Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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20881960
TITLE
Hundreds of variants clustered in genomic loci and biological pathways affect human height.
ABSTRACT
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
DATE PUBLISHED
2010 Oct 14
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2010/04/23
accepted 2010/07/28
aheadofprint 2010/09/29
entrez 2010/10/01 06:00
pubmed 2010/10/01 06:00
medline 2010/12/14 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Lango Allen H Lango Allen Hana H Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX1 2LU, UK.
Estrada K Estrada Karol K
Lettre G Lettre Guillaume G
Berndt SI Berndt Sonja I SI
Weedon MN Weedon Michael N MN
Rivadeneira F Rivadeneira Fernando F
Willer CJ Willer Cristen J CJ
Jackson AU Jackson Anne U AU
Vedantam S Vedantam Sailaja S
Raychaudhuri S Raychaudhuri Soumya S
Ferreira T Ferreira Teresa T
Wood AR Wood Andrew R AR
Weyant RJ Weyant Robert J RJ
Segrè AV Segrè Ayellet V AV
Speliotes EK Speliotes Elizabeth K EK
Wheeler E Wheeler Eleanor E
Soranzo N Soranzo Nicole N
Park JH Park Ju-Hyun JH
Yang J Yang Jian J
Gudbjartsson D Gudbjartsson Daniel D
Heard-Costa NL Heard-Costa Nancy L NL
Randall JC Randall Joshua C JC
Qi L Qi Lu L
Vernon Smith A Vernon Smith Albert A
Mägi R Mägi Reedik R
Pastinen T Pastinen Tomi T
Liang L Liang Liming L
Heid IM Heid Iris M IM
Luan J Luan Jian'an J
Thorleifsson G Thorleifsson Gudmar G
Winkler TW Winkler Thomas W TW
Goddard ME Goddard Michael E ME
Sin Lo K Sin Lo Ken K
Palmer C Palmer Cameron C
Workalemahu T Workalemahu Tsegaselassie T
Aulchenko YS Aulchenko Yurii S YS
Johansson A Johansson Asa A
Zillikens MC Zillikens M Carola MC
Feitosa MF Feitosa Mary F MF
Esko T Esko Tõnu T
Johnson T Johnson Toby T
Ketkar S Ketkar Shamika S
Kraft P Kraft Peter P
Mangino M Mangino Massimo M
Prokopenko I Prokopenko Inga I
Absher D Absher Devin D
Albrecht E Albrecht Eva E
Ernst F Ernst Florian F
Glazer NL Glazer Nicole L NL
Hayward C Hayward Caroline C
Hottenga JJ Hottenga Jouke-Jan JJ
Jacobs KB Jacobs Kevin B KB
Knowles JW Knowles Joshua W JW
Kutalik Z Kutalik Zoltán Z
Monda KL Monda Keri L KL
Polasek O Polasek Ozren O
Preuss M Preuss Michael M
Rayner NW Rayner Nigel W NW
Robertson NR Robertson Neil R NR
Steinthorsdottir V Steinthorsdottir Valgerdur V
Tyrer JP Tyrer Jonathan P JP
Voight BF Voight Benjamin F BF
Wiklund F Wiklund Fredrik F
Xu J Xu Jianfeng J
Zhao JH Zhao Jing Hua JH
Nyholt DR Nyholt Dale R DR
Pellikka N Pellikka Niina N
Perola M Perola Markus M
Perry JR Perry John R B JR
Surakka I Surakka Ida I
Tammesoo ML Tammesoo Mari-Liis ML
Altmaier EL Altmaier Elizabeth L EL
Amin N Amin Najaf N
Aspelund T Aspelund Thor T
Bhangale T Bhangale Tushar T
Boucher G Boucher Gabrielle G
Chasman DI Chasman Daniel I DI
Chen C Chen Constance C
Coin L Coin Lachlan L
Cooper MN Cooper Matthew N MN
Dixon AL Dixon Anna L AL
Gibson Q Gibson Quince Q
Grundberg E Grundberg Elin E
Hao K Hao Ke K
Juhani Junttila M Juhani Junttila M M
Kaplan LM Kaplan Lee M LM
Kettunen J Kettunen Johannes J
König IR König Inke R IR
Kwan T Kwan Tony T
