THU206 Constitutional Delay Of Puberty And Idiopathic Hypogonadotropic Hypogonadism: Differential Contributions Of Common Genetic Variants
Bibliographic record
Abstract
Abstract Disclosure: M.F. Lippincott: None. E. Schafer: None. A.A. Hindman: None. R. Brauner: None. A. Delaney: None. K. McElreavey: None. J.E. Hall: None. J.N. Hirschhorn: None. M.R. Palmert: None. S.B. Seminara: None. R.M. Salem: None. Y. Chan: None. Introduction: Disorders of pubertal timing include self-limited constitutional delay of puberty (CDP) and longer lasting idiopathic hypogonadotropic hypogonadism (IHH). Both conditions have strong genetic influences. We sought to determine if common genetic variants that influence pubertal timing contribute to CDP and IHH. Hypothesis: IHH and CDP can sometimes be caused by the accumulation of common genetic variants that delay pubertal onset. Therefore, compared to controls, patients with CDP and IHH have higher polygenic risk scores (PRS) based on genome-wide association studies (GWAS) for pubertal timing. Methods: All research and data-sharing were conducted with participant/guardian consent and institutional ethical approval. We defined CDP as puberty starting between 12 and 18 y in girls and between 13.5 and 18 y in boys and IHH as low sex steroids and non-elevated gonadotropins at ≥18 y, both with no cause identified on standard clinical evaluation. We genotyped CDP cases (n=106) on the Illumina Infinium OmniExpress Exome 8-1v6 platform and retrieved array-matched control data from dbGaP (n=9,222). IHH cases (n=713) and controls from the Schizophrenia Psychiatric GWAS (n=1,868) were genotyped on the Infinium PsychArray. After data harmonization, quality control, and principal components analysis were performed on combined sets, genotype imputation was performed on all unrelated individuals of European ancestry using the Michigan Imputation Server. We downloaded summary statistics for: 1) GWAS meta-analysis for age at menarche (AAM), 2) multi-trait GWAS for male pubertal hallmarks, and 3) a negative control using GWAS for basal cell carcinoma (BCC). We calculated and compared PRS between cases and controls using PRS-CS and PRSice2, with the first 10 ancestral principal components and sex as covariates. We also performed sex-stratified analyses. Results: Both the CDP and the IHH cohorts had significantly higher PRS for male pubertal hallmarks compared to controls, but the difference was smaller for IHH (CDP Cohen’s d=0.59, p=2×10-10; IHH d=0.13, p=0.007). The CDP cohort also had a significantly higher PRS for AAM compared to controls (d=0.83, p=8×10-20), but the IHH cohort did not (d=0.08, p=0.06). Of note, sex-specific PRS provided greater discrimination between CDP cases and controls in stratified analyses of the corresponding sex (AAM in females: d=1.1, p=4×10-11; AAM in males d=0.72, p=8×10-11; male hallmarks in females: d=0.52, p=0.001; male hallmarks in males: d=0.63, p=2×10-8). No significant differences were observed between cases and controls for BCC PRS. Conclusions: Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, with some sex-specificity, but only weakly to IHH. These findings support the hypothesis that the common-variant genetics of CDP and IHH are largely distinct. Presentation: Thursday, June 15, 2023
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".