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Mathieson, Iain

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Mathieson

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Iain

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Mathieson, Iain
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    A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans
    (Nature Pub. Group, 2014) Timpson, Nicholas J.; Walter, Klaudia; Min, Josine L.; Tachmazidou, Ioanna; Malerba, Giovanni; Shin, So-Youn; Chen, Lu; Futema, Marta; Southam, Lorraine; Iotchkova, Valentina; Cocca, Massimiliano; Huang, Jie; Memari, Yasin; McCarthy, Shane; Danecek, Petr; Muddyman, Dawn; Mangino, Massimo; Menni, Cristina; Perry, John R. B.; Ring, Susan M.; Gaye, Amadou; Dedoussis, George; Farmaki, Aliki-Eleni; Burton, Paul; Talmud, Philippa J.; Gambaro, Giovanni; Spector, Tim D.; Smith, George Davey; Durbin, Richard; Richards, J Brent; Humphries, Steve E.; Zeggini, Eleftheria; Soranzo, Nicole; Al Turki, Saeed; Anderson, Carl; Anney, Richard; Antony, Dinu; Soler Artigas, Maria; Ayub, Muhammad; Balasubramaniam, Senduran; Barrett, Jeffrey C.; Barroso, Inês; Beales, Phil; Bentham, Jamie; Bhattacharya, Shoumo; Birney, Ewan; Blackwood, Douglas; Bobrow, Martin; Bochukova, Elena; Bolton, Patrick; Bounds, Rebecca; Boustred, Chris; Breen, Gerome; Calissano, Mattia; Carss, Keren; Chatterjee, Krishna; Ciampi, Antonio; Cirak, Sebhattin; Clapham, Peter; Clement, Gail; Coates, Guy; Collier, David; Cosgrove, Catherine; Cox, Tony; Craddock, Nick; Crooks, Lucy; Curran, Sarah; Curtis, David; Daly, Allan; Davey Smith, George; Day-Williams, Aaron; Day, Ian N. M.; Down, Thomas; Du, Yuanping; Dunham, Ian; Edkins, Sarah; Ellis, Peter; Evans, David; Faroogi, Sadaf; Fatemifar, Ghazaleh; Fitzpatrick, David R.; Flicek, Paul; Flyod, James; Foley, A Reghan; Franklin, Christopher S; Gallagher, Louise; Gaunt, Tom; Geihs, Matthias; Geschwind, Daniel; Greenwood, Celia; Griffin, Heather; Grozeva, Detelina; Guo, Xueqin; Guo, Xiaosen; Gurling, Hugh; Hart, Deborah; Hendricks, Audrey; Holmans, Peter; Howie, Bryan; Huang, Liren; Hubbard, Tim; Hurles, Matthew E.; Hysi, Pirro; Jackson, David K.; Jamshidi, Yalda; Jing, Tian; Joyce, Chris; Kaye, Jane; Keane, Thomas; Keogh, Julia; Kemp, John; Kennedy, Karen; Kolb-Kokocinski, Anja; Lachance, Genevieve; Langford, Cordelia; Lawson, Daniel; Lee, Irene; Lek, Monkol; Liang, Jieqin; Lin, Hong; Li, Rui; Li, Yingrui; Liu, Ryan; Lönnqvist, Jouko; Lopes, Margarida; Lotchkova, Valentina; MacArthur, Daniel; Marchini, Jonathan; Maslen, John; Massimo, Mangino; Mathieson, Iain; Marenne, Gaëlle; McGuffin, Peter; McIntosh, Andrew; McKechanie, Andrew G.; McQuillin, Andrew; Metrustry, Sarah; Min, Josine; Mitchison, Hannah; Moayyeri, Alireza; Morris, James; Muntoni, Francesco; Northstone, Kate; O'Donnovan, Michael; Onoufriadis, Alexandros; O'Rahilly, Stephen; Oualkacha, Karim; Owen, Michael J.; Palotie, Aarno; Panoutsopoulou, Kalliope; Parker, Victoria; Parr, Jeremy