Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

PLoS Genetics

Volumn 11, Issue 1, 2015, Pages

  Mahajan, Anubha ^a   Sim, Xueling ^b   Ng, Hui Jin ^c   Manning, Alisa ^d   Rivas, Manuel A ^a   Highland, Heather M ^e   Locke, Adam E ^b   Grarup, Niels ^f   Im, Hae Kyung ^g   Cingolani, Pablo ^h   Flannick, Jason ^d,i   Fontanillas, Pierre ^d   Fuchsberger, Christian ^b   Gaulton, Kyle J ^a   Teslovich, Tanya M ^b   Rayner, N William ^a,c,j   Robertson, Neil R ^a,c   Beer, Nicola L ^c   Rundle, Jana K ^c   Bork Jensen, Jette ^f   Ladenvall, Claes ^k   Blancher, Christine ^a   Buck, David ^a   Buck, Gemma ^a   Burtt, Noël P ^d   Gabriel, Stacey ^d   Gjesing, Anette P ^f   Groves, Christopher J ^c   Hollensted, Mette ^f   Huyghe, Jeroen R ^b   Jackson, Anne U ^b   Jun, Goo ^b   Donnelly, Peter J ^a,bm,bm   Mangino, Massimo ^l   Murphy, Jacquelyn ^d   Neville, Matt ^c   Onofrio, Robert ^d   Small, Kerrin S ^l   Stringham, Heather M ^b   Syvänen, Ann Christine ^m   Trakalo, Joseph ^a   Abecasis, Goncalo ^b   Bell, Graeme I ^g   Blangero, John ⁿ   Cox, Nancy J ^g   Duggirala, Ravindranath ⁿ   Hanis, Craig L ^o   Seielstad, Mark ^p,q   Wilson, James G ^r   Christensen, Cramer ^s   Brandslund, Ivan ^s,t   Rauramaa, Rainer ^u   Surdulescu, Gabriela L ^l   Doney, Alex S F ^v   Lannfelt, Lars ^w   Linneberg, Allan ^x,y   Isomaa, Bo ^z,aa   Tuomi, Tiinamaija ^aa,ab   Jørgensen, Marit E ^ac   Jørgensen, Torben ^x,ad   Kuusisto, Johanna ^u,ae   Uusitupa, Matti ^u   Salomaa, Veikko ^af   Spector, Timothy D ^l   Morris, Andrew D ^v   Palmer, Colin N A ^v   Collins, Francis S ^ag   Hu, Frank B ^bj,bj   Bergman, Richard N ^ai   Ingelsson, Erik ^a,m   Lind, Lars ^m   Tuomilehto, Jaakko ^af,aj,ak,al   Hansen, Torben ^f,t   Watanabe, Richard M ^am   Prokopenko, Inga ^a,c,an   Dupuis, Josee ^ao,ap   Karpe, Fredrik ^c,aq   Groop, Leif ^k   Laakso, Markku ^u,ae   Pedersen, Oluf ^f   Florez, Jose C ^d,i,ar   Morris, Andrew P ^a,as,at   Altshuler, David ^d,i,ar,au   Meigs, James B ⁱ   Boehnke, Michael ^b   McCarthy, Mark I ^a,c,aq   Lindgren, Cecilia M ^a,d   Gloyn, Anna L ^c,aq   Abboud, Hanna E ^av   Afzal, Uzma ^an   Aguilar, David ^aw   Arya, Rector ^av   Atzmon, Gil ^ax   Aung, Tin ^ay,az   Banks, Eric ^d   Barroso, Inês ^j,ba   Barzilai, Nir ^ax   Liang, Liming ^bj,bj   Bharadwaj, Dwaipayan ^bb   Blackwell, Thomas W ^b   Bonnycastle, Lori L ^ag   Bowden, Don ^bc   Carey, Jason ^d   Carneiro, Mauricio O ^d   Chambers, John C ^an,bd,be   Chan, Edmund ^bf   Chan, Juliana ^bg   Chandak, Giriraj R ^bh   Chen, Peng ^bi   Chen, Yuhui ^a   Chen, Han ^ap,bj   Cheng, Ching Yu ^ay,az,bi,bk   Chia, Kee Seng ^bi   Cho, Yoon Shin ^bl   Correa, Adolfo ^r   Curran, Joanne E ⁿ   Daly, Mark J ⁱ   Day Williams, Aaron G ^j   DeFronzo, Ralph A ^av   DePristo, Mark ^d   Nilsson, Peter ^cn,cn   Elliott, Paul ^an   Esko, Tõnu ^d,ar,at,bo   Fadista, João ^k   Farjoun, Yossi ^d   Farmer, Andrew J ^bm   Farook, Vidya S ⁿ   Fennell, Timothy ^d   Ferreira, Teresa ^a   