Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal mode...
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| Veröffentlicht in: | Nature 2014-10, Vol.514 (7520), p.92-7 |
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| creator | Perry, John R.B Day, Felix Elks, Cathy E Sulem, Patrick Thompson, Deborah J Ferreira, Teresa He, Chunyan Chasman, Daniel I Esko, Tõnu Thorleifsson, Gudmar Albrecht, Eva Knight, Julia A Kosma, Veli-Matti Kutalik, Zoltan Lai, Sandra Lambrechts, Diether Lindblom, Annika Mägi, Reedik Magnusson, Patrik K Mannermaa, Arto Martin, Nicholas G Ang, Wei Q Masson, Gisli McArdle, Patrick F McArdle, Wendy L Melbye, Mads Michailidou, Kyriaki Mihailov, Evelin Milani, Lili Milne, Roger L Nevanlinna, Heli Neven, Patrick Corre, Tanguy Nohr, Ellen A Oldehinkel, Albertine J Oostra, Ben A Palotie, Aarno Peacock, Munro Pedersen, Nancy L Peterlongo, Paolo Peto, Julian Pharoah, Paul D.P Postma, Dirkje S Cousminer, Diana L Pouta, Anneli Pylkäs, Katri Radice, Paolo Ring, Susan Rivadeneira, Fernando Robino, Antonietta Rose, Lynda M Rudolph, Anja Salomaa, Veikko Sanna, Serena Feenstra, Bjarke Schlessinger, David Schmidt, Marjanka K Southey, Mellissa C Sovio, Ulla Stampfer, Meir J Stöckl, Doris Storniolo, Anna M Timpson, Nicholas J Tyrer, Jonathan Visser, Jenny A Franceschini, Nora Vollenweider, Peter Völzke, Henry Waeber, Gerard Waldenberger, Melanie Wallaschofski, Henri Wang, Qin Willemsen, Gonneke Winqvist, Robert Wolffenbuttel, Bruce H.R Wright, Margaret J Ganna, Andrea Australian Ovarian Cancer Study GENICA Network kConFab LifeLines Cohort Study InterAct Consortium Early Growth Genetics (EGG) Consortium Boomsma, Dorret I Econs, Michael J Khaw, Kay-Tee Loos, Ruth J.F Johnson, Andrew D McCarthy, Mark I Montgomery, Grant W Rice, John P Streeten, Elizabeth A Thorsteinsdottir, Unnur van Duijn, Cornelia M Alizadeh, Behrooz Z Bergmann, Sven Boerwinkle, Eric Boyd, Heather A Kjellqvist, Sanela Crisponi, Laura |
| description | Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P |
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It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.</description><identifier>ISSN: 0028-0836</identifier><language>eng</language><publisher>Nature Publishing Group</publisher><ispartof>Nature, 2014-10, Vol.514 (7520), p.92-7</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,315,776,780,27837</link.rule.ids></links><search><creatorcontrib>Perry, John R.B</creatorcontrib><creatorcontrib>Day, Felix</creatorcontrib><creatorcontrib>Elks, Cathy E</creatorcontrib><creatorcontrib>Sulem, Patrick</creatorcontrib><creatorcontrib>Thompson, Deborah J</creatorcontrib><creatorcontrib>Ferreira, Teresa</creatorcontrib><creatorcontrib>He, 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Kay-Tee</creatorcontrib><creatorcontrib>Loos, Ruth J.F</creatorcontrib><creatorcontrib>Johnson, Andrew D</creatorcontrib><creatorcontrib>McCarthy, Mark I</creatorcontrib><creatorcontrib>Montgomery, Grant W</creatorcontrib><creatorcontrib>Rice, John P</creatorcontrib><creatorcontrib>Streeten, Elizabeth A</creatorcontrib><creatorcontrib>Thorsteinsdottir, Unnur</creatorcontrib><creatorcontrib>van Duijn, Cornelia M</creatorcontrib><creatorcontrib>Alizadeh, Behrooz Z</creatorcontrib><creatorcontrib>Bergmann, Sven</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Boyd, Heather A</creatorcontrib><creatorcontrib>Kjellqvist, Sanela</creatorcontrib><creatorcontrib>Crisponi, Laura</creatorcontrib><title>Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche</title><title>Nature</title><description>Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.