Browsing by Author "Huffman, Jennifer E."

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    A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation
    (Springer Nature, 2022) Vujkovic, Marijana; Ramdas, Shweta; Lorenz, Kim M.; Guo, Xiuqing; Darlay, Rebecca; Cordell, Heather J.; He, Jing; Gindin, Yevgeniy; Chung, Chuhan; Myers, Robert P.; Schneider, Carolin V.; Park, Joseph; Lee, Kyung Min; Serper, Marina; Carr, Rotonya M.; Kaplan, David E.; Haas, Mary E.; MacLean, Matthew T.; Witschey, Walter R.; Zhu, Xiang; Tcheandjieu, Catherine; Kember, Rachel L.; Kranzler, Henry R.; Verma, Anurag; Giri, Ayush; Klarin, Derek M.; Sun, Yan V.; Huang, Jie; Huffman, Jennifer E.; Townsend Creasy, Kate; Hand, Nicholas J.; Liu, Ching-Ti; Long, Michelle T.; Yao, Jie; Budoff, Matthew; Tan, Jingyi; Li, Xiaohui; Lin, Henry J.; Chen, Yii-Der Ida; Taylor, Kent D.; Chang, Ruey-Kang; Krauss, Ronald M.; Vilarinho, Silvia; Brancale, Joseph; Nielsen, Jonas B.; Locke, Adam E.; Jones, Marcus B.; Verweij, Niek; Baras, Aris; Reddy, K. Rajender; Neuschwander-Tetri, Brent A.; Schwimmer, Jeffrey B.; Sanyal, Arun J.; Chalasani, Naga; Ryan, Kathleen A.; Mitchell, Braxton D.; Gill, Dipender; Wells, Andrew D.; Manduchi, Elisabetta; Saiman, Yedidya; Mahmud, Nadim; Miller, Donald R.; Reaven, Peter D.; Phillips, Lawrence S.; Muralidhar, Sumitra; DuVall, Scott L.; Lee, Jennifer S.; Assimes, Themistocles L.; Pyarajan, Saiju; Cho, Kelly; Edwards, Todd L.; Damrauer, Scott M.; Wilson, Peter W.; Gaziano, J. Michael; O'Donnell, Christopher J.; Khera, Amit V.; Grant, Struan F. A.; Brown, Christopher D.; Tsao, Philip S.; Saleheen, Danish; Lotta, Luca A.; Bastarache, Lisa; Anstee, Quentin M.; Daly, Ann K.; Meigs, James B.; Rotter, Jerome I.; Lynch, Julie A.; Regeneron Genetics Center; Geisinger-Regeneron DiscovEHR Collaboration; EPoS Consortium; VA Million Veteran Program; Rader, Daniel J.; Voight, Benjamin F.; Chang, Kyong-Mi; Medicine, School of Medicine
    Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.
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    Genome-wide association study identifies 48 common genetic variants associated with handedness
    (Springer Nature, 2021) Cuellar-Partida, Gabriel; Tung, Joyce Y.; Eriksson, Nicholas; Albrecht, Eva; Aliev, Fazil; Andreassen, Ole A.; Barroso, Inês; Beckmann, Jacques S.; Boks, Marco P.; Boomsma, Dorret I.; Boyd, Heather A.; Breteler, Monique M. B.; Campbell, Harry; Chasman, Daniel I.; Cherkas, Lynn F.; Davies, Gail; de Geus, Eco J. C.; Deary, Ian J.; Deloukas, Panos; Dick, Danielle M.; Duffy, David L.; Eriksson, Johan G.; Esko, Tõnu; Feenstra, Bjarke; Geller, Frank; Gieger, Christian; Giegling, Ina; Gordon, Scott D.; Han, Jiali; Hansen, Thomas F.; Hartmann, Annette M.; Hayward, Caroline; Heikkilä, Kauko; Hicks, Andrew A.; Hirschhorn, Joel N.; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Hwang, Liang-Dar; Ikram, M. Arfan; Kaprio, Jaakko; Kemp, John P.; Khaw, Kay-Tee; Klopp, Norman; Konte, Bettina; Kutalik, Zoltan; Lahti, Jari; Li, Xin; Loos, Ruth J. F.; Luciano, Michelle; Magnusson, Sigurdur H.; Mangino, Massimo; Marques-Vidal, Pedro; Martin, Nicholas G.; McArdle, Wendy L.; McCarthy, Mark I.; Medina-Gomez, Carolina; Melbye, Mads; Melville, Scott A.; Metspalu, Andres; Milani, Lili; Mooser, Vincent; Nelis, Mari; Nyholt, Dale R.; O'Connell, Kevin S.; Ophoff, Roel