CoChat
Sign Up
Cited by 21Genomics and Rare DiseasesGenetic Associations and EpidemiologyLipid metabolism and disorders

Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins

Open access
DeForest, Natalie, Kavitha, Babu, Hu, Siqi, Isaac, Roi, Krohn, Lynne, Wang, Minxian, Du, Xiaomi, De Arruda Saldanha, Camila +14 more·2023·Cell Genomics
DOI 10.1016/j.xgen.2023.100339PMC PMC10363808

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Abstract Loss-of-function mutations in Hepatocyte Nuclear Factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare protein-coding variant in HNF1A , most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found ∼1:5 rare protein-coding HNF1A variants found in the general population cause molecular gain-of-function (GOF), increasing the transcriptional activity of HNF1A by up to 50%. GOF in HNF1A conferred protection from type 2 diabetes (T2D) (OR=0.60, p=8.4 x 10 -7 ), but not against coronary artery disease. Independently of T2D, increased hepatic expression of HNF1A promoted a pro-inflammatory and pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including PCSK9 . In summary, ∼1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of metabolic disease risk factors.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.xgen.2023.100339

Cites

11 of 11 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 93

  1. [1]Lau H.H. Ng N.H.J. Loo L.S.W. Jasmen J.B. Teo A.K.K. The molecular functions of hepatocyte nuclear factors - in and beyond the liver J. Hepatol. 68 2018 1033 1048 29175243
  2. [2]Fajans S.S. Bell G.I. MODY: history, genetics, pathophysiology, and clinical decision making Diabetes Care 34 2011 1878 1884 21788644 PMC3142024
  3. [3]Yamagata K. Oda N. Kaisaki P.J. Menzel S. Furuta H. Vaxillaire M. Southam L. Cox R.D. Lathrop G.M. Boriraj V.V. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature 384 1996 455 458 8945470
  4. [4]Lehto M. Tuomi T. Mahtani M.M. Widén E. Forsblom C. Sarelin L. Gullström M. Isomaa B. Lehtovirta M. Hyrkkö A. Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect J. Clin. Invest. 99 1997 582 591 9045858 PMC507838
  5. [5]McDonald T.J. McEneny J. Pearson E.R. Thanabalasingham G. Szopa M. Shields B.M. Ellard S. Owen K.R. Malecki M.T. Hattersley A.T. Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes Clin. Chim. Acta 413 2012 927 932 22360925
  6. [6]McDonald T.J. Shields B.M. Lawry J. Owen K.R. Gloyn A.L. Ellard S. Hattersley A.T. High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes Diabetes Care 34 2011 1860 1862 21700917 PMC3142017
  7. [7]Goldberg I.J. Clinical review 124: diabetic dyslipidemia: causes and consequences J. Clin. Endocrinol. Metab. 86 2001 965 971 11238470
  8. [8]King D.E. Mainous A.G. 3rd Buchanan T.A. Pearson W.S. C-reactive protein and glycemic control in adults with diabetes Diabetes Care 26 2003 1535 1539 12716818
  9. [9]Shih D.Q. Bussen M. Sehayek E. Ananthanarayanan M. Shneider B.L. Suchy F.J. Shefer S. Bollileni J.S. Gonzalez F.J. Breslow J.L. Hepatocyte nuclear factor-1α is an essential regulator of bile acid and plasma cholesterol metabolism Nat. Genet. 27 2001 375 382 10.1038/86871 11279518 · DOI
