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, the Delayed Puberty Genetics Consortium
The Journal of Clinical Endocrinology & Metabolism, First published online March 13, 2024, dgae166
https://doi.org/10.1210/clinem/dgae166

Abstract

Context

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.

Objective

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

Design

Case-control study.

Participants

80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome (KS); 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).

Results

The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen's d = 0.67, P = 1 × 10⁻¹⁰; for AAM, d = 0.85, P = 1 × 10⁻¹⁶). 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 = .003; AAM d = 0.10, P = .055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.05, P = .45; AAM d = 0.03, P = .56).

Conclusion

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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