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Determination of Sequence Variation and Haplotype Structure for the Gonadotropin-Releasing Hormone (GnRH) and GnRH Receptor Genes: Investigation of Role in Pubertal Timing

Divisions of Endocrinology and Genetics (I.L.S., J.L.B., T.B., J.N.H.), Department of Medicine, Children’s Hospital, and Departments of Genetics and Pediatrics (I.L.S., J.L.B., T.B., J.N.H.), Harvard Medical School, Boston, Massachusetts 02115; Department of Preventive Medicine (C.L.P., B.E.H.), University of Southern California, Keck School of Medicine, Los Angeles, California 90089; Endocrine Science Research Group (J.A.T., P.E.C.), University of Manchester, Manchester M13 9PT, United Kingdom; Academic Unit of Medical Genetics (A.P.R.), St. Mary’s Hospital, Manchester M13 0JH, United Kingdom; Cancer Research Center (L.N.K.), University of Hawaii, Honolulu, Hawaii 96813; Program in Medical and Population Genetics (J.N.H.), Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02139; and Division of Pediatric Endocrinology and Metabolism (M.R.P.), Rainbow Babies and Children’s Hospital, University Hospitals of Cleveland, Departments of Pediatrics and Genetics, Case School of Medicine, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: Mark R. Palmert, M.D., Ph.D., Division of Pediatric Endocrinology and Metabolism, Rainbow Babies and Children’s Hospital, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: mark.palmert{at}cwru.edu.

Because GnRH and its receptor (GnRHR) are pivotal regulators of the reproductive endocrine axis and mutations in GNRHR lead to hypogonadotropic hypogonadism, we investigated whether genetic variation in GNRHR or GNRH1 affects pubertal timing in the general population.

To screen for missense mutations in these genes that might affect pubertal timing, we resequenced the coding regions of these genes in 48 probands with late but otherwise normal pubertal development. No missense variants were found in either gene, except for a previously identified single nucleotide polymorphism (SNP) in GNRH1 that was not associated with late pubertal development. To search for common variants that might affect pubertal timing, we took a haplotype-based association approach. To identify common haplotypes in these genes, we genotyped 41 SNPs in DNA from commercially available European-derived multigenerational pedigrees and participants in a multiethnic cohort (MEC). Two blocks of strong linkage disequilibrium were identified that spanned GNRHR and one was identified spanning GNRH1; within each block, more than 80% of chromosomes carried one of a few common haplotypes. A set of haplotype-tagging SNPs that mark these common haplotypes in all five ethnic groups within the MEC were defined and used to perform association studies among 125 trios (probands with late pubertal development and their parents) and 506 women from the MEC who had early (menarche < 11 yr of age, n = 216) or late (menarche 15 yr of age, n = 290) pubertal development. Three SNPs in GNRHR showed modest association with late pubertal development in the trios; among the 506 women, a different SNP was associated with late menarche, and one rare haplotype was associated with early age of menarche. All of the observed associations were relatively modest and only nominally statistically significant; replication is needed to determine their validity.

We conclude that genetic variation in GNRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population.

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