Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty.
Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants 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)), a menarche 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.
Institute for Molecular Medicine Finland (FIMM).
Diana L
DL
Cousminer
MRC Integrative Epidemiology Unit.
Evangelia
E
Stergiakouli
Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, UK.
Diane J
DJ
Berry
School of Women's and Infants' Health, The University of Western Australia, Perth, WA, Australia.
Wei
W
Ang
Department of Biological Psychology EMGO+ Institute for Health and Care Research.
Maria M
MM
Groen-Blokhuis
Center of Pediatric Research, Department of Women's & Child Health, University of Leipzig, Leipzig, Germany.
Antje
A
Körner
Research Centre of Applied and Preventive Cardiovascular Medicine.
Niina
N
Siitonen
Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
Ioanna
I
Ntalla
Center for Research in Environmental Epidemiology (CREAL), Barcelona, Catelonia, Spain Hospital del Mar Research Institute (IMIM), Barcelona, Catalonia, Spain Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Barcelona, Catalonia, Spain.
Marcella
M
Marinelli
MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
John R B
JR
Perry
Institute for Molecular Medicine Finland (FIMM) Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
Johannes
J
Kettunen
EMGO+ Institute for Health and Care Research Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
Rick
R
Jansen
Institute for Molecular Medicine Finland (FIMM) Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
Ida
I
Surakka
MRC Integrative Epidemiology Unit.
Nicholas J
NJ
Timpson
Avon Longitudinal Study of Parents and Children (ALSPAC), School of Social and Community Medicine, University of Bristol, Bristol, UK.
Susan
S
Ring
Avon Longitudinal Study of Parents and Children (ALSPAC), School of Social and Community Medicine, University of Bristol, Bristol, UK.
George
G
Mcmahon
Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, UK.
Chris
C
Power
School of Women's and Infants' Health, The University of Western Australia, Perth, WA, Australia.
Carol
C
Wang
Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere 33521, Finland.
Mika
M
Kähönen
Department of Medicine, University of Turku and Turku University Hospital, Turku 20521, Finland.
Jorma
J
Viikari
Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
Terho
T
Lehtimäki
Department of Biological Psychology Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
Christel M
CM
Middeldorp
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Hilleke E
HE
Hulshoff Pol
Center of Pediatric Research, Department of Women's & Child Health, University of Leipzig, Leipzig, Germany.
Madlen
M
Neef
Center of Pediatric Research, Department of Women's & Child Health, University of Leipzig, Leipzig, Germany.
Sebastian
S
Weise
Research Centre of Applied and Preventive Cardiovascular Medicine Paavo Nurmi Centre, Sports & Exercise Medicine Unit, Department of Physical Activity and Health.
Katja
K
Pahkala
Research Centre of Applied and Preventive Cardiovascular Medicine Department of Pediatrics, University of Turku, Turku, Finland.
Harri
H
Niinikoski
Wellcome Trust Sanger Institute, Hinxton, UK.
Eleftheria
E
Zeggini
Wellcome Trust Sanger Institute, Hinxton, UK.
Kalliope
K
Panoutsopoulou
Center for Research in Environmental Epidemiology (CREAL), Barcelona, Catelonia, Spain Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Barcelona, Catalonia, Spain Genes and genomes, Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain and.
Mariona
M
Bustamante
EMGO+ Institute for Health and Care Research Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands.
Brenda W J H
BW
Penninx
Department of Medicine, Section of General Internal Medicine, Boston University School of Medicine, Boston, MA, USA.
Joanne
J
Murabito
Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Barcelona, Catalonia, Spain ib-salut, Area de Salut de Menorca, Balearic Islands, Spain.
Maties
M
Torrent
Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
George V
GV
Dedoussis
Center of Pediatric Research, Department of Women's & Child Health, University of Leipzig, Leipzig, Germany.
Wieland
W
Kiess
Department of Biological Psychology EMGO+ Institute for Health and Care Research Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands.
Dorret I
DI
Boomsma
School of Women's and Infants' Health, The University of Western Australia, Perth, WA, Australia.
Craig E
CE
Pennell
Research Centre of Applied and Preventive Cardiovascular Medicine Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
Olli T
OT
Raitakari
Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, UK School of Population Health and Sansom Institute for Health Research, University of South Australia, North Terrace, Adelaide, Australia South Australian Health and Medical Research Institute, North Terrace, Adelaide, Australia.
Elina
E
Hyppönen
MRC Integrative Epidemiology Unit.
George
G
Davey Smith
Institute for Molecular Medicine Finland (FIMM) Hjelt Institute, University of Helsinki, Helsinki, Finland Wellcome Trust Sanger Institute, Hinxton, UK.
Samuli
S
Ripatti
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford, UK Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
Mark I
MI
McCarthy
Institute for Molecular Medicine Finland (FIMM) elisabeth.widen@helsinki.fi.
Elisabeth
E
Widén
D050154:Adiposity / Q000235:genetics; D000293:Adolescent; D015992:Body Mass Index; D001940:Breast / Q000254:growth & development; D002648:Child; D002885:Chromosomes, Human, Pair 16; D005260:Female; D056426:Genetic Loci; D005837:Genitalia, Male / Q000254:growth & development; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008572:Menarche / Q000235:genetics / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011627:Puberty / Q000235:genetics*; D012737:Sex Factors; D012741:Sexual Maturation / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D044465:White People
C478036:MRTFB protein, human; D014157:Transcription Factors