  10. [10]Voight B.F. Scott L.J. Steinthorsdottir V. Morris A.P. Dina C. Welch R.P. Zeggini E. Huth C. Aulchenko Y.S. Thorleifsson G. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis Nat. Genet. 42 2010 579 589 20581827 PMC3080658
  11. [11]Teslovich T.M. Musunuru K. Smith A.V. Edmondson A.C. Stylianou I.M. Koseki M. Pirruccello J.P. Ripatti S. Chasman D.I. Willer C.J. Biological, clinical and population relevance of 95 loci for blood lipids Nature 466 2010 707 713 20686565 PMC3039276
  12. [12]Wu Y. McDade T.W. Kuzawa C.W. Borja J. Li Y. Adair L.S. Mohlke K.L. Lange L.A. Genome-wide association with C-reactive protein levels in CLHNS: evidence for the CRP and HNF1A loci and their interaction with exposure to a pathogenic environment Inflammation 35 2012 574 583 21647738 PMC3193904
  13. [13]Giuffrida F.M.A. Furuzawa G.K. Kasamatsu T.S. Oliveira M.M. Reis A.F. Dib S.A. HNF1A gene polymorphisms and cardiovascular risk factors in individuals with late-onset autosomal dominant diabetes: a cross-sectional study Cardiovasc. Diabetol. 8 2009 28 19490620 PMC2696421
  14. [15]Reiner A.P. Gross M.D. Carlson C.S. Bielinski S.J. Lange L.A. Fornage M. Jenny N.S. Walston J. Tracy R.P. Williams O.D. Common coding variants of the HNF1A gene are associated with multiple cardiovascular risk phenotypes in community-based samples of younger and older European-American adults: the Coronary Artery Risk Development in Young Adults Study and the Cardiovascular Health Study Circ. Cardiovasc. Genet. 2 2009 244 254 20031592 PMC2841292
  15. [16]Reiner Ž. Hypertriglyceridaemia and risk of coronary artery disease Nat. Rev. Cardiol. 14 2017 401 411 28300080
  16. [17]Lagrand W.K. Visser C.A. Hermens W.T. Niessen H.W. Verheugt F.W. Wolbink G.J. Hack C.E. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation 100 1999 96 102 10393687
  17. [18]Flannick J. Beer N.L. Bick A.G. Agarwala V. Molnes J. Gupta N. Burtt N.P. Florez J.C. Meigs J.B. Taylor H. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes Nat. Genet. 45 2013 1380 1385 24097065 PMC4051627
  18. [20]Majithia A.R. Tsuda B. Agostini M. Gnanapradeepan K. Rice R. Peloso G. Patel K.A. Zhang X. Broekema M.F. Patterson N. Prospective functional classification of all possible missense variants in PPARG Nat. Genet. 48 2016 1570 1575 27749844 PMC5131844
  19. [21]Findlay G.M. Daza R.M. Martin B. Zhang M.D. Leith A.P. Gasperini M. Janizek J.D. Huang X. Starita L.M. Shendure J. Accurate classification of BRCA1 variants with saturation genome editing Nature 562 2018 217 222 30209399 PMC6181777
  20. [22]Abel E.V. Goto M. Magnuson B. Abraham S. Ramanathan N. Hotaling E. Alaniz A.A. Kumar-Sinha C. Dziubinski M.L. Urs S. HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties Elife 7 2018 e33947 10.7554/eLife.33947 30074477 PMC6122955 · DOI
  21. [23]Servitja J.-M. Pignatelli M. Maestro M.A. Cardalda C. Boj S.F. Lozano J. Blanco E. Lafuente A. McCarthy M.I. Sumoy L. Hnf1alpha (MODY3) controls tissue-specific transcriptional programs and exerts opposed effects on cell growth in pancreatic islets and liver Mol. Cell Biol. 29 2009 2945 2959 19289501 PMC2682018
  22. [24]Giacomelli A.O. Yang X. Lintner R.E. McFarland J.M. Duby M. Kim J. Howard T.P. Takeda D.Y. Ly S.H. Kim E. Mutational processes shape the landscape of TP53 mutations in human cancer Nat. Genet. 50 2018 1381 1387 30224644 PMC6168352