</description><issn>0028-0836</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>FZOIL</sourceid><recordid>eNqNjLsKwjAUQDMoWB__kM1BAmmbPpxFcXRwcSqXeBOjaVKaVPx8K_gBnc5wDmdGEs6zmvE6LxdkGcKTc16klUjI7QI9usi8Yr432jgWOpRGGUnBWrQ_huClgWi8CxRa7zRNeUk1Ot-O2o6SKt9T0Egh0hYd9PKBazJXYANu_lyR7el4PZzZa7A4vNE199CBxCbNclGUVb1vykzUhchXZDetbOIn5tO_XzAQT6U</recordid><startdate>201410</startdate><enddate>201410</enddate><creator>Perry, John R.B</creator><creator>Day, Felix</creator><creator>Elks, Cathy E</creator><creator>Sulem, Patrick</creator><creator>Thompson, Deborah J</creator><creator>Ferreira, Teresa</creator><creator>He, Chunyan</creator><creator>Chasman, Daniel I</creator><creator>Esko, Tõnu</creator><creator>Thorleifsson, Gudmar</creator><creator>Albrecht, 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Econs, Michael J ; Khaw, Kay-Tee ; Loos, Ruth J.F ; Johnson, Andrew D ; McCarthy, Mark I ; Montgomery, Grant W ; Rice, John P ; Streeten, Elizabeth A ; Thorsteinsdottir, Unnur ; van Duijn, Cornelia M ; Alizadeh, Behrooz Z ; Bergmann, Sven ; Boerwinkle, Eric ; Boyd, Heather A ; Kjellqvist, Sanela ; Crisponi, Laura</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-kuleuven_dspace_123456789_6248543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Perry, John R.B</creatorcontrib><creatorcontrib>Day, Felix</creatorcontrib><creatorcontrib>Elks, Cathy E</creatorcontrib><creatorcontrib>Sulem, Patrick</creatorcontrib><creatorcontrib>Thompson, Deborah J</creatorcontrib><creatorcontrib>Ferreira, Teresa</creatorcontrib><creatorcontrib>He, Chunyan</creatorcontrib><creatorcontrib>Chasman, Daniel I</creatorcontrib><creatorcontrib>Esko, Tõnu</creatorcontrib><creatorcontrib>Thorleifsson, Gudmar</creatorcontrib><creatorcontrib>Albrecht, Eva</creatorcontrib><creatorcontrib>Knight, Julia A</creatorcontrib><creatorcontrib>Kosma, Veli-Matti</creatorcontrib><creatorcontrib>Kutalik, Zoltan</creatorcontrib><creatorcontrib>Lai, Sandra</creatorcontrib><creatorcontrib>Lambrechts, Diether</creatorcontrib><creatorcontrib>Lindblom, Annika</creatorcontrib><creatorcontrib>Mägi, Reedik</creatorcontrib><creatorcontrib>Magnusson, Patrik K</creatorcontrib><creatorcontrib>Mannermaa, Arto</creatorcontrib><creatorcontrib>Martin, Nicholas G</creatorcontrib><creatorcontrib>Ang, Wei Q</creatorcontrib><creatorcontrib>Masson, Gisli</creatorcontrib><creatorcontrib>McArdle, Patrick F</creatorcontrib><creatorcontrib>McArdle, Wendy L</creatorcontrib><creatorcontrib>Melbye, Mads</creatorcontrib><creatorcontrib>Michailidou, Kyriaki</creatorcontrib><creatorcontrib>Mihailov, Evelin</creatorcontrib><creatorcontrib>Milani, Lili</creatorcontrib><creatorcontrib>Milne, Roger L</creatorcontrib><creatorcontrib>Nevanlinna, Heli</creatorcontrib><creatorcontrib>Neven, Patrick</creatorcontrib><creatorcontrib>Corre, Tanguy</creatorcontrib><creatorcontrib>Nohr, Ellen A</creatorcontrib><creatorcontrib>Oldehinkel, Albertine J</creatorcontrib><creatorcontrib>Oostra, Ben