A.; Palmer, Cameron; Palotie, Aarno; Palviainen, Teemu; Pare, Guillaume; Paternoster, Lavinia; Peltonen, Leena; Penninx, Brenda W. J. H.; Polasek, Ozren; Pramstaller, Peter P.; Prokopenko, Inga; Raikkonen, Katri; Ripatti, Samuli; Rivadeneira, Fernando; Rudan, Igor; Rujescu, Dan; Smit, Johannes H.; Smith, George Davey; Smoller, Jordan W.; Soranzo, Nicole; Spector, Tim D.; St. Pourcain, Beate; Starr, John M.; Stefánsson, Hreinn; Steinberg, Stacy; Teder-Laving, Maris; Thorleifsson, Gudmar; Stefánsson, Kári; Timpson, Nicholas J.; Uitterlinden, André G.; van Duijn, Cornelia M.; van Rooij, Frank J. A.; Vink, Jaqueline M.; Vollenweider, Peter; Vuoksimaa, Eero; Waeber, Gérard; Wareham, Nicholas J.; Warrington, Nicole; Waterworth, Dawn; Werge, Thomas; Wichmann, H-Erich; Widen, Elisabeth; Willemsen, Gonneke; Wright, Alan F.; Wright, Margaret J.; Xu, Mousheng; Zhao, Jing Hua; Kraft, Peter; Hinds, David A.; Lindgren, Cecilia M.; Mägi, Reedik; Neale, Benjamin M.; Evans, David M.; Medland, Sarah E.; Epidemiology, School of Public Health
    Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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    Identifying intragenic functional modules of genomic variations associated with cancer phenotypes by learning representation of association networks
    (Springer Nature, 2022-07-06) Kim, Minsu; Huffman, Jennifer E.; Justice, Amy; Goethert, Ian; Agasthya, Greeshma; VA Million Veteran Program; Danciu, Ioana; Medicine, School of Medicine
    Background: Genome-wide Association Studies (GWAS) aims to uncover the link between genomic variation and phenotype. They have been actively applied in cancer biology to investigate associations between variations and cancer phenotypes, such as susceptibility to certain types of cancer and predisposed responsiveness to specific treatments. Since GWAS primarily focuses on finding associations between individual genomic variations and cancer phenotypes, there are limitations in understanding the mechanisms by which cancer phenotypes are cooperatively affected by more than one genomic variation. Results: This paper proposes a network representation learning approach to learn associations among genomic variations using a prostate cancer cohort. The learned associations are encoded into representations that can be used to identify functional modules of genomic variations within genes associated with early- and late-onset prostate cancer. The proposed method was applied to a prostate cancer cohort provided by the Veterans Administration's Million Veteran Program to identify candidates for functional modules associated with early-onset prostate cancer. The cohort included 33,159 prostate cancer patients, 3181 early-onset patients, and 29,978 late-onset patients. The reproducibility of the proposed approach clearly showed that the proposed approach can improve the model performance in terms of robustness. Conclusions: To our knowledge, this is the first attempt to use a network representation learning approach to learn associations among genomic variations within genes. Associations learned in this way can lead to an understanding of the underlying mechanisms of how genomic variations cooperatively affect each cancer phenotype. This method can reveal unknown knowledge in the field of cancer biology and can be utilized to design more advanced cancer-targeted therapies.
