3 research outputs found
Rare and low-frequency coding variants alter human adult heigh
- Author
- A. A. Burt (7725410)
- A. D. Morris (7611470)
- A. E. Justice (7652732)
- A. E. Locke (7698281)
- A. G. Uitterlinden (7611476)
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- X. Guo (1820437)
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- X. Lin (3771379)
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- X. Zhan (1504810)
- Y. Jia (2014003)
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- Publication venue
- Publication date
- 01/02/2017
- Field of study
Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2âcentimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2âcentimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways
Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals
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- A. A. Hicks (7626671)
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- J. J. Kastelein (7685828)
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- J. Luan (7609367)
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- J. Tuomilehto (7611044)
- J. V. van Vliet-Ostaptchouk (7685513)
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- K. Midthjell (7685477)
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- K. R. Owen (7685480)
- K. Rice (7640519)
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- L. Kedenko (7685354)
- L. L. Bonnycastle (7609496)
- L. Lind (7625984)
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- L. M. Rose (7685768)
- L. P. LyytikÀinen (7626830)
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- L. Qi (2057833)
- L. S. Adair (7626569)
- L. Simpson (7685654)
- M. A. Allison (7685393)
- M. A. Morken (7609412)
- M. A. Province (7685642)
- M. Barbalic (7605845)
- M. Beekman (7645079)
- M. Bochud (7611158)
- M. Boehnke (7605344)
- M. C. Zillikens (7611512)
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- M. F. Feitosa (7685738)
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- M. Ganser (7685459)
- M. Garcia (7650347)
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- M. I. McCarthy (7609121)
- M. J. Caulfield (7602383)
- M. J. Daly (7605926)
- M. J. Go (7685744)
- M. J. Neville (7652672)
- M. J. Sampson (7685489)
- M. Kaakinen (7626740)
- M. Kivimaki (7602458)
- M. Kloppenburg (7685369)
- M. Koseki (7685729)
- M. Kumari (7602503)
- M. KÀhönen (3495260)
- M. L. Lokki (7685789)
- M. L. Nuotio (7652288)
- M. Laakso (7609358)
- M. Ladouceur (7685324)
- M. Li (621494)
- M. Mangino (7609385)
- M. Marmot (7611368)
- M. Marre (7611293)
- M. N. Cooper (7685579)
- M. N. Weedon (7611449)
- M. O. Goodarzi (7626941)
- M. Orho-Melander (7605839)
- M. OrrĂč (7685624)
- M. P. Reilly (7605332)
- M. Perola (7605860)
- M. R. Erdos (7611389)
- M. R. Jarvelin (7611464)
- M. Rieder (7685771)
- M. Roden (7609388)
- M. S. Nieminen (7605854)
- M. S. Sandhu (7609271)
- M. Sandhu (7636817)
- M. Seielstad (7685810)
- M. Serrano-RĂos (7609400)
- M. Stumvoll (7609448)
- M. T. MartĂnez-Larrad (7609391)
- M. Uda (7609529)
- M. van Hoek (7685429)
- M. Walker (1291794)
- MAGIC Consortium (7685378)
- MAGIC investigators (7685720)
- MuTHER Consortium (7685384)
- N. Amin (7611452)
- N. B. Freimer (7685804)
- N. Bouatia-Naji (7609265)
- N. D. Hastie (7650311)
- N. G. Forouhi (7611395)
- N. G. Martin (7639949)
- N. Grarup (7627439)
- N. Hammond (7685597)
- N. Hassanali (7685465)
- N. J. Timpson (7608851)
- N. J. Wareham (7608962)
- N. Klopp (7611599)
