%0 Journal Article %J Nat Genet %D 2018 %T Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. %A Lee, James J %A Wedow, Robbee %A Okbay, Aysu %A Kong, Edward %A Maghzian, Omeed %A Zacher, Meghan %A Nguyen-Viet, Tuan Anh %A Bowers, Peter %A Sidorenko, Julia %A Karlsson Linnér, Richard %A Fontana, Mark Alan %A Kundu, Tushar %A Lee, Chanwook %A Li, Hui %A Li, Ruoxi %A Royer, Rebecca %A Timshel, Pascal N %A Walters, Raymond K %A Willoughby, Emily A %A Yengo, Loic %A Alver, Maris %A Bao, Yanchun %A Clark, David W %A Day, Felix R %A Furlotte, Nicholas A %A Joshi, Peter K %A Kemper, Kathryn E %A Kleinman, Aaron %A Langenberg, Claudia %A Mägi, Reedik %A Trampush, Joey W %A Verma, Shefali Setia %A Wu, Yang %A Lam, Max %A Zhao, Jing Hua %A Zheng, Zhili %A Boardman, Jason D %A Campbell, Harry %A Freese, Jeremy %A Harris, Kathleen Mullan %A Hayward, Caroline %A Herd, Pamela %A Kumari, Meena %A Lencz, Todd %A Luan, Jian'an %A Malhotra, Anil K %A Metspalu, Andres %A Milani, Lili %A Ong, Ken K %A Perry, John R B %A Porteous, David J %A Ritchie, Marylyn D %A Smart, Melissa C %A Smith, Blair H %A Tung, Joyce Y %A Wareham, Nicholas J %A Wilson, James F %A Beauchamp, Jonathan P %A Conley, Dalton C %A Esko, Tõnu %A Lehrer, Steven F %A Magnusson, Patrik K E %A Oskarsson, Sven %A Pers, Tune H %A Robinson, Matthew R %A Thom, Kevin %A Watson, Chelsea %A Chabris, Christopher F %A Meyer, Michelle N %A Laibson, David I %A Yang, Jian %A Johannesson, Magnus %A Koellinger, Philipp D %A Turley, Patrick %A Visscher, Peter M %A Benjamin, Daniel J %A Cesarini, David %X

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

%B Nat Genet %V 50 %P 1112-1121 %8 2018 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/30038396?dopt=Abstract %R 10.1038/s41588-018-0147-3 %0 Journal Article %J Nat Genet %D 2018 %T Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. %A Tedja, Milly S %A Wojciechowski, Robert %A Hysi, Pirro G %A Eriksson, Nicholas %A Furlotte, Nicholas A %A Verhoeven, Virginie J M %A Iglesias, Adriana I %A Meester-Smoor, Magda A %A Tompson, Stuart W %A Fan, Qiao %A Khawaja, Anthony P %A Cheng, Ching-Yu %A Höhn, René %A Yamashiro, Kenji %A Wenocur, Adam %A Grazal, Clare %A Haller, Toomas %A Metspalu, Andres %A Wedenoja, Juho %A Jonas, Jost B %A Wang, Ya Xing %A Xie, Jing %A Mitchell, Paul %A Foster, Paul J %A Klein, Barbara E K %A Klein, Ronald %A Paterson, Andrew D %A Hosseini, S Mohsen %A Shah, Rupal L %A Williams, Cathy %A Teo, Yik Ying %A Tham, Yih Chung %A Gupta, Preeti %A Zhao, Wanting %A Shi, Yuan %A Saw, Woei-Yuh %A Tai, E-Shyong %A Sim, Xue Ling %A Huffman, Jennifer E %A Polasek, Ozren %A Hayward, Caroline %A Bencic, Goran %A Rudan, Igor %A Wilson, James F %A Joshi, Peter K %A Tsujikawa, Akitaka %A Matsuda, Fumihiko %A Whisenhunt, Kristina N %A Zeller, Tanja %A van der Spek, Peter J %A Haak, Roxanna %A Meijers-Heijboer, Hanne %A van Leeuwen, Elisabeth M %A Iyengar, Sudha K %A Lass, Jonathan H %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Vingerling, Johannes R %A Lehtimäki, Terho %A Raitakari, Olli T %A Biino, Ginevra %A Concas, Maria Pina %A Schwantes-An, Tae-Hwi %A Igo, Robert P %A Cuellar-Partida, Gabriel %A Martin, Nicholas G %A Craig, Jamie E %A Gharahkhani, Puya %A Williams, Katie M %A Nag, Abhishek %A Rahi, Jugnoo S %A Cumberland, Phillippa M %A Delcourt, Cécile %A Bellenguez, Céline %A Ried, Janina S %A Bergen, Arthur A %A Meitinger, Thomas %A Gieger, Christian %A Wong, Tien Yin %A Hewitt, Alex W %A Mackey, David A %A Simpson, Claire L %A Pfeiffer, Norbert %A Pärssinen, Olavi %A Baird, Paul N %A Vitart, Veronique %A Amin, Najaf %A van Duijn, Cornelia M %A Bailey-Wilson, Joan E %A Young, Terri L %A Saw, Seang-Mei %A Stambolian, Dwight %A MacGregor, Stuart %A Guggenheim, Jeremy A %A Tung, Joyce Y %A Hammond, Christopher J %A Klaver, Caroline C W %X