A</creatorcontrib><creatorcontrib>Palotie, Aarno</creatorcontrib><creatorcontrib>Peacock, Munro</creatorcontrib><creatorcontrib>Pedersen, Nancy L</creatorcontrib><creatorcontrib>Peterlongo, Paolo</creatorcontrib><creatorcontrib>Peto, Julian</creatorcontrib><creatorcontrib>Pharoah, Paul D.P</creatorcontrib><creatorcontrib>Postma, Dirkje S</creatorcontrib><creatorcontrib>Cousminer, Diana L</creatorcontrib><creatorcontrib>Pouta, Anneli</creatorcontrib><creatorcontrib>Pylkäs, Katri</creatorcontrib><creatorcontrib>Radice, Paolo</creatorcontrib><creatorcontrib>Ring, Susan</creatorcontrib><creatorcontrib>Rivadeneira, Fernando</creatorcontrib><creatorcontrib>Robino, Antonietta</creatorcontrib><creatorcontrib>Rose, Lynda M</creatorcontrib><creatorcontrib>Rudolph, Anja</creatorcontrib><creatorcontrib>Salomaa, Veikko</creatorcontrib><creatorcontrib>Sanna, Serena</creatorcontrib><creatorcontrib>Feenstra, Bjarke</creatorcontrib><creatorcontrib>Schlessinger, David</creatorcontrib><creatorcontrib>Schmidt, Marjanka K</creatorcontrib><creatorcontrib>Southey, Mellissa C</creatorcontrib><creatorcontrib>Sovio, Ulla</creatorcontrib><creatorcontrib>Stampfer, Meir J</creatorcontrib><creatorcontrib>Stöckl, Doris</creatorcontrib><creatorcontrib>Storniolo, Anna M</creatorcontrib><creatorcontrib>Timpson, Nicholas J</creatorcontrib><creatorcontrib>Tyrer, Jonathan</creatorcontrib><creatorcontrib>Visser, Jenny A</creatorcontrib><creatorcontrib>Franceschini, Nora</creatorcontrib><creatorcontrib>Vollenweider, Peter</creatorcontrib><creatorcontrib>Völzke, Henry</creatorcontrib><creatorcontrib>Waeber, Gerard</creatorcontrib><creatorcontrib>Waldenberger, Melanie</creatorcontrib><creatorcontrib>Wallaschofski, Henri</creatorcontrib><creatorcontrib>Wang, Qin</creatorcontrib><creatorcontrib>Willemsen, Gonneke</creatorcontrib><creatorcontrib>Winqvist, Robert</creatorcontrib><creatorcontrib>Wolffenbuttel, Bruce H.R</creatorcontrib><creatorcontrib>Wright, Margaret J</creatorcontrib><creatorcontrib>Ganna, Andrea</creatorcontrib><creatorcontrib>Australian Ovarian Cancer Study</creatorcontrib><creatorcontrib>GENICA Network</creatorcontrib><creatorcontrib>kConFab</creatorcontrib><creatorcontrib>LifeLines Cohort Study</creatorcontrib><creatorcontrib>InterAct Consortium</creatorcontrib><creatorcontrib>Early Growth Genetics (EGG) Consortium</creatorcontrib><creatorcontrib>Boomsma, Dorret I</creatorcontrib><creatorcontrib>Econs, Michael J</creatorcontrib><creatorcontrib>Khaw, Kay-Tee</creatorcontrib><creatorcontrib>Loos, Ruth J.F</creatorcontrib><creatorcontrib>Johnson, Andrew D</creatorcontrib><creatorcontrib>McCarthy, Mark I</creatorcontrib><creatorcontrib>Montgomery, Grant W</creatorcontrib><creatorcontrib>Rice, John P</creatorcontrib><creatorcontrib>Streeten, Elizabeth A</creatorcontrib><creatorcontrib>Thorsteinsdottir, Unnur</creatorcontrib><creatorcontrib>van Duijn, Cornelia M</creatorcontrib><creatorcontrib>Alizadeh, Behrooz Z</creatorcontrib><creatorcontrib>Bergmann, Sven</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Boyd, Heather A</creatorcontrib><creatorcontrib>Kjellqvist, Sanela</creatorcontrib><creatorcontrib>Crisponi, Laura</creatorcontrib><collection>Lirias (KU Leuven Association)</collection><jtitle>Nature</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Perry, John