- N. L. Glazer (7685534)
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- N. L. Smith (7646216)
- N. Narisu (7609415)
- N. P. Burtt (7605932)
- N. R. Robertson (7647422)
- N. Sattar (7608890)
- N. Soranzo (7608857)
- N. Timpson (7685309)
- N. Vogelzangs (7685675)
- N. W. Rayner (7626794)
- Nilesh Jayantilal Samani (7629899)
- O. D. Carlson (7685351)
- O. Le Bacquer (7685609)
- O. M. Hofmann (7685426)
- O. Melander (7602683)
- O. Pedersen (7627493)
- O. Polasek (7609424)
- O. Raitakari (3495236)
- O. Rolandsson (7652735)
- P. An (7685552)
- P. B. Munroe (7602386)
- P. Barter (7608935)
- P. Chines (7611539)
- P. Deloukas (7603691)
- P. E. Slagboom (7645244)
- P. Elliott (1293702)
- P. Froguel (7609517)
- P. Galan (7645211)
- P. Henneman (5044997)
- P. J. Wagner (7685678)
- P. K. Magnusson (7609379)
- P. Kovacs (7609346)
- P. Kraft (7685471)
- P. M. Ridker (7605368)
- P. Meneton (7626773)
- P. Navarro (1693129)
- P. Nilsson (3701965)
- P. P. Pramstaller (7626770)
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- P. Scheet (7611473)
- P. Schwarz (7609334)
- P. Sethupathy (7685567)
- P. Shrader (7609421)
- P. Vollenweider (4002164)
- P. W. Franks (7605191)
- Procardis Consortium (7685711)
- Q. Sun (1373196)
- R. A. Hegele (7685825)
- R. A. Scott (2840021)
- R. Benediktsson (7685435)
- R. Blagieva (7685438)
- R. Clarke (7602407)
- R. Frants (7685333)
- R. Gwilliam (7685594)
- R. J. Loos (7608845)
- R. Laaksonen (7640441)
- R. Luben (3537284)
- R. M. Krauss (7626722)
- R. M. Roccasecca (7685561)
- R. M. van Dam (7685504)
- R. M. Watanabe (7685531)
- R. Mahley (7608938)
- R. McPherson (7605974)
- R. MĂ€gi (7609376)
- R. N. Bergman (7611524)
- R. P. Tracy (7605272)
- R. P. Welch (7685411)
- R. Pakyz (7685627)
- R. Roberts (2820928)
- R. Saxena (7608878)
- R. Semple (7685390)
- R. Sladek (7608881)
- R. T. Ong (7685750)
- R. Y. Zee (7685759)
- S. A. McCarroll (7685423)
- S. B. Gabriel (7609124)
- S. Bandinelli (7611518)
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- S. C. Heath (7685600)
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- S. Demissie (7605914)
- S. Ebrahim (7611557)
- S. G. Buxbaum (7685396)
- S. Griffin (3537278)
- S. Grundy (7608929)
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- S. Musani (7685387)
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- T. Hansen (3919604)
- T. Haritunians (7685798)
- T. Harris (7640504)
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- T. Meitinger (14191)
- T. Park (7685747)
- T. Quertermous (7626788)
- T. SparsĂž (7685498)
- T. T. Valle (7685717)
- T. Tanaka (3979952)
- T. Tuomi (7611443)
- T. van Herpt (7685510)
- T. W. van Haeften (7685507)
- T. W. Winkler (7647401)
- T. Y. Wong (7626602)
- U. de Faire (7605206)
- U. Gyllensten (7612145)
- U. Seedorf (7602437)
- U. Sovio (7685657)
- U. Thorsteinsdottir (7606031)
- V. E. Mooser (7609406)
- V. Gudnason (7605347)
- V. Lyssenko (7609370)
- V. Mooser (7606070)
- V. Salomaa (7605350)
- V. Steinthorsdottir (7609442)
- V. Vitart (7609463)
- W. A. Hide (7685522)
- W. H. Kao (7609523)
- W. Igl (7670837)
- W. McArdle (7685780)
- W. Rathmann (3531737)
- W. Zhang (820655)
- X. Guo (1820437)
- X. Han (3042561)
- X. Li (536560)
- X. Sim (7626824)
- X. Yuan (696093)
- Y. A. Kesaniemi (7608941)
- Y. Ariyurek (7685570)
- Y. Ben-Shlomo (7605296)
- Y. Böttcher (7609547)
- Y. D. Chen (5184422)
- Y. J. Kim (1781752)
- Y. Li (696089)
- Y. Liu (543492)
- Y. S. Aulchenko (7611497)
- Y. S. Cho (7685741)
- Y. Wu (1590877)
- Z. Dastani (7685306)