  23. [25]Chi Y.-I. Frantz J.D. Oh B.-C. Hansen L. Dhe-Paganon S. Shoelson S.E. Diabetes mutations delineate an atypical POU domain in HNF-1α Mol. Cell 10 2002 1129 1137 10.1016/s1097-2765(02)00704-9 12453420 · DOI
  24. [26]Rose R.B. Endrizzi J.A. Cronk J.D. Holton J. Alber T. High-resolution structure of the HNF-1α dimerization domain Biochemistry 40 2001 3242 10.1021/bi0151263 11106484 · DOI
  25. [27]Cooper G.M. Stone E.A. Asimenos G. NISC Comparative Sequencing Program Green E.D. Batzoglou S. Sidow A. Distribution and intensity of constraint in mammalian genomic sequence Genome Res. 15 2005 901 913 15965027 PMC1172034
  26. [28]Adzhubei I. Jordan D.M. Sunyaev S.R. Predicting functional effect of human missense mutations using PolyPhen-2 Curr. Protoc. Hum. Genet. Chapter 7 2013 Unit7.20 PMC4480630 23315928
  27. [29]Rentzsch P. Witten D. Cooper G.M. Shendure J. Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome Nucleic Acids Res. 47 2019 D886 D894 30371827 PMC6323892
  28. [31]Käll L. Storey J.D. MacCoss M.J. Noble W.S. Posterior error probabilities and false discovery rates: two sides of the same coin J. Proteome Res. 7 2008 40 44 18052118
  29. [32]Bycroft C. Freeman C. Petkova D. Band G. Elliott L.T. Sharp K. Motyer A. Vukcevic D. Delaneau O. O’Connell J. The UK Biobank resource with deep phenotyping and genomic data Nature 562 2018 203 209 30305743 PMC6786975
  30. [33]Backman J.D. Li A.H. Marcketta A. Sun D. Mbatchou J. Kessler M.D. Benner C. Liu D. Locke A.E. Balasubramanian S. Exome sequencing and analysis of 454,787 UK Biobank participants Nature 599 2021 628 634 34662886 PMC8596853
  31. [35]Shields B.M. Hicks S. Shepherd M.H. Colclough K. Hattersley A.T. Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 53 2010 2504 2508 20499044
  32. [36]Najmi L.A. Aukrust I. Flannick J. Molnes J. Burtt N. Molven A. Groop L. Altshuler D. Johansson S. Bjørkhaug L. Functional investigations of HNF1A identify rare variants as risk factors for type 2 diabetes in the general population Diabetes 66 2017 335 346 10.2337/db16-0460 27899486 PMC5860263 · DOI
  33. [37]Balamurugan K. Bjørkhaug L. Mahajan S. Kanthimathi S. Njølstad P.R. Srinivasan N. Mohan V. Radha V. Structure-function studies of HNF1A (MODY3) gene mutations in South Indian patients with monogenic diabetes Clin. Genet. 90 2016 486 495 26853433
  34. [38]Galán M. García-Herrero C.M. Azriel S. Gargallo M. Durán M. Gorgojo J.-J. Andía V.M. Navas M.-A. Differential effects of HNF-1α mutations associated with familial young-onset diabetes on target gene regulation Mol. Med. 17 2011 256 265 21170474 PMC3060974
  35. [39]Dewey F.E. Gusarova V. Dunbar R.L. O’Dushlaine C. Schurmann C. Gottesman O. McCarthy S. Van Hout C.V. Bruse S. Dansky H.M. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease N. Engl. J. Med. 377 2017 211 221 28538136 PMC5800308
  36. [40]Musunuru K. Pirruccello J.P. Do R. Peloso G.M. Guiducci C. Sougnez C. Garimella K.V. Fisher S. Abreu J. Barry A.J. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia N. Engl. J. Med. 363 2010 2220 2227 20942659 PMC3008575
  37. [41]Odom D.T. Zizlsperger N. Gordon D.B. Bell G.W. Rinaldi N.J. Murray H.L. Volkert T.L. Schreiber J. Rolfe P.A. Gifford D.K. Control of pancreas and liver gene expression by HNF transcription factors Science 303 2004 1378 1381 14988562 PMC3012624