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    Large-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair
    (SpringerNature, 2015-11) Day, Felix R.; Ruth, Katherine S.; Thompson, Deborah J.; Lunetta, Kathryn L.; Pervjakova, Natalia; Chasman, Daniel I.; Stolk, Lisette; Finucane, Hilary K.; Sulem, Patrick; Bulik-Sullivan, Brendan; Esko, Tõnu; Johnson, Andrew D.; Elks, Cathy E.; Franceschini, Nora; He, Chunyan; Altmaier, Elisabeth; Brody, Jennifer A.; Franke, Lude L.; Huffman, Jennifer E.; Keller, Margaux F.; McArdle, Patrick F.; Nutile, Teresa; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Smith, Jennifer A.; Teumer, Alexander; Traglia, Michela; Vuckovic, Dragana; Yao, Jie; Zhao, Wei; Albrecht, Eva; Amin, Najaf; Corre, Tanguy; Hottenga, Jouke-Jan; Mangino, Massimo; Smith, Albert V.; Tanaka, Toshiko; Abecasis, Goncalo; Andrulis, Irene L.; Anton-Culver, Hoda; Antoniou, Antonis C.; Arndt, Volker; Arnold, Alice M.; Barbieri, Caterina; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bernstein, Leslie; Bielinski, Suzette J.; Blomqvist, Carl; Boerwinkle, Eric; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borresen-Dale, Anne-Lise; Boutin, Thibaud S.; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Campbell, Archie; Campbell, Harry; Chanock, Stephen J.; Chapman, J. Ross; Chen, Yii-Der Ida; Chenevix-Trench, Georgia; Couch, Fergus J.; Coviello, Andrea D.; Cox, Angela; Czene, Kamila; Darabi, Hatef; De Vivo, Immaculata; Demerath, Ellen W.; Dennis, Joe; Devilee, Peter; Dörk, Thilo; dos-Santos-Silva, Isabel; Dunning, Alison M.; Eicher, John D.; Fasching, Peter A.; Faul, Jessica D.; Figueroa, Jonine; Flesch-Janys, Dieter; Gandin, Ilaria; Garcia, Melissa E.; García-Closas, Montserrat; Giles, Graham G.; Girotto, Giorgia G.; Goldberg, Mark S.; González-Neira, Anna; Goodarzi, Mark O.; Grove, Megan L.; Gudbjartsson, Daniel F.; Guénel, Pascal; Guo, Xiuqing; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Henderson, Brian E.; Hocking, Lynne J.; Hofman, Albert; Homuth, Georg; Hooning, Maartje J.; Hopper, John L.; Hu, Frank B.; Huang, Jinyan; Humphreys, Keith; Hunter, David J.; Jakubowska, Anna; Jones, Samuel E.; Kabisch, Maria; Karasia, David; Knight, Julia A.; Kolcic, Ivana; Kooperberg, Charles; Kosma, Veli-Matti; Kriebel, Jennifer; Kristensen, Vessela; Lambrechts, Diether; Langenberg, Claudia; Li, Jingmei; Li, Xin; Lindström, Sara; Liu, Yongmei; Luan, Jian’an; Lubinski, Jan; Mägi, Reedik; Mannermaa, Arto; Manz, Judith; Margolin, Sara; Marten, Jonathan; Martin, Nicholas G.; Masciullo, Corrado; Meindl, Alfons; Michailidou, Kyriaki; Mihailov, Evelin; Milani, Lili; Milne, Roger L.; Müller-Nurasyid, Martina; Nalls, Michael; Neale, Ben M.; Nevanlinna, Heli; Neven, Patrick; Newman, Anne B.; Nordestgaard, Børge G.; Olson, Janet E.; Padmanabhan, Sandosh; Peterlongo, Paolo; Peters, Ulrike; Petersmann, Astrid; Peto, Julian; Pharoah, Paul D.P.; Pirastu, Nicola N.; Pirie, Ailith; Pistis, Giorgio; Polasek, Ozren; Porteous, David; Psaty, Bruce M.; Pylkäs, Katri; Radice, Paolo; Raffel, Leslie J.; Rivadeneira, Fernando; Rudan, Igor; Rudolph, Anja; Anja, Daniela; Sala, Cinzia F.; Sanna, Serena; Sawyer, Elinor J.; Schlessinger, David; Schmidt, Marjanka K.; Schmidt, Frank; Schmutzler, Rita K.; Schoemaker, Minouk J.; Scott, Robert A.; Seynaeve, Caroline M.; Simard, Jacques; Sorice, Rossella; Southey, Melissa C.; Stöckl, Doris; Strauch, Konstantin; Swerdlow, Anthony; Taylor, Kent D.; Thorsteinsdottir, Unnur; Toland, Amanda E.; Tomlinson, Ian; Truong, Thérèse; Tryggvadottir, Laufey; Turner, Stephen