- Ă . Johansson (7670804)
- Publication venue
- Publication date
- 29/03/2012
- Field of study
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (Pâ=â4.5Ă10(-8)-1.2Ă10(-43)). Using a novel method to combine data across ethnicities (Nâ=â4,232 African Americans, Nâ=â1,776 Asians, and Nâ=â29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3Ă10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (pâ=â4.3Ă10(-3), nâ=â22,044), increased triglycerides (pâ=â2.6Ă10(-14), nâ=â93,440), increased waist-to-hip ratio (pâ=â1.8Ă10(-5), nâ=â77,167), increased glucose two hours post oral glucose tolerance testing (pâ=â4.4Ă10(-3), nâ=â15,234), increased fasting insulin (pâ=â0.015, nâ=â48,238), but with lower in HDL-cholesterol concentrations (pâ=â4.5Ă10(-13), nâ=â96,748) and decreased BMI (pâ=â1.4Ă10(-4), nâ=â121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance
Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
- Author
- A-C. SyvÀnen (7785878)
- A-E. Farmaki (7737392)
- A. A. Hicks (7626671)
- A. Bonnefond (7609472)
- A. C. Alves (7635926)
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- A. C. Heath (7652336)
- A. Chakravarti (7626947)
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- A. E. Justice (7652732)
- A. F. Wright (7609490)
- A. G. Uitterlinden (7611476)
- A. Goel (7602413)
- A. Hamsten (7602395)
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- A. Hofman (4269889)
- A. J. M. de Craen (7785692)
- A. J. Oldehinkel (7785923)
- A. J. Swift (7609451)
- A. Jula (7609328)
- A. K. Henders (7785794)
- A. L. James (7628765)
- A. L. M. Verbeek (7785941)
- A. Linneberg (3444095)
- A. Mahajan (7603748)
- A. Metspalu (7626776)
- A. P. Morris (7611419)
- A. Palotie (7632986)
- A. Peters (6004598)
- A. Pouta (7650326)
- A. R. Sanders (7785863)
- A. R. Shuldiner (7685708)
- A. S. Buchman (7785761)
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- A. T. Hattersley (7609073)
- A. Teumer (7609454)
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- A. Tönjes (7609457)
- A. U. Jackson (7609325)
- A. V. Smith (7605131)
- A. W. Musk (3965711)
- A. Wong (7602695)
- arcOGEN Consortium (7747979)
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- B. Gigante (7606052)
- B. Lehne (7785719)
- B. M. Psaty (7605224)
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- B. O. Boehm (7660346)
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- C. Hayward (7609304)
- C. Hengstenberg (7603694)
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- C. Lanzani (7785830)
- C. M. Lindgren (7611374)
- C. M. van Duijn (7626872)
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- C. Rivolta (7698353)
- C. S. Fox (7609280)
- C. W. K. Chiang (7785701)
- C. Willenborg (7605947)
- CHARGE Consortium (7670858)
- D. A. Bennett (7681397)
- D. A. Evans (7785902)
- D. Absher (7626566)
- D. Baldassarre (7626578)
- D. C. Rao (7626791)
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- D. Hernandez (7785797)
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- D. I. Chasman (7605179)
- D. J. Clegg (7698299)
- D. J. Hunter (7611488)
- D. Kuh (7602698)
- D. P. Strachan (3809152)
- D. Schlessinger (7609430)
- DIAGRAM Consortium (7670852)
- E. A. Andersson (7785746)
- E. Albrecht (7612112)
- E. Boerwinkle (7609103)
- E. Eury (7785779)
- E. Ingelsson (7605335)
- E. J. C. de Geus (7785770)
- E. Kajantie (7652678)
- E. Mihailov (7645184)
- E. P. Bottinger (7689854)
- E. Tremoli (7626857)
- E. Tsafantakis (7636823)