  38. [43]Flannick J. Mercader J.M. Fuchsberger C. Udler M.S. Mahajan A. Wessel J. Teslovich T.M. Caulkins L. Koesterer R. Barajas-Olmos F. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls Nature 570 2019 71 76 31118516 PMC6699738
  39. [44]Gaulton K.J. Ferreira T. Lee Y. Raimondo A. Mägi R. Reschen M.E. Mahajan A. Locke A. Rayner N.W. Robertson N. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci Nat. Genet. 47 2015 1415 1425 26551672 PMC4666734
  40. [45]Prospective Studies Collaboration Lewington S. Whitlock G. Clarke R. Sherliker P. Emberson J. Halsey J. Qizilbash N. Peto R. Collins R. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths Lancet 370 2007 1829 1839 18061058
  41. [46]Targher G. Byrne C.D. Circulating markers of liver function and cardiovascular disease risk Arterioscler. Thromb. Vasc. Biol. 35 2015 2290 2296 25977566
  42. [47]Nielson C. Lange T. Hadjokas N. Blood glucose and coronary artery disease in nondiabetic patients Diabetes Care 29 2006 998 1001 16644627
  43. [49]GTEx Consortium Genetic effects on gene expression across human tissues (2017) Nature 550 2017 204 213 29022597 PMC5776756
  44. [50]GTEx Consortium The genotype-tissue expression (GTEx) project Nat. Genet. 45 2013 580 585 23715323 PMC4010069
  45. [51]Gusev A. Ko A. Shi H. Bhatia G. Chung W. Penninx B.W.J.H. Jansen R. de Geus E.J.C. Boomsma D.I. Wright F.A. Integrative approaches for large-scale transcriptome-wide association studies Nat. Genet. 48 2016 245 252 10.1038/ng.3506 26854917 PMC4767558 · DOI · Paper page
  46. [52]Pepys M.B. Hirschfield G.M. C-reactive protein: a critical update J. Clin. Invest. 111 2003 1805 1812 12813013 PMC161431
  47. [53]Yamagata K. Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY) Vitam. Horm. 95 2014 407 423 24559927
  48. [54]Dalmon J. Laurent M. Courtois G. The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element Mol. Cell Biol. 13 1993 1183 1193 8423785 PMC359003
  49. [56]Mootha V.K. Lindgren C.M. Eriksson K.-F. Subramanian A. Sihag S. Lehar J. Puigserver P. Carlsson E. Ridderstråle M. Laurila E. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes Nat. Genet. 34 2003 267 273 12808457
  50. [57]Lee D.-H. Blomhoff R. Jacobs D.R. Jr. Is serum gamma glutamyltransferase a marker of oxidative stress? Free Radic. Res. 38 2004 535 539 15346644
  51. [58]Kathiresan S. Srivastava D. Genetics of human cardiovascular disease Cell 148 2012 1242 1257 22424232 PMC3319439
  52. [59]Partridge E.C. Chhetri S.B. Prokop J.W. Ramaker R.C. Jansen C.S. Goh S.-T. Mackiewicz M. Newberry K.M. Brandsmeier L.A. Meadows S.K. Occupancy maps of 208 chromatin-associated proteins in one human cell type Nature 583 2020 720 728 32728244 PMC7398277
  53. [60]Bellanné-Chantelot C. Carette C. Riveline J.-P. Valéro R. Gautier J.-F. Larger E. Reznik Y. Ducluzeau P.-H. Sola A. Hartemann-Heurtier A. The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3 Diabetes 57 2008 503 508 18003757
  54. [61]Ellard S. Hepatocyte nuclear factor 1 alpha (HNF-1α) mutations in maturity-onset diabetes of the young Hum. Mutat. 16 2000 377 385 11058894