Lawrence RW Lawrence Robert W RW
Levinson DF Levinson Douglas F DF
Lorentzon M Lorentzon Mattias M
McKnight B McKnight Barbara B
Morris AP Morris Andrew P AP
Müller M Müller Martina M
Suh Ngwa J Suh Ngwa Julius J
Purcell S Purcell Shaun S
Rafelt S Rafelt Suzanne S
Salem RM Salem Rany M RM
Salvi E Salvi Erika E
Sanna S Sanna Serena S
Shi J Shi Jianxin J
Sovio U Sovio Ulla U
Thompson JR Thompson John R JR
Turchin MC Turchin Michael C MC
Vandenput L Vandenput Liesbeth L
Verlaan DJ Verlaan Dominique J DJ
Vitart V Vitart Veronique V
White CC White Charles C CC
Ziegler A Ziegler Andreas A
Almgren P Almgren Peter P
Balmforth AJ Balmforth Anthony J AJ
Campbell H Campbell Harry H
Citterio L Citterio Lorena L
De Grandi A De Grandi Alessandro A
Dominiczak A Dominiczak Anna A
Duan J Duan Jubao J
Elliott P Elliott Paul P
Elosua R Elosua Roberto R
Eriksson JG Eriksson Johan G JG
Freimer NB Freimer Nelson B NB
Geus EJ Geus Eco J C EJ
Glorioso N Glorioso Nicola N
Haiqing S Haiqing Shen S
Hartikainen AL Hartikainen Anna-Liisa AL
Havulinna AS Havulinna Aki S AS
Hicks AA Hicks Andrew A AA
Hui J Hui Jennie J
Igl W Igl Wilmar W
Illig T Illig Thomas T
Jula A Jula Antti A
Kajantie E Kajantie Eero E
Kilpeläinen TO Kilpeläinen Tuomas O TO
Koiranen M Koiranen Markku M
Kolcic I Kolcic Ivana I
Koskinen S Koskinen Seppo S
Kovacs P Kovacs Peter P
Laitinen J Laitinen Jaana J
Liu J Liu Jianjun J
Lokki ML Lokki Marja-Liisa ML
Marusic A Marusic Ana A
Maschio A Maschio Andrea A
Meitinger T Meitinger Thomas T
Mulas A Mulas Antonella A
Paré G Paré Guillaume G
Parker AN Parker Alex N AN
Peden JF Peden John F JF
Petersmann A Petersmann Astrid A
Pichler I Pichler Irene I
Pietiläinen KH Pietiläinen Kirsi H KH
Pouta A Pouta Anneli A
Ridderstråle M Ridderstråle Martin M
Rotter JI Rotter Jerome I JI
Sambrook JG Sambrook Jennifer G JG
Sanders AR Sanders Alan R AR
Schmidt CO Schmidt Carsten Oliver CO
Sinisalo J Sinisalo Juha J
Smit JH Smit Jan H JH
Stringham HM Stringham Heather M HM
Bragi Walters G Bragi Walters G G
Widen E Widen Elisabeth E
Wild SH Wild Sarah H SH
Willemsen G Willemsen Gonneke G
Zagato L Zagato Laura L
Zgaga L Zgaga Lina L
Zitting P Zitting Paavo P
Alavere H Alavere Helene H
Farrall M Farrall Martin M
McArdle WL McArdle Wendy L WL
Nelis M Nelis Mari M
Peters MJ Peters Marjolein J MJ
Ripatti S Ripatti Samuli S
van Meurs JB van Meurs Joyce B J JB
Aben KK Aben Katja K KK
Ardlie KG Ardlie Kristin G KG
Beckmann JS Beckmann Jacques S JS
Beilby JP Beilby John P JP
Bergman RN Bergman Richard N RN
Bergmann S Bergmann Sven S
Collins FS Collins Francis S FS
Cusi D Cusi Daniele D
den Heijer M den Heijer Martin M
Eiriksdottir G Eiriksdottir Gudny G
Gejman PV Gejman Pablo V PV
Hall AS Hall Alistair S AS
Hamsten A Hamsten Anders A
Huikuri HV Huikuri Heikki V HV
Iribarren C Iribarren Carlos C
Kähönen M Kähönen Mika M
Kaprio J Kaprio Jaakko J
Kathiresan S Kathiresan Sekar S
Kiemeney L Kiemeney Lambertus L
Kocher T Kocher Thomas T
Launer LJ Launer Lenore J LJ
Lehtimäki T Lehtimäki Terho T
Melander O Melander Olle O
Mosley TH Jr Mosley Tom H TH
Musk AW Musk Arthur W AW
Nieminen MS Nieminen Markku S MS
