Browse by author
Lookup NU author(s): Professor Mark Walker
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
© 2015, Public Library of Science, All Rights Reserved.Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
Author(s): Mahajan A, Sim X, Ng HJ, Manning A, Rivas MA, Highland HM, Locke AE, Grarup N, Im HK, Cingolani P, Flannick J, Fontanillas P, Fuchsberger C, Gaulton KJ, Teslovich TM, Rayner NW, Robertson NR, Beer NL, Rundle JK, Bork-Jensen J, Ladenvall C, Blancher C, Buck D, Buck G, Burtt NP, Gabriel S, Gjesing AP, Groves CJ, Hollensted M, Huyghe JR, Jackson AU, Jun G, Justesen JM, Mangino M, Murphy J, Neville M, Onofrio R, Small KS, Stringham HM, Syvanen A-C, Trakalo J, Abecasis G, Bell GI, Blangero J, Cox NJ, Duggirala R, Hanis CL, Seielstad M, Wilson JG, Christensen C, Brandslund I, Rauramaa R, Surdulescu GL, Doney ASF, Lannfelt L, Linneberg A, Isomaa B, Tuomi T, Jorgensen ME, Jorgensen T, Kuusisto J, Uusitupa M, Salomaa V, Spector TD, Morris AD, Palmer CNA, Collins FS, Mohlke KL, Bergman RN, Ingelsson E, Lind L, Tuomilehto J, Hansen T, Watanabe RM, Prokopenko I, Dupuis J, Karpe F, Groop L, Laakso M, Pedersen O, Florez JC, Morris AP, Altshuler D, Meigs JB, Boehnke M, McCarthy MI, Lindgren CM, Gloyn AL, Abboud HE, Afzal U, Aguilar D, Arya R, Atzmon G, Aung T, Banks E, Barroso I, Barzilai N, Below JE, Bharadwaj D, Blackwell TW, Bonnycastle LL, Bowden D, Carey J, Carneiro MO, Chambers JC, Chan E, Chan J, Chandak GR, Chen P, Chen Y, Chen H, Cheng C-Y, Chia KS, Cho YS, Correa A, Curran JE, Daly MJ, Day-Williams AG, DeFronzo RA, DePristo M, Donnelly PJ, Ebrahim SB, Elliott P, Esko T, Fadista J, Farjoun Y, Farmer AJ, Farook VS, Fennell T, Ferreira T, Fingerlin T, Forsen T, Fowler SP, Franks PW, Frayling TM, Freedman BI, Froguel P, Gamazon ER, Gieger C, Glaser B, Go MJ, Goldstein JI, Grallert H, Grant G, Green T, Griswold M, Hale DE, Han B-G, Hartl C, Hattersley AT, Hicks PJ, Hodgkiss D, Horikoshi M, Hrabe de Angelis M, Hu C, Hu FB, Huh I, Kamran Ikram M, Illig T, Jablonski KA, Jenkinson CP, Jia W, Kang HM, Khor C-C, Kim Y, Kim YJ, Kim B-J, Kinnunen L, Kooner JS, Kravic J, Kriebel J, Kumar A, Kumar S, Kuulasmaa T, Kwon M-S, Langenberg C, Lauritzen T, Lee S, Lee J, Lee J, Lee J-Y, Lehman DM, Lehne B, Levy JC, Li J, Liang L, Lim WY, Lin K-H, Liu J, Loh M, Ma RCW, Ma C, Magi R, Maguire J, Maxwell TJ, McVean G, Meisinger C, Meitinger T, Melander O, Metspalu A, Mihailov E, Milani L, Moutsianas L, Muller-Nurasyid M, K Musani S, Nagai Y, Narisu N, Neale BM, Ng MCY, Nilsson P, O'Rahilly SP, Orho-Melander M, Owen KR, Palmer ND, Park T, Pasko D, Pearson RD, Perry JRB, Peters A, Pollin TI, Poplin R, Prabhakaran D, Puppala S, Purcell S, Qi L, Qi Q, Roden M, Rolandsson O, Rosengren AH, Sandhu M, Schwarzmayr T, Scott LJ, Scott RA, Scott J, Scott WR, Sehmi J, Shakir K, Sladek R, Smith JD, Stancakova A, Strauch K, Strom TM, Swift A, Tai ES, Tajes JF, Tan S-T, Tandon N, Taylor HA, Teo YY, Thameem F, Thorand B, van de Bunt M, Varga TV, Walker M, Wareham NJ, Welch RP, Wieland T, Wilson G, Wong TY, Wood AR, Yoon J, Zeggini E, Zhang W
Publication type: Article
Publication status: Published
Journal: PLoS Genetics
Year: 2015
Volume: 11
Issue: 1
Online publication date: 27/01/2015
Acceptance date: 01/01/1900
ISSN (print): 1553-7390
ISSN (electronic): 1553-7404
Publisher: Public Library of Science
URL: https://doi.org/10.1371/journal.pgen.1004876
DOI: 10.1371/journal.pgen.1004876
PubMed id: 25625282
Altmetrics provided by Altmetric