R.; Paternoster, Lavinia; Paunio, Tiina; Payne, Felicity; Perry, John; Pietilainen, Olli; Plagnol, Vincent; Quaye, Lydia; Quail, Michael A.; Raymond, Lucy; Rehnström, Karola; Richards, Brent; Ring, Susan; Ritchie, Graham R. S.; Roberts, Nicola; Savage, David B.; Scambler, Peter; Schiffels, Stephen; Schmidts, Miriam; Schoenmakers, Nadia; Semple, Robert K.; Serra, Eva; Sharp, Sally I.; Shihab, Hasheem; Skuse, David; Small, Kerrin; Spasic-Boskovic, Olivera; Spector, Tim; St Clair, David; Stalker, Jim; Stevens, Elizabeth; St Pourcian, Beate; Sun, Jianping; Surdulescu, Gabriela; Suvisaari, Jaana; Tachmazidou, Ionna; Timpson, Nicholas; Tobin, Martin D.; Valdes, Ana; Van Kogelenberg, Margriet; Vijayarangakannan, Parthiban; Visscher, Peter M.; Wain, Louise V.; Walters, James T. R.; Wang, Guangbiao; Wang, Jun; Wang, Yu; Ward, Kirsten; Wheeler, Elanor; Whyte, Tamieka; Williams, Hywel; Williamson, Kathleen A.; Wilson, Crispian; Wilson, Scott G.; Wong, Kim; Xu, ChangJiang; Yang, Jian; Zhang, Fend; Zhang, Pingbo; Zheng, Hou-Feng
    The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (−1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10−8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (−1.0 s.d. (s.e.=0.173), P-value=7.32 × 10−9). This is consistent with an effect between 0.5 and 1.5 mmol l−1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.
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    Genome-wide patterns of selection in 230 ancient Eurasians
    (2016) Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Roodenberg, Songül Alpaslan; Harney, Eadaoin; Stewardson, Kristin; Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Jones, Eppie R.; Llamas, Bastien; Dryomov, Stanislav; Pickrel, Joseph; Arsuaga, Juan Luís; de Castro, José María Bermúdez; Carbonell, Eudald; Gerritsen, Fokke; Khokhlov, Aleksandr; Kuznetsov, Pavel; Lozano, Marina; Meller, Harald; Mochalov, Oleg; Moiseyev, Vayacheslav; Rojo Guerra, Manuel A.; Roodenberg, Jacob; Vergès, Josep Maria; Krause, Johannes; Cooper, Alan; Alt, Kurt W.; Brown, Dorcas; Anthony, David; Lalueza-Fox, Carles; Haak, Wolfgang; Pinhasi, Ron; Reich, David
    Ancient DNA makes it possible to directly witness natural selection by analyzing samples from populations before, during and after adaptation events. Here we report the first scan for selection using ancient DNA, capitalizing on the largest genome-wide dataset yet assembled: 230 West Eurasians dating to between 6500 and 1000 BCE, including 163 with newly reported data. The new samples include the first genome-wide data from the Anatolian Neolithic culture whose genetic material we extracted from the DNA-rich petrous bone and who we show were members of the population that was the source of Europe’s first farmers. We also report a complete transect of the steppe region in Samara between 5500 and 1200 BCE that allows us to recognize admixture from at least two external sources into steppe populations during this period. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height.