O'Donnell CJ O'Donnell Christopher J CJ
Ohlsson C Ohlsson Claes C
Oostra B Oostra Ben B
Palmer LJ Palmer Lyle J LJ
Raitakari O Raitakari Olli O
Ridker PM Ridker Paul M PM
Rioux JD Rioux John D JD
Rissanen A Rissanen Aila A
Rivolta C Rivolta Carlo C
Schunkert H Schunkert Heribert H
Shuldiner AR Shuldiner Alan R AR
Siscovick DS Siscovick David S DS
Stumvoll M Stumvoll Michael M
Tönjes A Tönjes Anke A
Tuomilehto J Tuomilehto Jaakko J
van Ommen GJ van Ommen Gert-Jan GJ
Viikari J Viikari Jorma J
Heath AC Heath Andrew C AC
Martin NG Martin Nicholas G NG
Montgomery GW Montgomery Grant W GW
Province MA Province Michael A MA
Kayser M Kayser Manfred M
Arnold AM Arnold Alice M AM
Atwood LD Atwood Larry D LD
Boerwinkle E Boerwinkle Eric E
Chanock SJ Chanock Stephen J SJ
Deloukas P Deloukas Panos P
Gieger C Gieger Christian C
Grönberg H Grönberg Henrik H
Hall P Hall Per P
Hattersley AT Hattersley Andrew T AT
Hengstenberg C Hengstenberg Christian C
Hoffman W Hoffman Wolfgang W
Lathrop GM Lathrop G Mark GM
Salomaa V Salomaa Veikko V
Schreiber S Schreiber Stefan S
Uda M Uda Manuela M
Waterworth D Waterworth Dawn D
Wright AF Wright Alan F AF
Assimes TL Assimes Themistocles L TL
Barroso I Barroso Inês I
Hofman A Hofman Albert A
Mohlke KL Mohlke Karen L KL
Boomsma DI Boomsma Dorret I DI
Caulfield MJ Caulfield Mark J MJ
Cupples LA Cupples L Adrienne LA
Erdmann J Erdmann Jeanette J
Fox CS Fox Caroline S CS
Gudnason V Gudnason Vilmundur V
Gyllensten U Gyllensten Ulf U
Harris TB Harris Tamara B TB
Hayes RB Hayes Richard B RB
Jarvelin MR Jarvelin Marjo-Riitta MR
Mooser V Mooser Vincent V
Munroe PB Munroe Patricia B PB
Ouwehand WH Ouwehand Willem H WH
Penninx BW Penninx Brenda W BW
Pramstaller PP Pramstaller Peter P PP
Quertermous T Quertermous Thomas T
Rudan I Rudan Igor I
Samani NJ Samani Nilesh J NJ
Spector TD Spector Timothy D TD
Völzke H Völzke Henry H
Watkins H Watkins Hugh H
Wilson JF Wilson James F JF
Groop LC Groop Leif C LC
Haritunians T Haritunians Talin T
Hu FB Hu Frank B FB
Kaplan RC Kaplan Robert C RC
Metspalu A Metspalu Andres A
North KE North Kari E KE
Schlessinger D Schlessinger David D
Wareham NJ Wareham Nicholas J NJ
Hunter DJ Hunter David J DJ
O'Connell JR O'Connell Jeffrey R JR
Strachan DP Strachan David P DP
Wichmann HE Wichmann H-Erich HE
Borecki IB Borecki Ingrid B IB
van Duijn CM van Duijn Cornelia M CM
Schadt EE Schadt Eric E EE
Thorsteinsdottir U Thorsteinsdottir Unnur U
Peltonen L Peltonen Leena L
Uitterlinden AG Uitterlinden André G AG
Visscher PM Visscher Peter M PM
Chatterjee N Chatterjee Nilanjan N
Loos RJ Loos Ruth J F RJ
Boehnke M Boehnke Michael M
McCarthy MI McCarthy Mark I MI
Ingelsson E Ingelsson Erik E
Lindgren CM Lindgren Cecilia M CM
Abecasis GR Abecasis Gonçalo R GR
Stefansson K Stefansson Kari K
Frayling TM Frayling Timothy M TM
Hirschhorn JN Hirschhorn Joel N JN
INVESTIGATORS
JOURNAL
VOLUME: 467
ISSUE: 7317
TITLE: Nature
ISOABBREVIATION: Nature
YEAR: 2010
MONTH: Oct
DAY: 14
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-4687
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nature
COUNTRY: England
ISSNLINKING: 0028-0836
