Ingenuity Pathway Analysis (IPA) Knowledge Base 8.5 (Ingenuity Systems, CA, USA) was used to explore the functional relationship between proteins encoded by the 42 known, confirmed and possible novel menarche loci. The IPA Knowledge base contains millions of findings curated from the literature. Genes or nearest genes to the 42 loci (as listed in Table 1) were entered into the Ingenuity database. These “focus genes” were analyzed for direct interactions only. Networks were generated with a maximum size of 35 genes and shown as graphical representations of the molecular relationships between genes and gene products. Proteins are depicted as nodes in various shapes representing the functional class of the protein. The biological relationships between nodes are depicted by lines. To determine the probability of the analyzed gene to be found together in a network from Ingenuity Pathways Knowledge Base due to random chance alone, IPA applies a Fisher’s exact test. The network score or P-value represents the significance of the focus gene enrichment. There are 25 diseases and disorders categories and 32 molecular and cellular function categories in the IPA