Fingerlin, Tasha ^bp   Forsén, Tom ^bq,br   Fowler, Sharon P ^av   Franks, Paul W ^bj,bs   Frayling, Timothy M ^bt   Freedman, Barry I ^bc   Froguel, Philippe ^bu   Gamazon, Eric R ^g   Gieger, Christian ^bv   Glaser, Benjamin ^bw   Go, Min Jin ^bx   Goldstein, Jacqueline I ^d,i   Grallert, Harald ^bv,by   Grant, George ^d   Green, Todd ^d   Griswold, Michael ^bz   Hale, Daniel Esten ^av   Han, Bok Ghee ^bx   Hartl, Christopher ^d   Hattersley, Andrew T ^bt   Hicks, Pamela J ^bc   Hodgkiss, Dylan ^l   Horikoshi, Momoko ^a,c   Hrabé de Angelis, Martin ^bv   Hu, Cheng ^ca   Huh, Iksoo ^cb   Kamran Ikram, Mohammad ^ay,az   Illig, Thomas ^bv,cc   Jablonski, Kathleen A ^cd   Jenkinson, Christopher P ^av,ce   Jia, Weiping ^ca   Kang, Hyun Min ^b   Khor, Chiea Chuen ^ay,az,bi,cf   Kim, Yongkang ^cb   Kim, Young Jin ^bx   Kim, Bong Jo ^bx   Kinnunen, Leena ^af   Kooner, Jaspal Singh ^cg   Kravic, Jasmina ^k   Kriebel, Jennifer ^bv,by   Kumar, Ashish ^a,ch   Kumar, Satish ⁿ   Kuulasmaa, Teemu ^u   Kwon, Min Seok ^cb   Langenberg, Claudia ^ba   Lauritzen, Torsten ^ci   Lee, Selyeong ^cb   Lee, Jaehoon ^cb   Lee, Juyoung ^bx   Lee, Jong Young ^cj   Lehman, Donna M ^av   Lehne, Benjamin ^an   Levy, Jonathan C ^c   Li, Jiang ^bc   Lim, Wei Yen ^bi   Lin, Keng Han ^b   Liu, Jianjun ^bi,cf   Loh, Marie ^an,ck   Ma, Ronald C W ^bg   Ma, Clement ^b   Mägi, Reedik ^at   Maguire, Jared ^d   Maxwell, Taylor J ^o   McVean, Gilean ^a   Meisinger, Christa ^bv   Meitinger, Thomas ^bv,cl,cm   Melander, Olle ^cn   Metspalu, Andres ^at   Mihailov, Evelin ^at   Milani, Lili ^at   Moutsianas, Loukas ^a   Müller Nurasyid, Martina ^bv,cl,co,cp   K Musani, Solomon ^bz   Nagai, Yoshihiko ^h,cq   Narisu, Narisu ^ag   Neale, Benjamin M ^d,i   Ng, Maggie C Y ^bc   O'Rahilly, Stephen P ^ba   Orho Melander, Marju ^cn   Owen, Katharine R ^c,aq   Palmer, Nicholette D ^bc   Park, Taesung ^cb   Pasko, Dorota ^bt   Pearson, Richard D ^a   Perry, John R B ^a,ba,bt   Peters, Annette ^bv,by,cl   Pollin, Toni I ^cr   Poplin, Ryan ^d   Prabhakaran, Dorairaj ^bn   Puppala, Sobha ⁿ   Purcell, Shaun ^d,i,cs   Qi, Lu ^bj,ct   Qi, Qibin ^ax,bj   Roden, Michael ^cu   Rolandsson, Olov ^bs   Rosengren, Anders H ^k   Sandhu, Manjinder ^j,cv   Schwarzmayr, Thomas ^bv   Scott, Laura J ^b   Scott, Robert A ^ba   Scott, James ^cg   Scott, William R ^an   Sehmi, Jobanpreet ^bd,cg   Shakir, Khalid ^d   Sladek, Rob ^h   Smith, Joshua D ^cw   Stancáková, Alena ^u   Strauch, Konstantin ^bv,cp   Strom, Tim M ^bv,cm   Swift, Amy ^ag   Tai, E Shyong ^bf,bi,bk   Tajes, Juan Fernandez ^a   Tan, Sian Tsung ^bd,cg   Tandon, Nikhil ^cx   Taylor, Herman A ^r   Teo, Yik Ying ^bi,cy   Thameem, Farook ^av   Thorand, Barbara ^bv,by   van de Bunt, Martijn ^a,c   Varga, Tibor V ^k   Walker, Mark ^cz   Wareham, Nicholas J ^ba   Welch, Ryan P ^b   Wieland, Thomas ^bv   Wilson, Gregory ^da   Wong, Tien Yin ^ay,az   Wood, Andrew R ^bt   Yoon, Joon ^cb   Zeggini, Eleftheria ^j   Zhang, Weihua ^an,bd   more..

