Table 2.

Frequencies of predicted deleterious MC3R variants in women with delayed or early menarche timing

Variant class	Menarche timing (age)	No. noncarriers	No. carriers	Carrier frequency, %	OR vs normal timing	95% CI	P
High	Delayed (≥16 y)	23 216	13	0.0560	2.3466	1.17-4.38	.0098
High	Early (<10 y)	9321	2	0.0215	0.8992	0.11-3.42	≥.999
High	Normal	213 725	51	0.0239	—	—	—
Moderate excl. benign	Delayed (≥16 y)	23 088	141	0.6070	1.5155	1.26-1.81	1.45E-05
Moderate excl. benign	Early (<10 y)	9298	25	0.2682	0.6672	0.43-0.99	.0430
Moderate excl. benign	Normal	212 918	858	0.4014	—		—
Moderate/high excl. benign	Delayed (≥16 y)	23 076	153	0.6587	1.5527	1.30-1.85	1.77E-06
Moderate/high excl. benign	Early (<10 y)	9296	27	0.2896	0.6802	0.45-1.00	.0489
Moderate/high excl. benign	Normal	212 867	909	0.4252	—	—	—
CADD ≥25	Delayed (≥16 y)	23 097	132	0.5683	1.6633	1.37-2.01	3.90E-07
CADD ≥25	Early (<10 y)	9300	23	0.2467	0.7198	0.45-1.09	.1437
CADD ≥25	Normal	213 044	732	0.3424	—	—	—

Data are from the UK Biobank 450k exome cohort. ORs were calculated for frequency of carriers for MC3R coding variants in clinically defined categories of self-reported menarche timing. Variant classes were defined by variant effect predictor: high = protein-truncating variants; moderate = missense variants/in-frame insertion/deletions. Benign variants were excluded as classified by SIFT/Polyphen. CADD score cutoff set to 25 or greater.

Abbreviations: CADD, Combined Annotation-Dependent Depletion; MC3R, melanocortin 3 receptor; OR, odds ratio.