T.; Vozzi, Diego; Wang, Qin; Wellons, Melissa; Willemsen, Gonneke; Wilson, James F.; Winqvist, Robert; Wolffenbuttel, Bruce B.H.R.; Wright, Alan F.; Yannoukakos, Drakoulis; Zemunik, Tatijana; Zheng, Wei; Zygmunt, Marek; Bergmann, Sven; Boomsma, Dorret I.; Buring, Julie E.; Ferrucci, Luigi; Montgomery, Grant W.; Gudnason, Vilmundur; Spector, Tim D.; van Duijn, Cornelia M; Alizadeh, Behrooz Z.; Ciullo, Marina; Crisponi, Laura; Easton, Douglas F.; Gasparini, Paolo P.; Gieger, Christian; Harris, Tamara B.; Hayward, Caroline; Kardia, Sharon L.R.; Kraft, Peter; McKnight, Barbara; Metspalu, Andres; Morrison, Alanna C.; Reiner, Alex P.; Ridker, Paul M.; Rotter, Jerome I.; Toniolo, Daniela; Uitterlinden, André G.; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J.; Weir, David R.; Yerges-Armstrong, Laura M.; Price, Alkes L.; Stefansson, Kari; Visser, Jenny A.; Ong, Ken K.; Chang-Claude, Jenny; Murabito, Joanne M.; Perry, John R.B.; Murray, Anna; Department of Epidemiology, Richard M. Fairbanks School of Public Health
    Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
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    Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
    (Nature Publishing Group, 2015-01-29) Wessel, Jennifer; Chu, Audrey Y.; Willems, Sara M.; Wang, Shuai; Yaghootkar, Hanieh; Brody, Jennifer A.; Dauriz, Marco; Hivert, Marie-France; Raghavan, Sridharan; Lipovich, Leonard; Hidalgo, Bertha; Fox, Keolu; Huffman, Jennifer E.; An, Ping; Lu, Yingchang; Rasmussen-Torvik, Laura J.; Grarup, Niels; Ehm, Margaret G.; Li, Li; Baldridge, Abigail S.; Stančáková, Alena; Abrol, Ravinder; Besse, Céline; Boland, Anne; Bork-Jensen, Jette; Fornage, Myriam; Freitag, Daniel F.; Garcia, Melissa E.; Guo, Xiuqing; Hara, Kazuo; Isaacs, Aaron; Jakobsdottir, Johanna; Lange, Leslie A.; Layton, Jill C.; Li, Man; Hua Zhao, Jing; Meidtner, Karina; Morrison, Alanna C.; Nalls, Mike A.; Peters, Marjolein J.; Sabater-Lleal, Maria; Schurmann, Claudia; Silveira, Angela; Smith, Albert V.; Southam, Lorraine; Stoiber, Marcus H.; Strawbridge, Rona J.; Taylor, Kent D.; Varga, Tibor V.; Allin, Kristine H.; Amin, Najaf; Aponte, Jennifer L.; Aung, Tin; Barbieri, Caterina; Bihlmeyer, Nathan A.; Boehnke, Michael; Bombieri, Cristina; Bowden, Donald W.; Burns, Sean M.; Chen, Yuning; Chen, Yii-DerI; Cheng, Ching-Yu; Correa, Adolfo; Czajkowski, Jacek; Dehghan, Abbas; Ehret, Georg B.; Eiriksdottir, Gudny; Escher, Stefan A.; Farmaki, Aliki-Eleni; Frånberg, Mattias; Gambaro, Giovanni; Giulianini, Franco; Goddard, William A.; Goel, Anuj; Gottesman, Omri; Grove, Megan L.; Gustafsson, Stefan; Hai, Yang; Hallmans, Göran; Heo, Jiyoung; Hoffmann, Per; Ikram, Mohammad K.; Jensen, Richard A.; Jørgensen, Marit E.; Jørgensen, Torben; Karaleftheri, Maria; Khor, Chiea C.; Kirkpatrick, Andrea; Kraja, Aldi T.; Kuusisto, Johanna; Lange, Ethan M.; Lee, I. T.; Lee, Wen-Jane; Leong, Aaron; Liao, Jiemin; Liu, Chunyu; Liu, Yongmei; Lindgren, Cecilia M.; Linneberg, Allan; Malerba, Giovanni; Mamakou, Vasiliki; Marouli, Eirini; Maruthur, Nisa M.; Matchan, Angela; McKean-Cowdin, Roberta; McLeod, Olga; Metcalf, Ginger A.; Mohlke, Karen L.; Muzny, Donna M.; Ntalla, Ioanna; Palmer, Nicholette D.; Pasko, Dorota; Peter, Andreas; Rayner, Nigel W.; Renström, Frida; Rice, Ken; Sala, Cinzia F.; Sennblad, Bengt; Serafetinidis, Ioannis; Smith, Jennifer A.; Soranzo, Nicole; Speliotes, Elizabeth K.; Stahl, Eli A.; Stirrups, Kathleen; Tentolouris, Nikos; Thanopoulou, Anastasia; Torres, Mina; Traglia, Michela; Tsafantakis, Emmanouil; Javad, Sundas; Yanek, Lisa R.; Zengini, Eleni; Becker, Diane M.; Bis, Joshua C.; Brown, James B.; Adrienne Cupples, L.; Hansen, Torben; Ingelsson, Erik; Karter, Andrew J.; Lorenzo, Carlos; Mathias, Rasika A.; Norris, Jill M.; Peloso, Gina M.; Sheu, Wayne H.