R.B</au><au>Day, Felix</au><au>Elks, Cathy E</au><au>Sulem, Patrick</au><au>Thompson, Deborah J</au><au>Ferreira, Teresa</au><au>He, Chunyan</au><au>Chasman, Daniel I</au><au>Esko, Tõnu</au><au>Thorleifsson, Gudmar</au><au>Albrecht, Eva</au><au>Knight, Julia A</au><au>Kosma, Veli-Matti</au><au>Kutalik, Zoltan</au><au>Lai, Sandra</au><au>Lambrechts, Diether</au><au>Lindblom, Annika</au><au>Mägi, Reedik</au><au>Magnusson, Patrik K</au><au>Mannermaa, Arto</au><au>Martin, Nicholas G</au><au>Ang, Wei Q</au><au>Masson, Gisli</au><au>McArdle, Patrick F</au><au>McArdle, Wendy L</au><au>Melbye, Mads</au><au>Michailidou, Kyriaki</au><au>Mihailov, Evelin</au><au>Milani, Lili</au><au>Milne, Roger L</au><au>Nevanlinna, Heli</au><au>Neven, Patrick</au><au>Corre, Tanguy</au><au>Nohr, Ellen A</au><au>Oldehinkel, Albertine J</au><au>Oostra, Ben A</au><au>Palotie, Aarno</au><au>Peacock, Munro</au><au>Pedersen, Nancy L</au><au>Peterlongo, Paolo</au><au>Peto, Julian</au><au>Pharoah, Paul D.P</au><au>Postma, Dirkje S</au><au>Cousminer, Diana L</au><au>Pouta, Anneli</au><au>Pylkäs, Katri</au><au>Radice, Paolo</au><au>Ring, Susan</au><au>Rivadeneira, Fernando</au><au>Robino, Antonietta</au><au>Rose, Lynda M</au><au>Rudolph, Anja</au><au>Salomaa, Veikko</au><au>Sanna, Serena</au><au>Feenstra, Bjarke</au><au>Schlessinger, David</au><au>Schmidt, Marjanka K</au><au>Southey, Mellissa C</au><au>Sovio, Ulla</au><au>Stampfer, Meir J</au><au>Stöckl, Doris</au><au>Storniolo, Anna M</au><au>Timpson, Nicholas J</au><au>Tyrer, Jonathan</au><au>Visser, Jenny A</au><au>Franceschini, Nora</au><au>Vollenweider, Peter</au><au>Völzke, Henry</au><au>Waeber, Gerard</au><au>Waldenberger, Melanie</au><au>Wallaschofski, Henri</au><au>Wang, Qin</au><au>Willemsen, Gonneke</au><au>Winqvist, Robert</au><au>Wolffenbuttel, Bruce H.R</au><au>Wright, Margaret J</au><au>Ganna, Andrea</au><au>Australian Ovarian Cancer Study</au><au>GENICA Network</au><au>kConFab</au><au>LifeLines Cohort Study</au><au>InterAct Consortium</au><au>Early Growth Genetics (EGG) Consortium</au><au>Boomsma, Dorret I</au><au>Econs, Michael J</au><au>Khaw, Kay-Tee</au><au>Loos, Ruth J.F</au><au>Johnson, Andrew D</au><au>McCarthy, Mark I</au><au>Montgomery, Grant W</au><au>Rice, John P</au><au>Streeten, Elizabeth A</au><au>Thorsteinsdottir, Unnur</au><au>van Duijn, Cornelia M</au><au>Alizadeh, Behrooz Z</au><au>Bergmann, Sven</au><au>Boerwinkle, Eric</au><au>Boyd, Heather A</au><au>Kjellqvist, Sanela</au><au>Crisponi, Laura</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche</atitle><jtitle>Nature</jtitle><date>2014-10</date><risdate>2014</risdate><volume>514</volume><issue>7520</issue><spage>92</spage><epage>7</epage><pages>92-7</pages><issn>0028-0836</issn><abstract>Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.</abstract><pub>Nature Publishing Group</pub><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature, 2014-10, Vol.514 (7520), p.92-7 |
| issn | 0028-0836 |
| language | eng |
| recordid | cdi_kuleuven_dspace_123456789_624854 |
| source | Lirias (KU Leuven Association); Springer Nature - Complete Springer Journals; Nature Journals Online |
| title | Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche |
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