Abstract：
BACKGROUND: 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.
METHODS: Case-control study.
METHODS: 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies.
METHODS: 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 = 0.85, 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).
CONCLUSIONS: 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.
OBJECTIVE: To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH.
METHODS: Case-control study.
METHODS: 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies.
METHODS: 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 = 0.85, 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).
CONCLUSIONS: 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.
摘要：
背景：青春期的宪法延迟（CDP）是高度遗传的，但是CDP的遗传基础在很大程度上是未知的。特发性低促性腺激素性性腺功能减退（IHH）可由罕见的遗传变异引起，但是在大约一半的案例中，没有发现罕见的变异原因。
目的：确定影响青春期时间的常见遗传变异是否有助于CDP和IHH。
方法：病例对照研究。
方法：80名CDP患者；301名正常IHH患者，348例患有Kallmann综合征；来自无关研究的对照基因分型数据。
方法：基于全基因组关联研究的多基因评分（PGS），用于男性青春期标志的时间和初潮年龄（AAM）。
结果：与对照组相比，CDP队列对男性青春期标志和AAM的PGS较高（对于男性标志，科恩的d=0.85，p=1×10-16；对于AAM，d=0.67，p=1×10-10)。与对照组相比，正常IHH队列的男性标志PGS也较高，但差异较小（男性标志d=0.20，p=0.003；AAMd=0.10，p=0.055）。与对照组相比，KS队列未见差异（男性标志d=0.04，p=0.45；AAMd=-0.03，p=0.86）。
结论：影响普通人群青春期时间的常见遗传变异对CDP的遗传学有很大贡献，弱于正常的IHH，可能根本不会去KS。这些发现表明，CDP和正常IHH的共同变异遗传学在很大程度上但并不完全不同。
目的：确定影响青春期时间的常见遗传变异是否有助于CDP和IHH。
方法：病例对照研究。
方法：80名CDP患者；301名正常IHH患者，348例患有Kallmann综合征；来自无关研究的对照基因分型数据。
方法：基于全基因组关联研究的多基因评分（PGS），用于男性青春期标志的时间和初潮年龄（AAM）。
结果：与对照组相比，CDP队列对男性青春期标志和AAM的PGS较高（对于男性标志，科恩的d=0.85，p=1×10-16；对于AAM，d=0.67，p=1×10-10)。与对照组相比，正常IHH队列的男性标志PGS也较高，但差异较小（男性标志d=0.20，p=0.003；AAMd=0.10，p=0.055）。与对照组相比，KS队列未见差异（男性标志d=0.04，p=0.45；AAMd=-0.03，p=0.86）。
结论：影响普通人群青春期时间的常见遗传变异对CDP的遗传学有很大贡献，弱于正常的IHH，可能根本不会去KS。这些发现表明，CDP和正常IHH的共同变异遗传学在很大程度上但并不完全不同。