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF MICHIGAN   (United States)

^c UNIVERSITY OF OXFORD   (United Kingdom)

^d BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^e UNIVERSITY OF TEXAS   (United States)

^f Capital Region   (Denmark)

^g UNIVERSITY OF CHICAGO   (United States)

^h MCGILL UNIVERSITY   (Canada)

ⁱ MASSACHUSETTS GENERAL HOSPITAL   (United States)

^j WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^k LUND UNIVERSITY DIABETES CENTRE   (Sweden)

^l KING'S COLLEGE LONDON   (United Kingdom)

^m UPPSALA UNIVERSITY   (Sweden)

ⁿ SOUTHWEST FOUNDATION FOR BIOMEDICAL RESEARCH   (United States)

^o UNIVERSITY OF TEXAS SCHOOL OF PUBLIC HEALTH   (United States)

^p BLOOD SYSTEMS RESEARCH INSTITUTE   (United States)

^q UNIVERSITY OF CALIFORNIA   (United States)

^r UNIVERSITY OF MISSISSIPPI SCHOOL OF MEDICINE   (United States)

^s LILLEBAELT HOSPITAL   (Denmark)

^t UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^u UNIVERSITY OF EASTERN FINLAND   (Finland)

^v UNIVERSITY OF DUNDEE   (United Kingdom)

^w UPPSALA UNIVERSITY   (Sweden)

^x GLOSTRUP UNIVERSITY HOSPITAL   (Denmark)

^y UNIVERSITY OF COPENHAGEN   (Denmark)

^z Steno Diabetes Center ^*  (Finland)

^aa FOLKHÄLSAN RESEARCH CENTER   (Finland)

^ab HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

^ac STENO DIABETES CENTER   (Denmark)

^ad AALBORG UNIVERSITY   (Denmark)

^ae KUOPIO UNIVERSITY HOSPITAL   (Finland)

^af NATIONAL PUBLIC HEALTH INSTITUTE   (Finland)

^ag NATIONAL HUMAN GENOME RESEARCH INSTITUTE   (United States)

^ah UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^ai CEDARS SINAI MEDICAL CENTER   (United States)

^aj KING ABDULAZIZ UNIVERSITY   (Saudi Arabia)

^ak HOSPITAL UNIVERSITARIO LA PAZ IDIPAZ   (Spain)

^al DANUBE UNIVERSITY KREMS   (Austria)

^am UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^an IMPERIAL COLLEGE LONDON   (United Kingdom)

^ao FRAMINGHAM HEART STUDY   (United States)

^ap BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH   (United States)

^aq OXFORD UNIVERSITY HOSPITALS NHS FOUNDATION TRUST   (United Kingdom)

^ar HARVARD MEDICAL SCHOOL   (United States)

^as UNIVERSITY OF LIVERPOOL   (United Kingdom)

^at UNIVERSITY OF TARTU   (Estonia)

^au MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^av Mays Cancer Center at UT Health San Antonio   (United States)

^aw BAYLOR COLLEGE OF MEDICINE   (United States)

^ax ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^ay NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^az SINGAPORE EYE RESEARCH INSTITUTE   (Singapore)

^ba UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^bb CSIR INSTITUTE OF GENOMICS AND INTEGRATIVE BIOLOGY   (India)

^bc WAKE FOREST SCHOOL OF MEDICINE   (United States)

^bd EALING HOSPITAL NHS TRUST   (United Kingdom)