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    Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel
    (Nature Pub. Group, 2015) Huang, Jie; Howie, Bryan; McCarthy, Shane; Memari, Yasin; Walter, Klaudia; Min, Josine L.; Danecek, Petr; Malerba, Giovanni; Trabetti, Elisabetta; Zheng, Hou-Feng; Al Turki, Saeed; Amuzu, Antoinette; Anderson, Carl A.; Anney, Richard; Antony, Dinu; Artigas, María Soler; Ayub, Muhammad; Bala, Senduran; Barrett, Jeffrey C.; Barroso, Inês; Beales, Phil; Benn, Marianne; Bentham, Jamie; Bhattacharya, Shoumo; Birney, Ewan; Blackwood, Douglas; Bobrow, Martin; Bochukova, Elena; Bolton, Patrick F.; Bounds, Rebecca; Boustred, Chris; Breen, Gerome; Calissano, Mattia; Carss, Keren; Pablo Casas, Juan; Chambers, John C.; Charlton, Ruth; Chatterjee, Krishna; Chen, Lu; Ciampi, Antonio; Cirak, Sebahattin; Clapham, Peter; Clement, Gail; Coates, Guy; Cocca, Massimiliano; Collier, David A.; Cosgrove, Catherine; Cox, Tony; Craddock, Nick; Crooks, Lucy; Curran, Sarah; Curtis, David; Daly, Allan; Day, Ian N. M.; Day-Williams, Aaron; Dedoussis, George; Down, Thomas; Du, Yuanping; van Duijn, Cornelia M.; Dunham, Ian; Edkins, Sarah; Ekong, Rosemary; Ellis, Peter; Evans, David M.; Farooqi, I. Sadaf; Fitzpatrick, David R.; Flicek, Paul; Floyd, James; Foley, A. Reghan; Franklin, Christopher S.; Futema, Marta; Gallagher, Louise; Gasparini, Paolo; Gaunt, Tom R.; Geihs, Matthias; Geschwind, Daniel; Greenwood, Celia; Griffin, Heather; Grozeva, Detelina; Guo, Xiaosen; Guo, Xueqin; Gurling, Hugh; Hart, Deborah; Hendricks, Audrey E.; Holmans, Peter; Huang, Liren; Hubbard, Tim; Humphries, Steve E.; Hurles, Matthew E.; Hysi, Pirro; Iotchkova, Valentina; Isaacs, Aaron; Jackson, David K.; Jamshidi, Yalda; Johnson, Jon; Joyce, Chris; Karczewski, Konrad; Kaye, Jane; Keane, Thomas; Kemp, John P.; Kennedy, Karen; Kent, Alastair; Keogh, Julia; Khawaja, Farrah; Kleber, Marcus E.; van Kogelenberg, Margriet; Kolb-Kokocinski, Anja; Kooner, Jaspal S.; Lachance, Genevieve; Langenberg, Claudia; Langford, Cordelia; Lawson, Daniel; Lee, Irene; van Leeuwen, Elisabeth M.; Lek, Monkol; Li, Rui; Li, Yingrui; Liang, Jieqin; Lin, Hong; Liu, Ryan; Lönnqvist, Jouko; Lopes, Luis R.; Lopes, Margarida; Luan, Jian'an; MacArthur, Daniel; Mangino, Massimo; Marenne, Gaëlle; März, Winfried; Maslen, John; Matchan, Angela; Mathieson, Iain; McGuffin, Peter; McIntosh, Andrew M.; McKechanie, Andrew G.; McQuillin, Andrew; Metrustry, Sarah; Migone, Nicola; Mitchison, Hannah M.; Moayyeri, Alireza; Morris, James; Morris, Richard; Muddyman, Dawn; Muntoni, Francesco; Nordestgaard, Børge G.; Northstone, Kate; O'Donovan, Michael C.; O'Rahilly, Stephen; Onoufriadis, Alexandros; Oualkacha, Karim; Owen, Michael J.; Palotie, Aarno; Panoutsopoulou, Kalliope; Parker, Victoria; Parr, Jeremy R.; Paternoster, Lavinia; Paunio, Tiina; Payne, Felicity; Payne, Stewart J.; Perry, John R. B.; Pietilainen, Olli; Plagnol, Vincent; Pollitt, Rebecca C.; Povey, Sue; Quail, Michael A.; Quaye, Lydia; Raymond, Lucy; Rehnström, Karola; Ridout, Cheryl K.; Ring, Susan; Ritchie, Graham R. S.; Roberts, Nicola; Robinson, Rachel L.; Savage, David B.; Scambler, Peter; Schiffels, Stephan; Schmidts, Miriam; Schoenmakers, Nadia; Scott, Richard H.; Scott, Robert A.; Semple, Robert K.; Serra, Eva; Sharp, Sally I.; Shaw, Adam; Shihab, Hashem A.; Shin, So-Youn; Skuse, David; Small, Kerrin S.; Smee, Carol; Smith, George Davey; Southam, Lorraine; Spasic-Boskovic, Olivera; Spector, Timothy D.; St Clair, David; St Pourcain, Beate; Stalker, Jim; Stevens, Elizabeth; Sun, Jianping; Surdulescu, Gabriela; Suvisaari, Jaana; Syrris, Petros; Tachmazidou, Ioanna; Taylor, Rohan; Tian, Jing; Tobin, Martin