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

%B Nat Genet %V 50 %P 834-848 %8 2018 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/29808027?dopt=Abstract %R 10.1038/s41588-018-0127-7 %0 Journal Article %J Nat Genet %D 2017 %T Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. %A Day, Felix R %A Thompson, Deborah J %A Helgason, Hannes %A Chasman, Daniel I %A Finucane, Hilary %A Sulem, Patrick %A Ruth, Katherine S %A Whalen, Sean %A Sarkar, Abhishek K %A Albrecht, Eva %A Altmaier, Elisabeth %A Amini, Marzyeh %A Barbieri, Caterina M %A Boutin, Thibaud %A Campbell, Archie %A Demerath, Ellen %A Giri, Ayush %A He, Chunyan %A Hottenga, Jouke J %A Karlsson, Robert %A Kolcic, Ivana %A Loh, Po-Ru %A Lunetta, Kathryn L %A Mangino, Massimo %A Marco, Brumat %A McMahon, George %A Medland, Sarah E %A Nolte, Ilja M %A Noordam, Raymond %A Nutile, Teresa %A Paternoster, Lavinia %A Perjakova, Natalia %A Porcu, Eleonora %A Rose, Lynda M %A Schraut, Katharina E %A Segrè, Ayellet V %A Smith, Albert V %A Stolk, Lisette %A Teumer, Alexander %A Andrulis, Irene L %A Bandinelli, Stefania %A Beckmann, Matthias W %A Benitez, Javier %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bojesen, Stig E %A Bolla, Manjeet K %A Brand, Judith S %A Brauch, Hiltrud %A Brenner, Hermann %A Broer, Linda %A Brüning, Thomas %A Buring, Julie E %A Campbell, Harry %A Catamo, Eulalia %A Chanock, Stephen %A Chenevix-Trench, Georgia %A Corre, Tanguy %A Couch, Fergus J %A Cousminer, Diana L %A Cox, Angela %A Crisponi, Laura %A Czene, Kamila %A Davey Smith, George %A de Geus, Eco J C N %A de Mutsert, Renée %A De Vivo, Immaculata %A Dennis, Joe %A Devilee, Peter %A Dos-Santos-Silva, Isabel %A Dunning, Alison M %A Eriksson, Johan G %A Fasching, Peter A %A Fernández-Rhodes, Lindsay %A Ferrucci, Luigi %A Flesch-Janys, Dieter %A Franke, Lude %A Gabrielson, Marike %A Gandin, Ilaria %A Giles, Graham G %A Grallert, Harald %A Gudbjartsson, Daniel F %A Guenel, Pascal %A Hall, Per %A Hallberg, Emily %A Hamann, Ute %A Harris, Tamara B %A Hartman, Catharina A %A Heiss, Gerardo %A Hooning, Maartje J %A Hopper, John L %A Hu, Frank %A Hunter, David J %A Ikram, M Arfan %A Im, Hae Kyung %A Järvelin, Marjo-Riitta %A Joshi, Peter K %A Karasik, David %A Kellis, Manolis %A Kutalik, Zoltán %A LaChance, Genevieve %A Lambrechts, Diether %A Langenberg, Claudia %A Launer, Lenore J %A Laven, Joop S E %A Lenarduzzi, Stefania %A Li, Jingmei %A Lind, Penelope A %A Lindström, Sara %A Liu, Yongmei %A Luan, Jian'an %A Mägi, Reedik %A Mannermaa, Arto %A Mbarek, Hamdi %A McCarthy, Mark I %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Metspalu, Andres %A Michailidou, Kyriaki %A Milani, Lili %A Milne, Roger L %A Montgomery, Grant W %A Mulligan, Anna M %A Nalls, Mike A %A Navarro, Pau %A Nevanlinna, Heli %A Nyholt, Dale R %A Oldehinkel, Albertine J %A O'Mara, Tracy A %A Padmanabhan, Sandosh %A Palotie, Aarno %A Pedersen, Nancy %A Peters, Annette %A Peto, Julian %A Pharoah, Paul D P %A Pouta, Anneli %A Radice, Paolo %A Rahman, Iffat %A Ring, Susan M %A Robino, Antonietta %A Rosendaal, Frits R %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Sala, Cinzia F %A Schmidt, Marjanka K %A Scott, Robert A %A Shah, Mitul %A Sorice, Rossella %A Southey, Melissa C %A Sovio, Ulla %A Stampfer, Meir %A Steri, Maristella %A Strauch, Konstantin %A Tanaka, Toshiko %A Tikkanen, Emmi %A Timpson, Nicholas J %A Traglia, Michela %A Truong, Therese %A Tyrer, Jonathan P %A Uitterlinden, André G %A Edwards, Digna R Velez %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Wang, Qin %A Widen, Elisabeth %A van Dijk, Ko Willems %A Willemsen, Gonneke %A Winqvist, Robert %A Wolffenbuttel, Bruce H R %A Zhao, Jing Hua %A Zoledziewska, Magdalena %A Zygmunt, Marek %A Alizadeh, Behrooz Z %A Boomsma, Dorret I %A Ciullo, Marina %A Cucca, Francesco %A Esko, Tõnu %A Franceschini, Nora %A Gieger, Christian %A Gudnason, Vilmundur %A Hayward, Caroline %A Kraft, Peter %A Lawlor, Debbie A %A Magnusson, Patrik K E %A Martin, Nicholas G %A Mook-Kanamori, Dennis O %A Nohr, Ellen A %A Polasek, Ozren %A Porteous, David %A Price, Alkes L %A Ridker, Paul M %A Snieder, Harold %A Spector, Tim D %A Stöckl, Doris %A Toniolo, Daniela %A Ulivi, Sheila %A Visser, Jenny A %A Völzke, Henry %A Wareham, Nicholas J %A Wilson, James F %A Spurdle, Amanda B %A Thorsteindottir, Unnur %A Pollard, Katherine S %A Easton, Douglas F %A Tung, Joyce Y %A Chang-Claude, Jenny %A Hinds, David %A Murray, Anna %A Murabito, Joanne M %A Stefansson, Kari %A Ong, Ken K %A Perry, John R B %K Adolescent %K Age Factors %K Body Mass Index %K Databases, Genetic %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomic Imprinting %K Humans %K Intercellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Menarche %K Neoplasms %K Polymorphism, Single Nucleotide %K Puberty %K Quantitative Trait Loci %K Ribonucleoproteins %K Risk Factors %X

