Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty
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Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. / The ReproGen Consortium; The Early Growth Genetics (EGG) Consortium; The Early Growth Genetics (EGG) Consortium; The ReproGen Consortium; The GIANT Consortium.
In: Human Molecular Genetics, Vol. 23, No. 16, 01.01.2014, p. 4452-4464.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty
AU - Cousminer, Diana L.
AU - Stergiakouli, Evangelia
AU - Berry, Diane J.
AU - Ang, Wei
AU - Groen-Blokhuis, Maria M.
AU - Körner, Antje
AU - Siitonen, Niina
AU - Ntalla, Ioanna
AU - Marinelli, Marcella
AU - Perry, John R.B.
AU - Kettunen, Johannes
AU - Jansen, Rick
AU - Surakka, Ida
AU - Timpson, Nicholas J.
AU - Ring, Susan
AU - McMahon, George
AU - Power, Chris
AU - Wang, Carol
AU - Kähönen, Mika
AU - Viikari, Jorma
AU - Lehtimäki, Terho
AU - Middeldorp, Christel M.
AU - Hulshoff Pol, Hilleke E.
AU - Neef, Madlen
AU - Weise, Sebastian
AU - Pahkala, Katja
AU - Niinikoski, Harri
AU - Zeggini, Eleftheria
AU - Panoutsopoulou, Kalliope
AU - Bustamante, Mariona
AU - Penninx, Brenda W.J.H.
AU - Murabito, Joanne
AU - Torrent, Maties
AU - Dedoussis, George V.
AU - Kiess, Wieland
AU - Boomsma, Dorret I.
AU - Pennell, Craig E.
AU - Raitakari, Olli T.
AU - Hyppönen, Elina
AU - Smith, George Davey
AU - Ripatti, Samuli
AU - Hinney, Anke
AU - Holst, Claus
AU - Kilpeläinen, Tuomas O.
AU - Melbye, Mads
AU - Nohr, Ellen Aagaard
AU - Sørensen, Thorkild I.A.
AU - Zhao, Jing Hua
AU - Chen, Wei
AU - Loos, Ruth J.F.
AU - The ReproGen Consortium
AU - The Early Growth Genetics (EGG) Consortium
AU - The Early Growth Genetics (EGG) Consortium
AU - The ReproGen Consortium
AU - The GIANT Consortium
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Little is known about genes regulating male puberty. Further, while many identified pubertal timing 1variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9×10-9), amenarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6×10-5) and short adult stature (p = 7.5×10-6) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
AB - Little is known about genes regulating male puberty. Further, while many identified pubertal timing 1variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9×10-9), amenarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6×10-5) and short adult stature (p = 7.5×10-6) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
U2 - 10.1093/hmg/ddu150
DO - 10.1093/hmg/ddu150
M3 - Journal article
C2 - 24770850
AN - SCOPUS:84904751759
VL - 23
SP - 4452
EP - 4464
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 16
ER -
ID: 258832783