^be IMPERIAL COLLEGE HEALTHCARE NHS TRUST   (United Kingdom)

^bf Dept Medicine Endocrinol Diabet   (Singapore)

^bg CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

^bh CENTRE FOR CELLULAR AND MOLECULAR BIOLOGY   (India)

^bi NATIONAL UNIVERSITY HEALTH SYSTEM   (Singapore)

^bj HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^bk DUKE NUS MEDICAL SCHOOL   (Singapore)

^bl Hallym University   (South Korea)

^bm UNIVERSITY OF OXFORD   (United Kingdom)

^bn CENTRE FOR CHRONIC DISEASE CONTROL   (India)

^bo BOSTON CHILDREN S HOSPITAL   (United States)

^bp Global Health and Health Disparities   (United States)

^bq UNIVERSITY OF HELSINKI   (Finland)

^br Vasa Health Care Center   (Finland)

^bs UMEÅ UNIVERSITY   (Sweden)

^bt UNIVERSITY OF EXETER MEDICAL SCHOOL   (United Kingdom)

^bu INSTITUT DE BIOLOGIE DE LILLE   (France)

^bv INSTITUTE OF EPIDEMIOLOGY   (Germany)

^bw HADASSAH HEBREW UNIVERSITY MEDICAL CENTER   (Israel)

^bx Korea National Institute of Health   (South Korea)

^by GERMAN CENTER FOR DIABETES RESEARCH DZD   (Germany)

^bz UNIVERSITY OF MISSISSIPPI MEDICAL CENTER   (United States)

^ca SHANGHAI JIAO TONG UNIVERSITY AFFILIATED SIXTH PEOPLE S HOSPITAL   (China)

^cb Seoul National University   (South Korea)

^cc HANNOVER MEDICAL SCHOOL   (Germany)

^cd GEORGE WASHINGTON UNIVERSITY   (United States)

^ce SOUTH TEXAS VETERANS HEALTH CARE SYSTEM   (United States)

^cf GENOME INSTITUTE OF SINGAPORE   (Singapore)

^cg NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^ch UNIVERSITY OF BASEL   (Switzerland)

^ci AARHUS UNIVERSITY   (Denmark)

^cj Ministry of Health and Welfare   (South Korea)

^ck UNIVERSITY OF OULU   (Finland)

^cl DZHK GERMAN CENTRE FOR CARDIOVASCULAR RESEARCH   (Germany)

^cm TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^cn LUND UNIVERSITY   (Sweden)

^co LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^cp UNIVERSITY OF MUNICH   (Germany)

^cq RESEARCH INSTITUTE OF THE MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

^cr UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^cs MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^ct BRIGHAM AND WOMEN S HOSPITAL   (United States)

^cu HEINRICH HEINE UNIVERSITY   (Germany)

^cv UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^cw UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^cx ALL INDIA INSTITUTE OF MEDICAL SCIENCES   (India)

^cy NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^cz NEWCASTLE UNIVERSITY   (United Kingdom)

^da JACKSON STATE UNIVERSITY   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

BILE SALT EXPORT PUMP; GLUCOSE; HISTIDINE; LEUCINE; SERINE; TYROSINE; VALINE; G6PC2 PROTEIN, HUMAN; GLP1R PROTEIN, HUMAN; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCAGON RECEPTOR; GLUCOSE 6 PHOSPHATASE; GLUCOSE BLOOD LEVEL; INSULIN;

ABCB11 GENE; ARTICLE; CONTROLLED STUDY; EXOME; G6PC2 GENE; GENE FREQUENCY; GENE FUNCTION; GENE IDENTIFICATION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC TRAIT; GENETIC VARIABILITY; GLUCOSE BLOOD LEVEL; HAPLOTYPE; HUMAN; HUMAN EXPERIMENT; MARKER GENE; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; BLOOD; GENETICS; GENOME-WIDE ASSOCIATION STUDY; GLYCEMIC INDEX; META ANALYSIS; NON INSULIN DEPENDENT DIABETES MELLITUS; PATHOLOGY;

BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 2; EXOME; GENE FREQUENCY; GENOME-WIDE ASSOCIATION STUDY; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; GLUCOSE-6-PHOSPHATASE; GLYCEMIC INDEX; HUMANS; INSULIN; POLYMORPHISM, SINGLE NUCLEOTIDE; RECEPTORS, GLUCAGON;