D.; Toniolo, Daniela; Traglia, Michela; Tybjaerg-Hansen, Anne; Valdes, Ana M.; Vandersteen, Anthony M.; Varbo, Anette; Vijayarangakannan, Parthiban; Visscher, Peter M.; Wain, Louise V.; Walters, James T. R.; Wang, Guangbiao; Wang, Jun; Wang, Yu; Ward, Kirsten; Wheeler, Eleanor; Whincup, Peter; Whyte, Tamieka; Williams, Hywel J.; Williamson, Kathleen A.; Wilson, Crispian; Wilson, Scott G.; Wong, Kim; Xu, ChangJiang; Yang, Jian; Zaza, Gianluigi; Zeggini, Eleftheria; Zhang, Feng; Zhang, Pingbo; Zhang, Weihua; Gambaro, Giovanni; Richards, J. Brent; Durbin, Richard; Timpson, Nicholas J.; Marchini, Jonathan; Soranzo, Nicole
    Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.
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    Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome
    (Nature Pub. Group, 2015) Day, Felix R.; Hinds, David A.; Tung, Joyce Y.; Stolk, Lisette; Styrkarsdottir, Unnur; Saxena, Richa; Bjonnes, Andrew; Broer, Linda; Dunger, David B.; Halldorsson, Bjarni V.; Lawlor, Debbie A.; Laval, Guillaume; Mathieson, Iain; McCardle, Wendy L.; Louwers, Yvonne; Meun, Cindy; Ring, Susan; Scott, Robert A.; Sulem, Patrick; Uitterlinden, André G.; Wareham, Nicholas J.; Thorsteinsdottir, Unnur; Welt, Corrine; Stefansson, Kari; Laven, Joop S. E.; Ong, Ken K.; Perry, John R. B.
    Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10−8), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10−9), higher insulin resistance (P=6 × 10−4) and lower serum sex hormone binding globulin concentrations (P=5 × 10−4). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10−8) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10−5). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk.
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    The Simons Genome Diversity Project: 300 genomes from 142 diverse populations
    (Springer Nature, 2016) Mallick, Swapan; Li, Heng; Lipson, Mark; Mathieson, Iain; Gymrek, Melissa Ann; Racimo, Fernando; Zhao, Mengyao; Chennagiri, Niru; Nordenfelt, Susanne; Tandon, Arti; Skoglund, Pontus R; Lazaridis, Iosif; Sankararaman, Sriram; Fu, Qiaomei; Rohland-Pinello, Nadin; Renaud, Gabriel; Erlich, Yaniv; Willems, Thomas; Gallo, Carla; Spence, Jeffrey P.; Song, Yun; Poletti, Giovanni; Balloux, Francois; van Driem, George; de Knijff, Peter; Romero, Irene Gallego; Jha, Aashish R.; Behar, Doron M.; Bravi, Claudio M.; Capelli, Cristian; Hervig, Tor; Moreno-Estrada, Andres; Posukh, Olga L.; Balanovska, Elena; Balanovsky, Oleg; Karachanak-Yankova, Sena; Sahakyan, Hovhannes; Toncheva, Draga; Yepiskoposyan, Levon; Tyler-Smith, Chris; Xue, Yali; Abdullah, M. Syafiq; Ruiz-Linares, Andres; Beall, Cynthia M.; Di Rienzo, Anna; Jeong, Choongwon; Starikovskaya, Elena B.; Metspalu, Ene; Parik, Jüri; Villems, Richard; Henn, Brenna M.; Hodoglugil, Ugur; Mahley, Robert; Sajantila, Antti; Stamatoyannopoulos, George; Wee, Joseph T. S.; Khusainova, Rita; Khusnutdinova, Elza; Litvinov, Sergey; Ayodo, George; Comas, David; Hammer, Michael F.; Kivisild, Toomas; Klitz, William; Winkler, Cheryl A.; Labuda, Damian; Bamshad, Michael; Jorde, Lynn B.; Tishkoff, Sarah A.; Watkins, W. Scott; Metspalu, Mait; Dryomov, Stanislav; Sukernik, Rem; Singh, Lalji; Thangaraj, Kumarasamy; Pääbo, Svante; Kelso, Janet; Patterson, Nick; Reich, David
    We report the Simons Genome Diversity Project (SGDP) dataset: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioral modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that in other non-Africans.
