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Eight of the 389 lead variants were nonsynonymous, and a further 24 genes were implicated by highly correlated nonsynonymous variants (r 0.8) (Supplementary Table 6).
Accordingly, 217 of 377 (57.7%) autosomal index SNPs had larger effect estimates on early than on late AAM (binomial P = 0.004 versus 50% expected), and the aggregated effect of the 377 SNPs also differed between strata (P = 2.3 × 10The 377 index AAM-associated SNPs are ordered from smallest to largest P value for their continuous association with AAM.
Two approaches were used to interrogate publicly available gene expression data sets, both of which use one or more SNPs (not restricted to lead SNPs) to infer patterns of gene expression based on imputation reference panels (Online Methods).
First, to maximize power, we analyzed data from the largest available e QTL data set for any tissue (whole blood, N = 5,311), under the assumption that some causal genes and regulatory mechanisms might be ubiquitously expressed or functionally involved in blood tissues.
First, we identified a rare 5′ UTR variant, rs530324840 (MAF = 0.80% in Iceland), in MKRN3 that was associated with AAM under the paternal model (P = 6.4 × 10) (Table 1 and Supplementary Table 13).
rs530324840 was by far the most significant variant at the MKRN3 locus and is uncorrelated with our previously reported common variant rs12148769 at the same locus (r (Supplementary Fig. We note that the rare 5′ UTR variant rs184950120 detected in the current genome-wide association study (GWAS) meta-analysis also showed paternal-specific association in de CODE and, despite being in close proximity (235 bp from rs530324840), is uncorrelated with rs530324840 (r The second new robust parent-of-origin-specific signal is indicated by a rare intergenic variant at the DLK1 locus (rs138827001; MAF = 0.36% in Iceland) that associated with AAM under the paternal model (P = 4.7 × 10.
The distribution of genome-wide test statistics demonstrated significant inflation (λ = 1.75); however, linkage disequilibrium (LD) score regression analyses confirmed that this inflation was solely due to polygenicity rather than population structure (LD score intercept = 1.00, standard error (SE) = 0.02).
In total, 37,925 variants were associated with AAM at P )) and one rare variant not captured by the 1000 Genomes Project reference panel (p. Independent replication in the de CODE study (N = 39,543 women) showed that 367 (94.3%) of the 389 signals had directionally concordant effects (187 at P = 32%, SE = 1%) for AAM, estimated in UK Biobank. Consequently, the reported genetic signals explained only a small fraction of the population variance, suggesting that several hundred or thousand signals are involved and using more densely imputed genomic data. Our findings increase by more than threefold the number of independently associated signals and indicate likely causal effects of puberty timing on risks of various sex-steroid-sensitive cancers in men and women. To identify other mechanisms that regulate pubertal timing, we tested all SNPs across the genome for enrichment of AAM associations with genes in predefined biological pathways. Ten pathways reached study-wise significance (FDR ). To test for asymmetry in the genetic effects on puberty timing, we defined two groups of women in the UK Biobank study on the basis of approximated quintiles for AAM—'early' (8–11 years inclusive; N = 14,922) and 'late' (15–19 years; N = 12,290).