{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:03:43Z","timestamp":1791378223565,"version":"4.3.2"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,11,9]],"date-time":"2015-11-09T00:00:00Z","timestamp":1447027200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,11,9]],"date-time":"2015-11-09T00:00:00Z","timestamp":1447027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Understanding of the genetic regulation of puberty timing has come largely from studies of rare disorders and population-based studies in women. Here, we report the largest genomic analysis for puberty timing in 55,871 men, based on recalled age at voice breaking. Analysis across all genomic variants reveals strong genetic correlation (0.74,\n                    <jats:italic>P<\/jats:italic>\n                    =2.7 \u00d7 10\n                    <jats:sup>\u221270<\/jats:sup>\n                    ) between male and female puberty timing. However, some loci show sex-divergent effects, including directionally opposite effects between sexes at the\n                    <jats:italic>SIM1<\/jats:italic>\n                    \/\n                    <jats:italic>MCHR2<\/jats:italic>\n                    locus (\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>heterogeneity<\/jats:sub>\n                    =1.6 \u00d7 10\n                    <jats:sup>\u221212<\/jats:sup>\n                    ). We find five novel loci for puberty timing (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;5 \u00d7 10\n                    <jats:sup>\u22128<\/jats:sup>\n                    ), in addition to nine signals in men that were previously reported in women. Newly implicated genes include two retinoic acid-related receptors,\n                    <jats:italic>RORB<\/jats:italic>\n                    and\n                    <jats:italic>RXRA<\/jats:italic>\n                    , and two genes reportedly disrupted in rare disorders of puberty,\n                    <jats:italic>LEPR<\/jats:italic>\n                    and\n                    <jats:italic>KAL1.<\/jats:italic>\n                    Finally, we identify genetic correlations that indicate shared aetiologies in both sexes between puberty timing and body mass index, fasting insulin levels, lipid levels, type 2 diabetes and cardiovascular disease.\n                  <\/jats:p>","DOI":"10.1038\/ncomms9842","type":"journal-article","created":{"date-parts":[[2015,11,9]],"date-time":"2015-11-09T05:08:50Z","timestamp":1447045730000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["Shared genetic aetiology of puberty timing between sexes and with health-related outcomes"],"prefix":"10.1038","volume":"6","author":[{"given":"Felix R.","family":"Day","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Bulik-Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Hinds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary K.","family":"Finucane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne M.","family":"Murabito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce Y.","family":"Tung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken K.","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.B.","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,11,9]]},"reference":[{"key":"BFncomms9842_CR1","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1136\/adc.77.5.445","volume":"77","author":"ML Harries","year":"1997","unstructured":"Harries, M. L., Walker, J. M., Williams, D. M., Hawkins, S. & Hughes, I. A. Changes in the male voice at puberty. Arch. Dis. Child. 77, 445\u2013447 (1997).","journal-title":"Arch. Dis. Child."},{"key":"BFncomms9842_CR2","doi-asserted-by":"publisher","first-page":"2844","DOI":"10.1210\/jc.2011-3445","volume":"97","author":"KK Ong","year":"2012","unstructured":"Ong, K. K. et al. Timing of voice breaking in males associated with growth and weight gain across the life course. J. Clin. Endocrinol. Metab. 97, 2844\u20132852 (2012).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"BFncomms9842_CR3","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1210\/er.2002-0019","volume":"24","author":"AS Parent","year":"2003","unstructured":"Parent, A. S. et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev. 24, 668\u2013693 (2003).","journal-title":"Endocr. 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Central precocious puberty caused by mutations in the imprinted gene MKRN3. N. Engl. J. Med. 368, 2467\u20132475 (2013).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms9842_CR10","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1038\/ng.2686","volume":"45","author":"DA Hinds","year":"2013","unstructured":"Hinds, D. A. et al. A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. Nat. Genet. 45, 907\u2013911 (2013).","journal-title":"Nat. Genet."},{"key":"BFncomms9842_CR11","doi-asserted-by":"crossref","unstructured":"Bulik-Sullivan, B. K. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. (in the press) doi:10.1038\/ng.3406 (2015).","DOI":"10.1038\/ng.3406"},{"key":"BFncomms9842_CR12","doi-asserted-by":"publisher","first-page":"e23473","DOI":"10.1371\/journal.pone.0023473","volume":"6","author":"JY Tung","year":"2011","unstructured":"Tung, J. Y. et al. 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Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197\u2013206 (2015).","journal-title":"Nature"},{"key":"BFncomms9842_CR18","doi-asserted-by":"crossref","unstructured":"Day, F. R., Perry, J. R. & Ong, K. K. Genetic regulation of puberty timing in humans. Neuroendocrinology (in the press) doi: 10.1159\/000431023 (2015).","DOI":"10.1159\/000431023"},{"key":"BFncomms9842_CR19","doi-asserted-by":"publisher","first-page":"3042","DOI":"10.1172\/JCI68016","volume":"123","author":"S Ramachandrappa","year":"2013","unstructured":"Ramachandrappa, S. et al. Rare variants in single-minded 1 (SIM1) are associated with severe obesity. J. Clin. Invest. 123, 3042\u20133050 (2013).","journal-title":"J. Clin. Invest."},{"key":"BFncomms9842_CR20","doi-asserted-by":"publisher","first-page":"11208","DOI":"10.1038\/srep11208","volume":"5","author":"F Day","year":"2015","unstructured":"Day, F., Elks, C. E., Murray, A. M., Ong, K. K. & Perry, J. R. 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The remaining authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8842"}}