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. 2024 Dec 18;110(1):e61-e67.
doi: 10.1210/clinem/dgae166.

Contributions of Common Genetic Variants to Constitutional Delay of Puberty and Idiopathic Hypogonadotropic Hypogonadism

Margaret F Lippincott  1   2 , Evan C Schafer  3 , Anna A Hindman  1 , Wen He  3 , Raja Brauner  4 , Angela Delaney  5 , Romina Grinspon  6 , Janet E Hall  7 , Joel N Hirschhorn  2   3   8 , Kenneth McElreavey  9 , Mark R Palmert  10 , Rodolfo Rey  6 , Stephanie B Seminara  1   2   8 , Rany M Salem  11 , Yee-Ming Chan  2   3   8 ; Delayed Puberty Genetics Consortium
Collaborators, Affiliations

Contributions of Common Genetic Variants to Constitutional Delay of Puberty and Idiopathic Hypogonadotropic Hypogonadism

Margaret F Lippincott et al. J Clin Endocrinol Metab. .

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.

Keywords: Kallmann syndrome; common genetic variants; constitutional delay of puberty; idiopathic hypogonadotropic hypogonadism; polygenic scores.

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Figures

Figure 1.
Figure 1.
Contribution of common genetic variants to CDP and IHH. PGS for male pubertal hallmarks were significantly higher in CDP cases compared to controls (A), as well as in nIHH cases, though to a lesser extent (B), but not in KS cases (C). For age at menarche, CDP cases similarly had significantly higher PGS compared to controls (D), nIHH cases had nominally higher PGS (E), and again KS cases did not (F). Comparisons were adjusted for sex and the first 10 genetic principal components. PGS are expressed as normalized scores with a mean of 0 and a SD of 1. Density is the proportion of the cohort with PGS within the range indicated by the width of each bar.
Figure 2.
Figure 2.
PGS for pubertal timing in IHH subcohorts. PGS for male pubertal hallmarks were not different between cases and controls for IHH with reversal (A) or for normosmic IHH with an apparent rare-variant cause (B) but were significantly higher for normosmic IHH with no apparent rare-variant cause (C). Similar results were found for PGS for age at menarche (D-F). Comparisons were adjusted for sex and the first 10 genetic principal components. PGS are expressed as normalized scores with a mean of 0 and a SD of 1. Density is the proportion of the cohort with PGS within the range indicated by the width of each bar.
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