  55. [62]Althari S. Najmi L.A. Bennett A.J. Aukrust I. Rundle J.K. Colclough K. Molnes J. Kaci A. Nawaz S. van der Lugt T. Unsupervised clustering of missense variants in HNF1A using multidimensional functional data aids clinical interpretation Am. J. Hum. Genet. 107 2020 670 682 32910913 PMC7536579
  56. [63]Lotta L.A. Mokrosiński J. Mendes de Oliveira E. Li C. Sharp S.J. Luan J. ’an Brouwers B. Ayinampudi V. Bowker N. Kerrison N. Human gain-of-function MC4R variants show signaling bias and protect against obesity Cell 177 2019 597 607.e9 31002796 PMC6476272
  57. [64]Toth P.P. High-density lipoprotein and cardiovascular risk Circulation 109 2004 1809 1812 15096460
  58. [65]Kannel W.B. Anderson K. Wilson P.W. White blood cell count and cardiovascular disease. Insights from the Framingham Study JAMA 267 1992 1253 1256 1538564
  59. [66]Sahin U. Karikó K. Türeci Ö. mRNA-based therapeutics—developing a new class of drugs Nat. Rev. Drug Discov. 13 2014 759 780 25233993
  60. [68]Lupo M.G. Ferri N. Angiopoietin-like 3 (ANGPTL3) and atherosclerosis: lipid and non-lipid related effects J. Cardiovasc. Dev. Dis. 5 2018 39 30011918 PMC6162638
  61. [69]Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism Trends Biochem. Sci. 32 2007 71 77 17215125 PMC2711871
  62. [70]Sun H. Samarghandi A. Zhang N. Yao Z. Xiong M. Teng B.-B. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor Arterioscler. Thromb. Vasc. Biol. 32 2012 1585 1595 22580899
  63. [71]Graham M.J. Lemonidis K.M. Whipple C.P. Subramaniam A. Monia B.P. Crooke S.T. Crooke R.M. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice J. Lipid Res. 48 2007 763 767 10.1194/jlr.C600025-JLR200 17242417 · DOI
  64. [72]Frank-Kamenetsky M. Grefhorst A. Anderson N.N. Racie T.S. Bramlage B. Akinc A. Butler D. Charisse K. Dorkin R. Fan Y. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates Proc. Natl. Acad. Sci. USA 105 2008 11915 11920 10.1073/pnas.0805434105 18695239 PMC2575310 · DOI
  65. [73]Duff C.J. Scott M.J. Kirby I.T. Hutchinson S.E. Martin S.L. Hooper N.M. Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor Biochem. J. 419 2009 577 584 10.1042/BJ20082407 19196236 PMC2669217 · DOI · Paper page
  66. [74]Kotowski I.K. Pertsemlidis A. Luke A. Cooper R.S. Vega G.L. Cohen J.C. Hobbs H.H. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol Am. J. Hum. Genet. 78 2006 410 422 16465619 PMC1380285
  67. [75]Shende V.R. Wu M. Singh A.B. Dong B. Kan C.F.K. Liu J. Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice J. Lipid Res. 56 2015 801 809 25652089 PMC4373738
  68. [76]Dong B. Singh A.B. Shende V.R. Liu J. Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters Int. J. Mol. Med. 39 2017 749 756 28204827
  69. [77]Wang J. Zhao J. Yan C. Xi C. Wu C. Zhao J. Li F. Ding Y. Zhang R. Qi S. Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial Cell Metab. 34 2022 667 680.e6 35427476
  70. [78]Dubuc G. Chamberland A. Wassef H. Davignon J. Seidah N.G. Bernier L. Prat A. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia Arterioscler. Thromb. Vasc. Biol. 24 2004 1454 1459 15178557
  71. [79]Kim J. Hu C. Moufawad El Achkar C. Black L.E. Douville J. Larson A. Pendergast M.K. Goldkind S.F. Lee E.A. Kuniholm A. Patient-customized oligonucleotide therapy for a rare genetic disease N. Engl. J. Med. 381 2019 1644 1652 31597037 PMC6961983
