DOI: 10.1210/clinem/dgae166 ISSN: 0021-972X

Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism

Margaret F Lippincott, Evan C Schafer, Anna A Hindman, Wen He, Raja Brauner, Angela Delaney, Romina Grinspon, Janet E Hall, Joel N Hirschhorn, Kenneth McElreavey, Mark R Palmert, Rodolfo Rey, Stephanie B Seminara, Rany M Salem, Yee-Ming Chan, Sasha R Howard, Leo Dunkel, Ana Claudia Latronico, Alexander A de Lima Jorge, Aristeides Giannakopoulos, Verónica Mericq, Paulina Merino,
  • Biochemistry (medical)
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry
  • Endocrinology, Diabetes and Metabolism



Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found.


To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH


Case-control study


80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies

Main Outcome Measures

Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM)


The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen’s d = 0.85, p = 1 × 10-16; for AAM, d = 0.67, p = 1 × 10-10). The normosmic IHH cohort also had higher PGS for male hallmarks compared to controls, but the difference was smaller (male hallmarks d = 0.20, p = 0.003; AAM d = 0.10, p = 0.055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.04, p = 0.45; AAM d = -0.03, p = 0.86).


Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, weakly to normosmic IHH, and potentially not at all to KS. These findings demonstrate that the common-variant genetics of CDP and normosmic IHH are largely but not entirely distinct.

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