EID: 84929200986     PISSN: 15537390     EISSN: 15537404     Source Type: Journal    
DOI: 10.1371/journal.pgen.1004876     Document Type: Article

References (42)

1. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, et al. (2009) Variants in MTNR1B influence fasting glucose levels. Nat Genet 41: 77–81. doi: 10.1038/ng.290 19060907
2. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42: 105–116. doi: 10.1038/ng.520 20081858
3. Manning AK, Hivert M-F, Scott RA, Grimsby JL, Bouatia-Naji N, et al. (2012) A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat Genet 44: 659–669. doi: 10.1038/ng.2274 22581228
4. Scott RA, Lagou V, Welch RP, Wheeler E, Montasser ME, et al. (2012) Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet 44: 991–991005. doi: 10.1038/ng.2385 22885924
5. Kang HM, Sul JH, Service SK, Zaitlen NA, Kong S-Y, et al. (2010) Variance component model to account for sample structure in genome-wide association studies. Nat Genet 42: 348–354. doi: 10.1038/ng.548 20208533
6. Liu DJ, Peloso GM, Zhan X, Holmen OL, Zawistowski M, et al. (2014) Meta-analysis of gene-level tests for rare variant association. Nat Genet 46: 200–204. doi: 10.1038/ng.2852 24336170
7. Feng S, Liu D, Zhan X, Wing MK, Abecasis GR, (2014) RAREMETAL: fast and powerful meta-analysis for rare variants. Bioinformatics. doi: 10.1093/bioinformatics/btu367 24894501
8. Wu MC, Lee S, Cai T, Li Y, Boehnke M, et al. (2011) Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet 89: 82–93. doi: 10.1016/j.ajhg.2011.05.029 21737059
9. Magi R, Kumar A, Morris AP, (2011) Assessing the impact of missing genotype data in rare variant association analysis. BMC Proc 5 Suppl 9. doi: 10.1186/1753-6561-5-S9-S107 22373025
10. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, et al. (2014) A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506: 185–190. doi: 10.1038/nature12975 24463508
11. Vaxillaire M, Cavalcanti-Proenca C, Dechaume A, Tichet J, Marre M, et al. (2008) The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population. Diabetes 57: 2253–2257. doi: 10.2337/db07-1807 18556336
12. Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PRV, et al. (2009) The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 18: 4081–4088. doi: 10.1093/hmg/ddp357 19643913
13. Rees MG, Wincovitch S, Schultz J, Waterstradt R, Beer NL, et al. (2012) Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk. Diabetologia 55: 114–122. doi: 10.1007/s00125-011-2348-5 22038520
14. Drucker DJ, Nauck MA, (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368: 1696–1705. doi: 10.1016/S0140-6736(06)69705-5 17098089
15. Service SK, Teslovich TM, Fuchsberger C, Ramensky V, Yajnik P, et al. (2014) Re-sequencing expands our understanding of the phenotypic impact of variants at GWAS loci. PLoS genetics 10: e1004147. doi: 10.1371/journal.pgen.1004147 24497850
16. Khajavi M, Inoue K, Lupski JR, . (2006) Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet 14: 1074–81. doi: 10.1038/sj.ejhg.5201649 16757948
17. Chen W-M, Erdos MR, Jackson AU, Saxena R, Sanna S, et al. (2008) Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels. J Clin Invest 118: 2620–2628. doi: 10.1172/JCI34566 18521185
18. Bouatia-Naji N, Rocheleau G, Van Lommel L, Lemaire K, Schuit F, et al. (2008) A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science 320: 1085–1088. doi: 10.1126/science.1156849 18451265
19. Baerenwald DA, Bonnefond A, Bouatia-Naji N, Flemming BP, Umunakwe OC, et al. (2013) Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels. Diabetologia 56: 1306–1316. doi: 10.1007/s00125-013-2875-3 23508304
20. Pound LD, Oeser JK, O’Brien TP, Wang Y, Faulman CJ, et al. (2013) G6PC2: a negative regulator of basal glucose-stimulated insulin secretion. Diabetes 62: 1547–1556. doi: 10.2337/db12-1067 23274894
21. Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV, et al. (2012) Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44: 981–990. doi: 10.1038/ng.2383 22885922