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    Differences in the rare variant spectrum among human populations
    (Public Library of Science, 2017) Mathieson, Iain; Reich, David
    Mutations occur at vastly different rates across the genome, and populations, leading to differences in the spectrum of segregating polymorphisms. Here, we investigate variation in the rare variant spectrum in a sample of human genomes representing all major world populations. We find at least two distinct signatures of variation. One, consistent with a previously reported signature is characterized by an increased rate of TCC>TTC mutations in people from Western Eurasia and South Asia, likely related to differences in the rate, or efficiency of repair, of damage due to deamination of methylated guanine. We describe the geographic extent of this signature and show that it is detectable in the genomes of ancient, but not archaic humans. The second signature is private to certain Native American populations, and is concentrated at CpG sites. We show that this signature is not driven by differences in the CpG mutation rate, but is a result of the fact that highly mutable CpG sites are more likely to undergo multiple independent mutations across human populations, and the spectrum of such mutations is highly sensitive to recent demography. Both of these effects dramatically affect the spectrum of rare variants across human populations, and should be taken into account when using mutational clocks to make inference about demography.
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    Whole-genome sequence-based analysis of thyroid function
    (Nature Pub. Group, 2015) Taylor, Peter N.; Porcu, Eleonora; Chew, Shelby; Campbell, Purdey J.; Traglia, Michela; Brown, Suzanne J.; Mullin, Benjamin H.; Shihab, Hashem A.; Min, Josine; Walter, Klaudia; Memari, Yasin; Huang, Jie; Barnes, Michael R.; Beilby, John P.; Charoen, Pimphen; Danecek, Petr; Dudbridge, Frank; Forgetta, Vincenzo; Greenwood, Celia; Grundberg, Elin; Johnson, Andrew D.; Hui, Jennie; Lim, Ee M.; McCarthy, Shane; Muddyman, Dawn; Panicker, Vijay; Perry, John R.B.; Bell, Jordana T.; Yuan, Wei; Relton, Caroline; Gaunt, Tom; Schlessinger, David; Abecasis, Goncalo; Cucca, Francesco; Surdulescu, Gabriela L.; Woltersdorf, Wolfram; Zeggini, Eleftheria; Zheng, Hou-Feng; Toniolo, Daniela; Dayan, Colin M.; Naitza, Silvia; Walsh, John P.; Spector, Tim; Davey Smith, George; Durbin, Richard; Brent Richards, J.; Sanna, Serena; Soranzo, Nicole; Timpson, Nicholas J.; Wilson, Scott G.; Turki, Saeed Al; Anderson, Carl; Anney, Richard; Antony, Dinu; Artigas, Maria Soler; Ayub, Muhammad; Balasubramaniam, Senduran; Barrett, Jeffrey