Association studies of common variants in 10 hypogonadotropic hypogonadism genes with age at menarche.
BACKGROUND
Although the timing of puberty is a highly heritable trait, little is known about the genes that regulate pubertal timing in the general population. Several genes have been identified that, when mutated, cause disorders of delayed or absent puberty such as hypogonadotropic hypogonadism (HH).


OBJECTIVE
Because severe variants in HH-related genes cause a severe puberty phenotype, we hypothesized that common subtle variation in these genes could contribute to the population variation in pubertal timing.


METHODS
We assessed common genetic variation in 10 HH-related genes in 1801 women from the Hawaii and Los Angeles Multiethnic Cohort with either early (age<11 yr) or late (age>14 yr) menarche and in other replication samples. In addition to these common variants, we also studied the most frequently reported HH mutations to assess their role in the population variation in pubertal timing. SETTING AND PATIENTS/OTHER PARTICIPANTS: Within the general community, 1801 women from the Hawaii and Los Angeles Multiethnic Cohort participated.


METHODS
We assessed the association of genetic variation with age at menarche.


RESULTS
We found no significant association between any of the variants tested and age at menarche, although we cannot rule out modest effects of these variants or of other variants at long distances from the coding region. In several self-reported racial/ethnic groups represented in our study, we observed an association between estimated genetic ancestry and age at menarche.


CONCLUSIONS
Our results suggest that common variants near 10 HH-related loci do not play a substantial role in the regulation of age at menarche in the general population.
Gajdos
Zofia K Z
ZK
Program in Genomics and Division of Endocrinology, Children's Hospital, and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Butler
Johannah L
JL
Henderson
Katherine DeLellis
KD
He
Chunyan
C
Supelak
Pamela J
PJ
Egyud
Matthew
M
Price
Alkes
A
Reich
David
D
Clayton
Peter E
PE
Le Marchand
Loic
L
Hunter
David J
DJ
Henderson
Brian E
BE
Palmert
Mark R
MR
Hirschhorn
Joel N
JN
D000293:Adolescent; D000367:Age Factors; D015992:Body Mass Index; D002648:Child; D005260:Female; D014644:Genetic Variation; D006254:Hawaii; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D015141:Los Angeles; D008572:Menarche / Q000235:genetics*; D011627:Puberty / Q000235:genetics*; D011628:Puberty, Delayed / Q000235:genetics; D044469:Racial Groups; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D011966:Receptors, LHRH / Q000235:genetics; D011795:Surveys and Questionnaires
C484844:GNRHR protein, human; D011966:Receptors, LHRH; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1