-H.; Toniolo, Daniela; Vaidya, Dhananjay; Varma, Rohit; Wagenknecht, Lynne E.; Boeing, Heiner; Bottinger, Erwin P.; Dedoussis, George; Deloukas, Panos; Ferrannini, Ele; Franco, Oscar H.; Franks, Paul W.; Gibbs, Richard A.; Gudnason, Vilmundur; Hamsten, Anders; Harris, Tamara B.; Hattersley, Andrew T.; Hayward, Caroline; Hofman, Albert; Jansson, Jan-Håkan; Langenberg, Claudia; Launer, Lenore J.; Levy, Daniel; Oostra, Ben A.; O'Donnell, Christopher J.; O'Rahilly, Stephen; Padmanabhan, Sandosh; Pankow, James S.; Polasek, Ozren; Province, Michael A.; Rich, Stephen S.; Ridker, Paul M.; Rudan, Igor; Schulze, Matthias B.; Smith, Blair H.; Uitterlinden, André G.; Walker, Mark; Watkins, Hugh; Wong, Tien Y.; Zeggini, Eleftheria; Laakso, Markku; Borecki, Ingrid B.; Chasman, Daniel I.; Pedersen, Oluf; Psaty, Bruce M.; Shyong Tai, E.; van Duijn, Cornelia M.; Wareham, Nicholas J.; Waterworth, Dawn M.; Boerwinkle, Eric; Linda Kao, W. H.; Florez, Jose C.; Loos, Ruth J. F.; Wilson, James G.; Frayling, Timothy M.; Siscovick, David S.; Dupuis, Josée; Rotter, Jerome I.; Meigs, James B.; Scott, Robert A.; Goodarzi, Mark O.; Department of Epidemiology, Richard M. Fairbanks School of Public Health
    Fasting ​glucose and ​insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in ​GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early ​insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h ​glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at ​G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ​ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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    Rare coding variants and X-linked loci associated with age at menarche
    (Nature Publishing Group, 2015-08-04) Lunetta, Kathryn L.; Day, Felix R.; Sulem, Patrick; Ruth, Katherine S.; Tung, Joyce Y.; Hinds, David A.; Esko, Tõnu; Elks, Cathy E.; Altmaier, Elisabeth; He, Chunyan; Huffman, Jennifer E.; Mihailov, Evelin; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Stolk, Lisette; Teumer, Alexander; Thompson, Deborah J.; Traglia, Michela; Wang, Carol A.; Yerges-Armstrong, Laura M.; Antoniou, Antonis C.; Barbieri, Caterina; Coviello, Andrea D.; Cucca, Francesco; Demerath, Ellen W.; Dunning, Alison M.; Gandin, Ilaria; Grove, Megan L.; Gudbjartsson, Daniel F.; Hocking, Lynne J.; Hofman, Albert; Huang, Jinyan; Jackson, Rebecca D.; Karasik, David; Kriebel, Jennifer; Lange, Ethan M.; Lange, Leslie A.; Langenberg, Claudia; Li, Xin; Luan, Jian'an; Mägi, Reedik; Morrison, Alanna C.; Padmanabhan, Sandosh; Pirie, Ailith; Polasek, Ozren; Porteous, David; Reiner, Alex P.; Rivadeneira, Fernando; Rudan, Igor; Sala, Cinzia F.; Schlessinger, David; Scott, Robert A.; Stöckl, Doris; Visser, Jenny A.; Völker, Uwe; Vozzi, Diego; Wilson, James G.; Zygmunt, Marek; Boerwinkle, Eric; Buring, Julie E.; Crisponi, Laura; Easton, Douglas F.; Hayward, Caroline; Hu, Frank B.; Liu, Simin; Metspalu, Andres; Pennell, Craig E.; Ridker, Paul M.; Strauch, Konstantin; Streeten, Elizabeth A.; Toniolo, Daniela; Uitterlinden, André G.; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J.; Wellons, Melissa; Franceschini, Nora; Chasman, Daniel I.; Thorsteinsdottir, Unnur; Murray, Anna; Stefansson, Kari; Murabito, Joanne M.; Ong, Ken K.; Perry, John R. B.; Department of Epidemiology, Richard M. Fairbanks School of Public Health
    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.