  72. [81]Nishikawa T. Hagihara K. Serada S. Isobe T. Matsumura A. Song J. Tanaka T. Kawase I. Naka T. Yoshizaki K. Transcriptional complex formation of c-Fos, STAT3, and hepatocyte NF-1 alpha is essential for cytokine-driven C-reactive protein gene expression J. Immunol. 180 2008 3492 3501 18292576
  73. [82]Toniatti C. Demartis A. Monaci P. Nicosia A. Ciliberto G. Synergistic trans-activation of the human C-reactive protein promoter by transcription factor HNF-1 binding at two distinct sites EMBO J. 9 1990 4467 4475 2265613 PMC552239
  74. [83]Li S.P. Goldman N.D. Regulation of human C-reactive protein gene expression by two synergistic IL-6 responsive elements Biochemistry 35 1996 9060 9068 8703909
  75. [84]Cingolani P. Platts A. Wang L.L. Coon M. Nguyen T. Wang L. Land S.J. Lu X. Ruden D.M. 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 6 2012 80 92 22728672 PMC3679285
  76. [85]Bray N.L. Pimentel H. Melsted P. Pachter L. Near-optimal probabilistic RNA-seq quantification Nat. Biotechnol. 34 2016 525 527 27043002
  77. [86]Love M.I. Huber W. Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 15 2014 1550 PMC4302049 25516281
  78. [87]Majithia A.R. Flannick J. Shahinian P. Guo M. Bray M.-A. Fontanillas P. Gabriel S.B. GoT2D Consortium NHGRI JHS/FHS Allelic Spectrum Project SIGMA T2D Consortium Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes Proc. Natl. Acad. Sci. USA 111 2014 13127 13132 25157153 PMC4246964
  79. [88]Klarin D. Damrauer S.M. Cho K. Sun Y.V. Teslovich T.M. Honerlaw J. Gagnon D.R. DuVall S.L. Li J. Peloso G.M. Genetics of blood lipids among ∼300,000 multi-ethnic participants of the Million Veteran Program Nat. Genet. 50 2018 1514 1523 10.1038/s41588-018-0222-9 30275531 PMC6521726 · DOI
  80. [90]Tan X. Benedict C. Increased risk of myocardial infarction among patients with type 2 diabetes who carry the common rs10830963 variant in the MTNR1B gene Diabetes Care 43 2020 2289 2292 10.2337/dc20-0507 32616615 PMC7440907 · DOI
  81. [91]Korotkevich G. Sukhov V. Sergushichev A. Fast gene set enrichment analysis Cold Spring Harb. Lab. 2019 060012 10.1101/060012 · DOI
  82. [92]Liberzon A. Birger C. Thorvaldsdóttir H. Ghandi M. Mesirov J.P. Tamayo P. The molecular signatures database Hallmark gene set collection Cell Syst. 1 2015 417 425 10.1016/j.cels.2015.12.004 26771021 PMC4707969 · DOI · Paper page
  83. [93]Ashburner M. Ball C.A. Blake J.A. Botstein D. Butler H. Cherry J.M. Davis A.P. Dolinski K. Dwight S.S. Eppig J.T. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium Nat. Genet. 25 2000 25 29 10802651 PMC3037419
  84. [94]Gene Ontology Consortium The Gene Ontology resource: enriching a GOld mine Nucleic Acids Res. 49 2021 D325 D334 33290552 PMC7779012
  85. [95]Heinz S. Texari L. Hayes M.G.B. Urbanowski M. Chang M.W. Givarkes N. Rialdi A. White K.M. Albrecht R.A. Pache L. Transcription elongation can affect genome 3D structure Cell 174 2018 1522 1536.e22 30146161 PMC6130916
  86. [96]Fornes O. Castro-Mondragon J.A. Khan A. van der Lee R. Zhang X. Richmond P.A. Modi B.P. Correard S. Gheorghe M. Baranašić D. JASPAR 2020: update of the open-access database of transcription factor binding profiles Nucleic Acids Res. 48 2020 D87 D92 31701148 PMC7145627
