association between variants near LIN28B and pubertal growth (rs7759938; female p = 4.0 x 10(-9), male p = 1.5 x 10(-4), combined p = 5.0 x 10(-11), n = 5038). Analysis of growth during early puberty confirmed an effect on the timing of the growth spurt. Correlated SNPs have previously been implicated as influencing both adult stature and age at menarche, the same alleles associating with taller height and later age of menarche in other studies as with later pubertal growth here. Additionally, a partially correlated LIN28B SNP, rs314277, has been associated previously with final height. Testing both rs7759938 and rs314277 (pairwise r(2) = 0.29) for independent effects on postnatal growth in 8903 subjects indicated that the pubertal timing-associated marker rs7759938 affects prepubertal growth in females (p = 7 x 10(-5)) and final height in males (p = 5 x 10(-4)), whereas rs314277 has sex-specific effects on growth (p for interaction = 0.005) that were distinct from those observed at rs7759938. In conclusion, partially correlated variants at LIN28B tag distinctive, complex, and sex-specific height-growth-regulating effects, influencing the entire period of postnatal growth. These findings imply a critical role for LIN28B in the regulation of human growth.
Widén
Elisabeth
E
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. elisabeth.widen@helsinki.fi
Ripatti
Samuli
S
Cousminer
Diana L
DL
Surakka
Ida
I
Lappalainen
Tuuli
T
Järvelin
Marjo-Riitta
MR
Eriksson
Johan G
JG
Raitakari
Olli
O
Salomaa
Veikko
V
Sovio
Ulla
U
Hartikainen
Anna-Liisa
AL
Pouta
Anneli
A
McCarthy
Mark I
MI
Osmond
Clive
C
Kajantie
Eero
E
Lehtimäki
Terho
T
Viikari
Jorma
J
Kähönen
Mika
M
Tyler-Smith
Chris
C
Freimer
Nelson
N
Hirschhorn
Joel N
JN
Peltonen
Leena
L
Palotie
Aarno
A
D000293:Adolescent; D000328:Adult; D001827:Body Height; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006128:Growth / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008572:Menarche / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins; D044465:White People / Q000235:genetics*
D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; D016601:RNA-Binding Proteins
Nat Genet. 2009 Jul;41(7):843-8
19483683
Ann Hum Biol. 1977 Sep;4(5):417-30
564159
Nat Genet. 2009 Jun;41(6):734-8
19448622
Am J Epidemiol. 2000 Jul 15;152(2):125-31
10909949
Nat Genet. 2009 Jun;41(6):729-33
19448623
Trends Ecol Evol. 2009 Apr;24(4):218-25
19246118
Nat Genet. 2008 May;40(5):609-15
18391951
Nat Genet. 2009 Jan;41(1):18-24
19079260
Ann Hum Biol. 1983 Mar-Apr;10(2):163-71
6682302
Mol Biol Evol. 1999 Jan;16(1):37-48
10331250
Clin Endocrinol (Oxf). 2008 Jan;68(1):4-15
17645565
Dev Biol. 2003 Jun 15;258(2):432-42
12798299
Hum Mol Genet. 2009 Sep 15;18(18):3502-7
19553259
Genome Res. 2009 May;19(5):826-37
19307593
Am J Hum Biol. 2008 Jul-Aug;20(4):417-23
18293372
Am J Clin Nutr. 2001 Sep;74(3):287-94
11522550
Nat Genet. 2009 Jun;41(6):648-50
19448620
Best Pract Res Clin Endocrinol Metab. 2002 Jun;16(2):225-41
12064890
Nat Genet. 2009 Jun;41(6):724-8
19448621
Eur J Hum Genet. 2010 Apr;18(4):471-8
19844263
BMJ. 2001 Apr 21;322(7292):949-53
11312225
Nat Genet. 2008 May;40(5):584-91
18391950
Nat Genet. 2009 Jan;41(1):25-34
19079261
Hum Biol. 1995 Oct;67(5):739-53
8543288
Am J Clin Nutr. 2008 Jun;87(6):1876-82
18541580
Nat Genet. 2009 Jan;41(1):35-46
19060910
Am J Clin Nutr. 2008 Jun;87(6):1769-75
18541567
Trends Genet. 2008 Dec;24(12):595-603
18950892
J Clin Endocrinol Metab. 2001 Jun;86(6):2364-8
11397824
Am J Hum Biol. 2008 May-Jun;20(3):292-8
18203123
Genome Res. 2005 Nov;15(11):1553-65
16251465
Am J Hum Genet. 2007 Sep;81(3):559-75
17701901
Pediatr Res. 2001 Feb;49(2):244-51
11158521
J Clin Endocrinol Metab. 2004 May;89(5):2114-8
15126528
Int J Epidemiol. 2008 Dec;37(6):1220-6
18263651
Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20216-9
18077366
Int J Obes (Lond). 2006 Jan;30(1):14-22
16344844
Curr Opin Pediatr. 2009 Aug;21(4):515-22
19455035