NLMUNIQUEID: 0410462
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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R01-MH59571 NIMH NIH HHS United States
R01-MH59586 NIMH NIH HHS United States
R01-MH59587 NIMH NIH HHS United States
R01-MH59588 NIMH NIH HHS United States
R01-MH60870 NIMH NIH HHS United States
R01-MH60879 NIMH NIH HHS United States
R01-MH61675 NIMH NIH HHS United States
R01-MH63706 NIMH NIH HHS United States
R01-MH67257 NIMH NIH HHS United States
R01-MH79469 NIMH NIH HHS United States
R01-MH81800 NIMH NIH HHS United States
RC2 HG005581 NHGRI NIH HHS United States
RC2 HG005581-02 NHGRI NIH HHS United States
RL1 MH083268 NIMH NIH HHS United States
RL1 MH083268-05 NIMH NIH HHS United States
RL1-MH083268 NIMH NIH HHS United States
T32-HG00040 NHGRI NIH HHS United States
U01 CA049449 NCI NIH HHS United States
U01 CA049449-21 NCI NIH HHS United States
U01 CA098233 NCI NIH HHS United States
U01 CA098233-08 NCI NIH HHS United States
U01 DK062370 NIDDK NIH HHS United States
U01 DK062370-08 NIDDK NIH HHS United States
U01 DK062418 NIDDK NIH HHS United States
U01 GM074518 NIGMS NIH HHS United States
U01 GM074518-05 NIGMS NIH HHS United States
U01 HG004399 NHGRI NIH HHS United States
U01 HG004399-02 NHGRI NIH HHS United States
U01 HG004402 NHGRI NIH HHS United States
U01 HG004402-02 NHGRI NIH HHS United States
U01 HG005214 NHGRI NIH HHS United States
U01 HG005214-02 NHGRI NIH HHS United States
U01 HL069757 NHLBI NIH HHS United States
U01 HL069757-10 NHLBI NIH HHS United States
U01 HL072515 NHLBI NIH HHS United States
U01 HL072515-06 NHLBI NIH HHS United States
U01 HL080295 NHLBI NIH HHS United States
U01 HL080295-04 NHLBI NIH HHS United States
U01 HL084729 NHLBI NIH HHS United States
U01 HL084729-03 NHLBI NIH HHS United States
U01 HL084756 NHLBI NIH HHS United States
U01 HL084756-03 NHLBI NIH HHS United States
U01 MH079469 NIMH NIH HHS United States
U01 MH079469-03 NIMH NIH HHS United States
U01 MH079470 NIMH NIH HHS United States
U01 MH079470-03 NIMH NIH HHS United States
U01-CA098233 NCI NIH HHS United States
U01-GM074518 NIGMS NIH HHS United States
U01-HG004399 NHGRI NIH HHS United States
U01-HG004402 NHGRI NIH HHS United States
U01-HL080295 NHLBI NIH HHS United States
U01-HL084756 NHLBI NIH HHS United States
U01-HL72515 NHLBI NIH HHS United States
U01-MH79469 NIMH NIH HHS United States
U01-MH79470 NIMH NIH HHS United States
U54-RR020278 NCRR NIH HHS United States
UL1-RR025005 NCRR NIH HHS United States
Z01-AG00675 NIA NIH HHS United States
Z01-AG007380 NIA NIH HHS United States
Z01-HG000024 NHGRI NIH HHS United States
Cancer Research UK United Kingdom
Intramural NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Body Height genetics
Chromosomes, Human, Pair 3 genetics
Genetic Loci genetics
Genetic Predisposition to Disease genetics
Genome, Human genetics
Genome-Wide Association Study genetics
Humans genetics
Metabolic Networks and Pathways genetics
Multifactorial Inheritance genetics
Phenotype genetics
Polymorphism, Single Nucleotide genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
OTHERID SOURCE
NIHMS225625 NLM
PMC2955183 NLM