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

%B Nat Genet %V 49 %P 834-841 %8 2017 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/28436984?dopt=Abstract %R 10.1038/ng.3841 %0 Journal Article %J Nature %D 2016 %T Genome-wide association study identifies 74 loci associated with educational attainment. %A Okbay, Aysu %A Beauchamp, Jonathan P %A Fontana, Mark Alan %A Lee, James J %A Pers, Tune H %A Rietveld, Cornelius A %A Turley, Patrick %A Chen, Guo-Bo %A Emilsson, Valur %A Meddens, S Fleur W %A Oskarsson, Sven %A Pickrell, Joseph K %A Thom, Kevin %A Timshel, Pascal %A de Vlaming, Ronald %A Abdellaoui, Abdel %A Ahluwalia, Tarunveer S %A Bacelis, Jonas %A Baumbach, Clemens %A Bjornsdottir, Gyda %A Brandsma, Johannes H %A Pina Concas, Maria %A Derringer, Jaime %A Furlotte, Nicholas A %A Galesloot, Tessel E %A Girotto, Giorgia %A Gupta, Richa %A Hall, Leanne M %A Harris, Sarah E %A Hofer, Edith %A Horikoshi, Momoko %A Huffman, Jennifer E %A Kaasik, Kadri %A Kalafati, Ioanna P %A Karlsson, Robert %A Kong, Augustine %A Lahti, Jari %A van der Lee, Sven J %A deLeeuw, Christiaan %A Lind, Penelope A %A Lindgren, Karl-Oskar %A Liu, Tian %A Mangino, Massimo %A Marten, Jonathan %A Mihailov, Evelin %A Miller, Michael B %A van der Most, Peter J %A Oldmeadow, Christopher %A Payton, Antony %A Pervjakova, Natalia %A Peyrot, Wouter J %A Qian, Yong %A Raitakari, Olli %A Rueedi, Rico %A Salvi, Erika %A Schmidt, Börge %A Schraut, Katharina E %A Shi, Jianxin %A Smith, Albert V %A Poot, Raymond A %A St Pourcain, Beate %A Teumer, Alexander %A Thorleifsson, Gudmar %A Verweij, Niek %A Vuckovic, Dragana %A Wellmann, Juergen %A Westra, Harm-Jan %A Yang, Jingyun %A Zhao, Wei %A Zhu, Zhihong %A Alizadeh, Behrooz Z %A Amin, Najaf %A Bakshi, Andrew %A Baumeister, Sebastian E %A Biino, Ginevra %A Bønnelykke, Klaus %A Boyle, Patricia A %A Campbell, Harry %A Cappuccio, Francesco P %A Davies, Gail %A De Neve, Jan-Emmanuel %A Deloukas, Panos %A Demuth, Ilja %A Ding, Jun %A Eibich, Peter %A Eisele, Lewin %A Eklund, Niina %A Evans, David M %A Faul, Jessica D %A Feitosa, Mary F %A Forstner, Andreas J %A Gandin, Ilaria %A Gunnarsson, Bjarni %A Halldórsson, Bjarni V %A Harris, Tamara B %A Heath, Andrew C %A Hocking, Lynne J %A Holliday, Elizabeth G %A Homuth, Georg %A Horan, Michael A %A Hottenga, Jouke-Jan %A de Jager, Philip L %A Joshi, Peter K %A Jugessur, Astanand %A Kaakinen, Marika A %A Kähönen, Mika %A Kanoni, Stavroula %A Keltigangas-Järvinen, Liisa %A Kiemeney, Lambertus A L M %A Kolcic, Ivana %A Koskinen, Seppo %A Kraja, Aldi T %A Kroh, Martin %A Kutalik, Zoltán %A Latvala, Antti %A Launer, Lenore J %A Lebreton, Maël P %A Levinson, Douglas F %A Lichtenstein, Paul %A Lichtner, Peter %A Liewald, David C M %A Loukola, Anu %A Madden, Pamela A %A Mägi, Reedik %A Mäki-Opas, Tomi %A Marioni, Riccardo E %A Marques-Vidal, Pedro %A Meddens, Gerardus A %A McMahon, George %A Meisinger, Christa %A Meitinger, Thomas %A Milaneschi, Yusplitri %A Milani, Lili %A Montgomery, Grant W %A Myhre, Ronny %A Nelson, Christopher P %A Nyholt, Dale R %A Ollier, William E R %A Palotie, Aarno %A Paternoster, Lavinia %A Pedersen, Nancy L %A Petrovic, Katja E %A Porteous, David J %A Räikkönen, Katri %A Ring, Susan M %A Robino, Antonietta %A Rostapshova, Olga %A Rudan, Igor %A Rustichini, Aldo %A Salomaa, Veikko %A Sanders, Alan R %A Sarin, Antti-Pekka %A Schmidt, Helena %A Scott, Rodney J %A Smith, Blair H %A Smith, Jennifer A %A Staessen, Jan A %A Steinhagen-Thiessen, Elisabeth %A Strauch, Konstantin %A Terracciano, Antonio %A Tobin, Martin D %A Ulivi, Sheila %A Vaccargiu, Simona %A Quaye, Lydia %A van Rooij, Frank J A %A Venturini, Cristina %A Vinkhuyzen, Anna A E %A Völker, Uwe %A Völzke, Henry %A Vonk, Judith M %A Vozzi, Diego %A Waage, Johannes %A Ware, Erin B %A Willemsen, Gonneke %A Attia, John R %A Bennett, David A %A Berger, Klaus %A Bertram, Lars %A Bisgaard, Hans %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bültmann, Ute %A Chabris, Christopher F %A Cucca, Francesco %A Cusi, Daniele %A Deary, Ian J %A Dedoussis, George V %A van Duijn, Cornelia M %A Eriksson, Johan G %A Franke, Barbara %A Franke, Lude %A Gasparini, Paolo %A Gejman, Pablo V %A Gieger, Christian %A Grabe, Hans-Jörgen %A Gratten, Jacob %A Groenen, Patrick J F %A Gudnason, Vilmundur %A van der Harst, Pim %A Hayward, Caroline %A Hinds, David A %A Hoffmann, Wolfgang %A Hyppönen, Elina %A Iacono, William G %A Jacobsson, Bo %A Järvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Kaprio, Jaakko %A Kardia, Sharon L R %A Lehtimäki, Terho %A Lehrer, Steven F %A Magnusson, Patrik K E %A Martin, Nicholas G %A McGue, Matt %A Metspalu, Andres %A Pendleton, Neil %A Penninx, Brenda W J H %A Perola, Markus %A Pirastu, Nicola %A Pirastu, Mario %A Polasek, Ozren %A Posthuma, Danielle %A Power, Christine %A Province, Michael A %A Samani, Nilesh J %A Schlessinger, David %A Schmidt, Reinhold %A Sørensen, Thorkild I A %A Spector, Tim D %A Stefansson, Kari %A Thorsteinsdottir, Unnur %A Thurik, A Roy %A Timpson, Nicholas J %A Tiemeier, Henning %A Tung, Joyce Y %A Uitterlinden, André G %A Vitart, Veronique %A Vollenweider, Peter %A Weir, David R %A Wilson, James F %A Wright, Alan F %A Conley, Dalton C %A Krueger, Robert F %A Davey Smith, George %A Hofman, Albert %A Laibson, David I %A Medland, Sarah E %A Meyer, Michelle N %A Yang, Jian %A Johannesson, Magnus %A Visscher, Peter M %A Esko, Tõnu %A Koellinger, Philipp D %A Cesarini, David %A Benjamin, Daniel J %K Alzheimer Disease %K Bipolar Disorder %K Brain %K Cognition %K Computational Biology %K Educational Status %K Fetus %K Gene Expression Regulation %K Gene-Environment Interaction %K Genome-Wide Association Study %K Great Britain %K Humans %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Schizophrenia %X