22. Wang H, Liu L, Zhao J, Cui G, Chen C, et al. (2013) Large scale meta-analyses of fasting plasma glucose raising variants in GCK, GCKR, MTNR1B and G6PC2 and their impacts on type 2 diabetes mellitus risk. PLoS One 8: e67665. doi: 10.1371/journal.pone.0067665 23840762
23. Hu C, Zhang R, Wang C, Ma X, Fang Q, et al. (2009) A genetic variant of G6PC2 is associated with type 2 diabetes and fasting plasma glucose level in the Chinese population. Diabetologia 52: 451–456. doi: 10.1007/s00125-008-1241-3 19082990
24. Pickett LA, Yourshaw M, Albornoz V, Chen Z, Solorzano-Vargas RS, et al. (2013) Functional consequences of a novel variant of PCSK1. PLoS One 8: e55065. doi: 10.1371/journal.pone.0055065 23383060
25. Liu G, Clement LC, Kanwar YS, Avila-Casado C, Chugh SS, (2006) ZHX proteins regulate podocyte gene expression during the development of nephrotic syndrome. J Biol Chem 281: 39681–39692. doi: 10.1074/jbc.M606664200 17056598
26. Gargalovic PS, Erbilgin A, Kohannim O, Pagnon J, Wang X, et al. (2010) Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism. Circ Cardiovasc Genet 3: 60–67. doi: 10.1161/CIRCGENETICS.109.902320 20160197
27. Mahajan A, (2014) Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet 46: 234–244. doi: 10.1038/ng.2897 24509480
28. Vlcek S, Foisner R, Wilson KL, (2004) Lco1 is a novel widely expressed lamin-binding protein in the nuclear interior. Exp Cell Res 298: 499–511. doi: 10.1016/j.yexcr.2004.04.028 15265697
29. Hegele RA, Anderson CM, Wang J, Jones DC, Cao H, (2000) Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. Genome Res 10: 652–658. doi: 10.1101/gr.10.5.652 10810087
30. Mesa JL, Loos RJF, Franks PW, Ong KK, Luan Ja, et al. (2007) Lamin A/C polymorphisms, type 2 diabetes, and the metabolic syndrome: case-control and quantitative trait studies. Diabetes 56: 884–889. doi: 10.2337/db06-1055 17327461
31. Lappalainen T, Montgomery SB, Nica AC, Dermitzakis ET, (2011) Epistatic selection between coding and regulatory variation in human evolution and disease. Am J Hum Genet 89: 459–463. doi: 10.1016/j.ajhg.2011.08.004 21907014
32. Rees MG, Ng D, Ruppert S, Turner C, Beer NL, et al. (2012) Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes. J Clin Invest 122: 205–217. doi: 10.1172/JCI46425 22182842
33. Bonnefond A, Clement N, Fawcett K, Yengo L, Vaillant E, et al. (2012) Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet 44: 297–301. doi: 10.1038/ng.1053 22286214
34. Zuk O, Schaffner SF, Samocha K, Do R, Hechter E, et al. (2014) Searching for missing heritability: designing rare variant association studies. Proc Natl Acad Sci U S A 111: 455–464. doi: 10.1073/pnas.1322563111 24443550
35. D’Orazio P, Burnett RW, Fogh-Andersen N, Jacobs E, Kuwa K, et al. (2005) Approved IFCC recommendation on reporting results for blood glucose (abbreviated). Clin Chem 51: 1573–1576. doi: 10.1373/clinchem.2005.051979 16120945
36. Willer CJ, Li Y, Abecasis GR, (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26: 2190–2191. doi: 10.1093/bioinformatics/btq340 20616382
37. McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, et al. (2010) Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 26: 2069–2070. doi: 10.1093/bioinformatics/btq330 20562413
38. Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, et al. (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6: 80–92. doi: 10.4161/fly.19695
39. Kumar P, Henikoff S, Ng PC, (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4: 1073–1081. doi: 10.1038/nprot.2009.86 19561590
40. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7: 248–249. doi: 10.1038/nmeth0410-248 20354512
41. Gonzalez-Perez A, Lopez-Bigas N, (2011) Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am J Hum Genet 88: 440–449. doi: 10.1016/j.ajhg.2011.03.004 21457909
42. Cooper GM, Stone EA, Asimenos G, Green ED, Batzoglou S, et al. (2005) Distribution and intensity of constraint in mammalian genomic sequence. Genome Res 15: 901–913. doi: 10.1101/gr.3577405 15965027