C.; Barroso, Inês; Beales, Phil; Bentham, Jamie; Bhattacharya, Shoumo; Birney, Ewan; Blackwood, Douglas; Bobrow, Martin; Bochukova, Elena; Bolton, Patrick; Bounds, Rebecca; Boustred, Chris; Breen, Gerome; Calissano, Mattia; Carss, Keren; Chatterjee, Krishna; Chen, Lu; Ciampi, Antonio; Cirak, Sebhattin; Clapham, Peter; Clement, Gail; Coates, Guy; Collier, David; Cosgrove, Catherine; Cox, Tony; Craddock, Nick; Crooks, Lucy; Curran, Sarah; Curtis, David; Daly, Allan; Day-Williams, Aaron; Day, Ian N.M.; Down, Thomas; Du, Yuanping; Dunham, Ian; Edkins, Sarah; Ellis, Peter; Evans, David; Faroogi, Sadaf; Fatemifar, Ghazaleh; Fitzpatrick, David R.; Flicek, Paul; Flyod, James; Foley, A. Reghan; Franklin, Christopher S.; Futema, Marta; Gallagher, Louise; Geihs, Matthias; Geschwind, Daniel; Griffin, Heather; Grozeva, Detelina; Guo, Xueqin; Guo, Xiaosen; Gurling, Hugh; Hart, Deborah; Hendricks, Audrey; Holmans, Peter; Howie, Bryan; Huang, Liren; Hubbard, Tim; Humphries, Steve E.; Hurles, Matthew E.; Hysi, Pirro; Jackson, David K.; Jamshidi, Yalda; Jing, Tian; Joyce, Chris; Kaye, Jane; Keane, Thomas; Keogh, Julia; Kemp, John; Kennedy, Karen; Kolb-Kokocinski, Anja; Lachance, Genevieve; Langford, Cordelia; Lawson, Daniel; Lee, Irene; Lek, Monkol; Liang, Jieqin; Lin, Hong; Li, Rui; Li, Yingrui; Liu, Ryan; Lönnqvist, Jouko; Lopes, Margarida; Lotchkova, Valentina; MacArthur, Daniel; Marchini, Jonathan; Maslen, John; Massimo, Mangino; Mathieson, Iain; Marenne, Gaëlle; McGuffin, Peter; McIntosh, Andrew; McKechanie, Andrew G.; McQuillin, Andrew; Metrustry, Sarah; Mitchison, Hannah; Moayyeri, Alireza; Morris, James; Muntoni, Francesco; Northstone, Kate; O'Donnovan, Michael; Onoufriadis, Alexandros; O'Rahilly, Stephen; Oualkacha, Karim; Owen, Michael J.; Palotie, Aarno; Panoutsopoulou, Kalliope; Parker, Victoria; Parr, Jeremy R.; Paternoster, Lavinia; Paunio, Tiina; Payne, Felicity; Pietilainen, Olli; Plagnol, Vincent; Quaye, Lydia; Quai, Michael A.; Raymond, Lucy; Rehnström, Karola; Richards, Brent; Ring, Susan; Ritchie, Graham R.S.; Roberts, Nicola; Savage, David B.; Scambler, Peter; Schiffels, Stephen; Schmidts, Miriam; Schoenmakers, Nadia; Semple, Robert K.; Serra, Eva; Sharp, Sally I.; Shin, So-Youn; Skuse, David; Small, Kerrin; Southam, Lorraine; Spasic-Boskovic, Olivera; Clair, David St; Stalker, Jim; Stevens, Elizabeth; Pourcian, Beate St; Sun, Jianping; Suvisaari, Jaana; Tachmazidou, Ionna; Tobin, Martin D.; Valdes, Ana; Kogelenberg, Margriet Van; Vijayarangakannan, Parthiban; Visscher, Peter M.; Wain, Louise V.; Walters, James T.R.; Wang, Guangbiao; Wang, Jun; Wang, Yu; Ward, Kirsten; Wheeler, Elanor; Whyte, Tamieka; Williams, Hywel; Williamson, Kathleen A.; Wilson, Crispian; Wong, Kim; Xu, ChangJiang; Yang, Jian; Zhang, Fend; Zhang, Pingbo
    Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10−9) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10−14). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10−9) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10−11). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.