  87. [97]ENCODE Project Consortium An integrated encyclopedia of DNA elements in the human genome Nature 489 2012 57 74 22955616 PMC3439153
  88. [98]Deaton A.M. Parker M.M. Ward L.D. Flynn-Carroll A.O. BonDurant L. Hinkle G. Akbari P. Lotta L.A. Baras A. Nioi P. Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes Sci. Rep. 11 2021 21565 34732801 PMC8566487
  89. [99]Willer C.J. Li Y. Abecasis G.R. METAL: fast and efficient meta-analysis of genomewide association scans Bioinformatics 26 2010 2190 2191 20616382 PMC2922887
  90. [100]Dey R. Schmidt E.M. Abecasis G.R. Lee S. A fast and accurate algorithm to test for binary phenotypes and its application to PheWAS Am. J. Hum. Genet. 101 2017 37 49 28602423 PMC5501775
  91. [101]Purcell S. Cherny S.S. Sham P.C. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits Bioinformatics 19 2003 149 150 12499305
  92. [102]Purcell S. Neale B. Todd-Brown K. Thomas L. Ferreira M.A.R. Bender D. Maller J. Sklar P. de Bakker P.I.W. Daly M.J. PLINK: a tool set for whole-genome association and population-based linkage analyses Am. J. Hum. Genet. 81 2007 559 575 17701901 PMC1950838
  93. [103]Reiner A.P. Barber M.J. Guan Y. Ridker P.M. Lange L.A. Chasman D.I. Walston J.D. Cooper G.M. Jenny N.S. Rieder M.J. Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1α are associated with C-reactive protein Am. J. Hum. Genet. 82 2008 1193 1201 10.1016/j.ajhg.2008.03.017 18439552 PMC2427318 · DOI

Cited by

Sorted by citations

Authors
DeForest, N., Kavitha, B., Hu, S., Isaac, R., Krohn, L., Wang, M., Du, X., De Arruda Saldanha, C., Gylys, J., Merli, E., Abagyan, R., Najmi, L., Mohan, V., Flannick, J., Peloso, G. M., Gordts, P. L. S. M., Heinz, S., Deaton, A. M., Khera, A. V., Olefsky, J., Radha, V., & Majithia, A. R.
Affiliations
  • University of California San Diego (US)
  • University of Madras (IN)
  • Alnylam Pharmaceuticals (United States) (US)
  • Broad Institute (US)
  • Madras Diabetes Research Foundation (IN)
  • Boston University (US)
Corresponding author
Majithia, Amit R.
ORCID
Venue
Cell Genomics
Publisher
Elsevier BV
Published
2023-07
Volume
3
Issue
7
Pages
100339
ISSN
2666-979X (ISSN-L)
DOI
10.1016/j.xgen.2023.100339
PMC
PMC10363808
OpenAlex
W4381572831
Cited by
21
References
11
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 2 · 2022: 1
FWCI
3.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Genomics (publishedVersion, cc-by-nc-nd)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-nd)
Funders
  • University of California, Los Angeles (P30 DK063491, T32 GM008666)
  • National Heart, Lung, and Blood Institute (S10 OD026929, R01HL142711, R01HL127564)
  • National Institute of General Medical Sciences (R01GM129523)
  • National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK123422, 1R01DK125490, 1R03DK113328, P30DK120515, P30DK063491)
  • University of California, San Diego
  • NIH
  • Alnylam Pharmaceuticals
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
HNF1A, gain-of-function mutations, atherogenic lipoproteins, hepatic lipoprotein secretion, deep mutational scanning, ANGPTL3, PCSK9, transcriptional activity, genetic risk variants, allelic series

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review