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- E. Widén (7653272)
- E. Zeggini (7632767)
- F. Bonnet (7658774)
- F. Cucca (7683212)
- F. Frau (7785707)
- F. Geller (7653116)
- F. Hu (4376644)
- F. L. Moll (7785917)
- F. Renström (7611431)
- F. Rivadeneira (7611509)
- F. Rizzi (7785728)
- F. S. Collins (7609505)
- F. W. Asselbergs (3801271)
- G. B. Ehret (7626533)
- G. Boucher (7698341)
- G. Cadby (7785695)
- G. Dedoussis (7626908)
- G. Delgado (7626614)
- G. Eiriksdottir (7650329)
- G. Lettre (7685792)
- G. MĂŒller (3988166)
- G. Pasterkamp (7626023)
- G. R. Abecasis (7602524)
- G. Thorleifsson (7606022)
- G. W. Montgomery (7652342)
- G. Waeber (4002158)
- G. Willemsen (7609478)
- GLGC Consortium (7685723)
- Global-BPGen Consortium (7785944)
- H-J. Westra (7602398)
- H. A. Boyd (7785755)
- H. A. Koistinen (7737416)
- H. Campbell (7609436)
- H. Grallert (4107469)
- H. Grönberg (7698320)
- H. Hillege (7785800)
- H. M. den Ruijter (7626017)
- H. M. Stringham (7605209)
- H. Scharnagl (7640582)
- H. Schunkert (7603670)
- H. Snieder (7611185)
- H. V. Huikuri (7785905)
- H. Völzke (6643736)
- H. Wallaschofski (7609466)
- H. Watkins (7602419)
- I. B. Borecki (7685702)
- I. Barroso (7609532)
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- I. Kolcic (7650395)
- I. M. Heid (7611266)
- I. M. Nolte (3809176)
- I. Mateo Leach (7698371)
- I. NjĂžlstad (3531731)
- I. Pichler (7648376)
- I. Prokopenko (7608875)
- I. Rudan (7609409)
- I. Tachmazidou (7632716)
- ICBP Consortium (7778762)
- J-C. Tardif (7737476)
- J-J. Hottenga (7785713)
- J. A. Staessen (7602608)
- J. Beilby (7650389)
- J. Blangero (3485027)
- J. C. Bis (7625957)
- J. C. Chambers (7605185)
- J. C. Murray (7785920)
- J. Cole (7785767)
- J. Czajkowski (7785671)
- J. D. Rioux (7725635)
- J. Duan (7785776)
- J. E. Huffman (7628750)
- J. Erdmann (7603664)
- J. Eriksson (7653191)
- J. F. Wilson (7605311)
- J. G. Eriksson (7647449)
- J. GrĂ€Ăler (7626551)
- J. H. Smit (7626827)
- J. H. Zhao (1395031)
- J. Hui (6291092)
- J. I. Rotter (7626935)
- J. Karjalainen (7778708)
- J. KrĂŒger (7785827)
- J. Kuusisto (7609355)
- J. L. Bragg-Gresham (7785689)
- J. Lahti (7785716)
- J. Lindström (3847444)
- J. Luan (7609367)
- J. M. Jordan (7785908)
- J. M. Vonk (3809224)
- J. N. Hirschhorn (7609139)
- J. P. Tyrer (7725671)
- J. R. O'Connell (7698419)
- J. S. Beckmann (7612118)
- J. S. Kooner (7605356)
- J. S. Pankow (7609316)
- J. S. Viikari (7647428)
- J. Saltevo (7626917)
- J. Shi (1478902)
- J. Simino (7785680)
- J. Sinisalo (6254942)
- J. Tuomilehto (7611044)
- J. V. van Vliet-Ostaptchouk (7685513)
- J. van Setten (7625924)
- J. W. Jukema (7625996)
- J. Yang (1558195)
- K. A. Ryan (2940573)
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- Publication venue
- Publication date
- 29/06/2016
- Field of study
The arcOGEN Consortium should be listed as an author of this article. They contributed to the genome-wide association study results presented in this work. They should be listed in the author byline at position 292 and affiliated with The Arthritis Research UK Osteoarthritis Genetics Consortium. They should also be included in the footnote designating consortia which is underneath the author affiliation list in the PDF version of the article, and in the S2 Text. Please view the correct S2 Text below, containing correct consortia members. S2 Text. Consortia members and extended acknowledgments.
https://doi.org/10.1371/journal.pgen.1006166.s001
(DOCX) [This corrects the article DOI: 10.1371/journal.pgen.1005378.]