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

%B Nature %V 533 %P 539-42 %8 2016 May 26 %G eng %N 7604 %1 http://www.ncbi.nlm.nih.gov/pubmed/27225129?dopt=Abstract %R 10.1038/nature17671 %0 Journal Article %J Nat Commun %D 2015 %T Rare coding variants and X-linked loci associated with age at menarche. %A Lunetta, Kathryn L %A Day, Felix R %A Sulem, Patrick %A Ruth, Katherine S %A Tung, Joyce Y %A Hinds, David A %A Esko, Tõnu %A Elks, Cathy E %A Altmaier, Elisabeth %A He, Chunyan %A Huffman, Jennifer E %A Mihailov, Evelin %A Porcu, Eleonora %A Robino, Antonietta %A Rose, Lynda M %A Schick, Ursula M %A Stolk, Lisette %A Teumer, Alexander %A Thompson, Deborah J %A Traglia, Michela %A Wang, Carol A %A Yerges-Armstrong, Laura M %A Antoniou, Antonis C %A Barbieri, Caterina %A Coviello, Andrea D %A Cucca, Francesco %A Demerath, Ellen W %A Dunning, Alison M %A Gandin, Ilaria %A Grove, Megan L %A Gudbjartsson, Daniel F %A Hocking, Lynne J %A Hofman, Albert %A Huang, Jinyan %A Jackson, Rebecca D %A Karasik, David %A Kriebel, Jennifer %A Lange, Ethan M %A Lange, Leslie A %A Langenberg, Claudia %A Li, Xin %A Luan, Jian'an %A Mägi, Reedik %A Morrison, Alanna C %A Padmanabhan, Sandosh %A Pirie, Ailith %A Polasek, Ozren %A Porteous, David %A Reiner, Alex P %A Rivadeneira, Fernando %A Rudan, Igor %A Sala, Cinzia F %A Schlessinger, David %A Scott, Robert A %A Stöckl, Doris %A Visser, Jenny A %A Völker, Uwe %A Vozzi, Diego %A Wilson, James G %A Zygmunt, Marek %A Boerwinkle, Eric %A Buring, Julie E %A Crisponi, Laura %A Easton, Douglas F %A Hayward, Caroline %A Hu, Frank B %A Liu, Simin %A Metspalu, Andres %A Pennell, Craig E %A Ridker, Paul M %A Strauch, Konstantin %A Streeten, Elizabeth A %A Toniolo, Daniela %A Uitterlinden, André G %A Ulivi, Sheila %A Völzke, Henry %A Wareham, Nicholas J %A Wellons, Melissa %A Franceschini, Nora %A Chasman, Daniel I %A Thorsteinsdottir, Unnur %A Murray, Anna %A Stefansson, Kari %A Murabito, Joanne M %A Ong, Ken K %A Perry, John R B %X

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

%B Nat Commun %V 6 %P 7756 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26239645?dopt=Abstract %R 10.1038/ncomms8756