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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- Source :
- Wessel , J , Chu , AY , Willems , SM , Wang , S , Yaghootkar , H , Brody , JA , Dauriz , M , Hivert , MF , Raghavan , S , Lipovich , L , Hidalgo , B , Fox , K , Huffman , JE , An , P , Lu , YC , Rasmussen-Torvik , LJ , Grarup , N , Ehm , MG , Li , L , Baldridge , AS , Stancakova , A , Abrol , R , Besse , CL , Boland , A , Bork-Jensen , J , Fornage , M , Freitag , DF , Garcia , ME , Guo , XQ , Hara , K , Isaacs , A , Jakobsdottir , J , Lange , LA , Layton , JC , Li , M , Zhao , JH , Meidtner , K , Morrison , AC , Nalls , MA , Peters , M , Sabater-Lleal , M , Schurmann , C , Silveira , A , Smith , AV , Southam , L , Stoiber , MH , Strawbridge , RJ , Taylor , KD , Varga , TV , Allin , KH , Amin , N , Aponte , JL , Aung , T , Barbieri , C , Bihlmeyer , NA , Boehnke , M , Bombieri , C , Bowden , DW , Burns , SM , Chen , YN , Chen , YD , Cheng , CY , Correa , A , Czajkowski , J , Dehghan , A , Ehret , GB , Eiriksdottir , G , Escher , SA , Farmaki , AE , Franberg , M , Gambaro , G , Giulianini , F , Goddard , WA , Goel , A , Gottesman , O , Grove , ML , Gustafsson , S , Hai , Y , Hallmans , G , Heo , J , Hoffmann , P , Ikram , MK , Jensen , RA , Jorgensen , ME , Jorgensen , T , Karaleftheri , M , Khor , CC , Kirkpatrick , A , Kraja , AT , Kuusisto , J , Lange , E , Lee , IT , Lee , WJ , Leong , A , Liao , JM , Liu , CY , Liu , YM , Lindgren , CM , Linneberg , A , Malerba , G , Mamakou , V , Marouli , E , Maruthur , NM , Matchan , A , McKean-Cowdin , R , McLeod , O , Metcalf , GA , Mohlke , KL , Muzny , DM , Ntalla , I , Palmer , ND , Pasko , D , Peter , A , Rayner , NW , Renstrom , F , Rice , K , Sala , CF , Sennblad , B , Serafetinidis , I , Smith , JA , Soranzo , N , Speliotes , EK , Stahl , EA , Stirrups , K , Tentolouris , N , Thanopoulou , A , Torres , M , Traglia , M , Tsafantakis , E , Javad , S , Yanek , LR , Zengini , E , Becker , DM , Bis , JC , Brown , JB , Cupples , LA , Hansen , T , Ingelsson , E , Karter , AJ , Lorenzo , C , Mathias , RA , Norris , JM , Pelos
- Publication Year :
- 2015
-
Abstract
- 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 (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 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 (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Details
- Database :
- OAIster
- Journal :
- Wessel , J , Chu , AY , Willems , SM , Wang , S , Yaghootkar , H , Brody , JA , Dauriz , M , Hivert , MF , Raghavan , S , Lipovich , L , Hidalgo , B , Fox , K , Huffman , JE , An , P , Lu , YC , Rasmussen-Torvik , LJ , Grarup , N , Ehm , MG , Li , L , Baldridge , AS , Stancakova , A , Abrol , R , Besse , CL , Boland , A , Bork-Jensen , J , Fornage , M , Freitag , DF , Garcia , ME , Guo , XQ , Hara , K , Isaacs , A , Jakobsdottir , J , Lange , LA , Layton , JC , Li , M , Zhao , JH , Meidtner , K , Morrison , AC , Nalls , MA , Peters , M , Sabater-Lleal , M , Schurmann , C , Silveira , A , Smith , AV , Southam , L , Stoiber , MH , Strawbridge , RJ , Taylor , KD , Varga , TV , Allin , KH , Amin , N , Aponte , JL , Aung , T , Barbieri , C , Bihlmeyer , NA , Boehnke , M , Bombieri , C , Bowden , DW , Burns , SM , Chen , YN , Chen , YD , Cheng , CY , Correa , A , Czajkowski , J , Dehghan , A , Ehret , GB , Eiriksdottir , G , Escher , SA , Farmaki , AE , Franberg , M , Gambaro , G , Giulianini , F , Goddard , WA , Goel , A , Gottesman , O , Grove , ML , Gustafsson , S , Hai , Y , Hallmans , G , Heo , J , Hoffmann , P , Ikram , MK , Jensen , RA , Jorgensen , ME , Jorgensen , T , Karaleftheri , M , Khor , CC , Kirkpatrick , A , Kraja , AT , Kuusisto , J , Lange , E , Lee , IT , Lee , WJ , Leong , A , Liao , JM , Liu , CY , Liu , YM , Lindgren , CM , Linneberg , A , Malerba , G , Mamakou , V , Marouli , E , Maruthur , NM , Matchan , A , McKean-Cowdin , R , McLeod , O , Metcalf , GA , Mohlke , KL , Muzny , DM , Ntalla , I , Palmer , ND , Pasko , D , Peter , A , Rayner , NW , Renstrom , F , Rice , K , Sala , CF , Sennblad , B , Serafetinidis , I , Smith , JA , Soranzo , N , Speliotes , EK , Stahl , EA , Stirrups , K , Tentolouris , N , Thanopoulou , A , Torres , M , Traglia , M , Tsafantakis , E , Javad , S , Yanek , LR , Zengini , E , Becker , DM , Bis , JC , Brown , JB , Cupples , LA , Hansen , T , Ingelsson , E , Karter , AJ , Lorenzo , C , Mathias , RA , Norris , JM , Pelos
- Notes :
- application/pdf, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1313618280
- Document Type :
- Electronic Resource