Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction

PLoS Genetics

Volumn 11, Issue 2, 2015, Pages 1-23

  Thormaehlen, Aenne S ^a   Schuberth, Christian ^a   Won, Hong Hee ^b,c,d   Blattmann, Peter ^a,e   Joggerst Thomalla, Brigitte ^a   Theiss, Susanne ^a   Asselta, Rosanna ^f   Duga, Stefano ^f   Merlini, Pier Angelica ^g   Ardissino, Diego ^h   Lander, Eric S ^c   Gabriel, Stacey ^c   Rader, Daniel J ⁱ   Peloso, Gina M ^b,c   Pepperkok, Rainer ^a,e   Kathiresan, Sekar ^b,c,g   Runz, Heiko ^a,b,c  

^a UNIVERSITY OF HEIDELBERG   (Germany)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

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

^d HARVARD MEDICAL SCHOOL   (United States)

^e EUROPEAN MOLECULAR BIOLOGY LABORATORY   (Germany)

^f HUMANITAS UNIVERSITY   (Italy)

^g OSPEDALE NIGUARDA CA GRANDA   (Italy)

^h Parma Hospital   (Italy)

ⁱ UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

LOW DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR;

ADULT; ALLELE; ARTICLE; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; EXOME; GENE; GENE FUNCTION; GENE IDENTIFICATION; GENE LOCUS; GENE OVEREXPRESSION; GENE SEQUENCE; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOTYPE; HEART INFARCTION; HETEROZYGOTE; HUMAN; HUMAN CELL; IN VITRO STUDY; LDLR GENE; MAJOR CLINICAL STUDY; MIDDLE AGED; MISSENSE MUTATION; PHENOTYPE; SITE DIRECTED MUTAGENESIS; BLOOD; DNA SEQUENCE; GENETIC ASSOCIATION STUDY; GENETICS; PATHOLOGY; SINGLE NUCLEOTIDE POLYMORPHISM;

ALLELES; CHOLESTEROL, LDL; EXOME; GENETIC ASSOCIATION STUDIES; HETEROZYGOTE; HUMANS; MUTATION, MISSENSE; MYOCARDIAL INFARCTION; PHENOTYPE; POLYMORPHISM, SINGLE NUCLEOTIDE; RECEPTORS, LDL; SEQUENCE ANALYSIS, DNA;

EID: 84924406215     PISSN: 15537390     EISSN: 15537404     Source Type: Journal    
DOI: 10.1371/journal.pgen.1004855     Document Type: Article

References (49)

1. Kiezun A, Garimella K, Do R, Stitziel NO, Neale BM, et al. (2012) Exome sequencing and the genetic basis of complex traits. Nat Genet 10: 623–630. doi: 10.1038/ng.2303
2. Goldstein DB, Allen A, Keebler J, Margulies EH, Petrou S, et al. (2013) Sequencing studies in human genetics: design and interpretation. Nat Rev Genet 14: 460–470. doi: 10.1038/nrg3455 23752795
3. Rehm HL, (2013) Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet 14: 295–300. doi: 10.1038/nrg3463 23478348
4. Cutting GR, (2014) Annotating DNA variants is the next major goal for human genetics. Am J Hum Genet 94: 5–10. doi: 10.1016/j.ajhg.2013.12.008 24387988
5. Cotton RG, Scriver CR, (1998) Proof of “disease causing” mutation. Hum Mutat 12: 1–3. doi: 10.1002/(SICI)1098-1004(1998)12:1%3C1::AID-HUMU1%3E3.0.CO;2-M 9633813
6. Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, et al. (2013) A systematic approach to assessing the clinical significance of genetic variants. Clin Genet 84: 453–463. doi: 10.1111/cge.12257 24033266
7. Flannick J, Beer NL, Bick AG, Agarwala V, Molnes J, et al. (2013) Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat Genet 45: 1380–1385. doi: 10.1038/ng.2794 24097065
8. Ormond KE, (2008) Medical ethics for the genome world: a paper from the 2007 William Beaumont hospital symposium on molecular pathology. J Mol Diag 10: 377–382. doi: 10.2353/jmoldx.2008.070162
9. Cooper GM, Shendure J, (2011) Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data. Nat Rev Genet 12: 628–640. doi: 10.1038/nrg3046 21850043
10. 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: E455–464. doi: 10.1073/pnas.1322563111 24443550
11. 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
12. Do R, Stitziel NO, Won HH, Berg Jørgensen A, Duga S, et al. (2014) Multiple rare alleles at LDLR and APOA5 confer risk for early-onset myocardial infarction. Nature. In press. doi: 10.1038/nature13917 25487149
13. Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, et al. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491: 56–65. doi: 10.1038/nature11632 23128226
14. MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, et al. (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science 335: 823–828. doi: 10.1126/science.1215040 22344438
15. Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, et al. (2008) ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 10: 294–300. doi: 10.1097/GIM.0b013e31816b5cae 18414213
16. Brown MS, Goldstein JL, (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–47. doi: 10.1126/science.3513311 3513311
17. Goldstein JL, Hazzard WR, Schrott HG, Bierman EL, Motulsky AG, (1973) Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest 52: 1533–1543. doi: 10.1172/JCI107331 4718952
18. Hobbs HH, Russell DW, Brown MS, Goldstein JL, (1990) The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Ann Rev Genet 24: 133–170. doi: 10.1146/annurev.ge.24.120190.001025 2088165
19. Marks D, Thorogood M, Neil HA, Humphries SE, (2003) A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168: 1–14. doi: 10.1016/S0021-9150(02)00330-1 12732381
20. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, et al. (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15: 565–574. doi: 10.1038/gim.2013.73 23788249
21. Bartz F, Kern L, Erz D, Zhu M, Gilbert D, et al. (2009) Identification of cholesterol-regulating genes by targeted RNAi screening. Cell Metab 10: 63–75. doi: 10.1016/j.cmet.2009.05.009 19583955
22. Blattmann P, Schuberth C, Pepperkok R, Runz H, (2013) RNAi–Based Functional Profiling of Loci from Blood Lipid Genome-Wide Association Studies Identifies Genes with Cholesterol-Regulatory Function. PLoS Genet 9: e1003338. doi: 10.1371/journal.pgen.1003338 23468663
23. Davis CG, Lehrman MA, Russell DW, Anderson RGW, Brown MS, et al. (1986) The J. D. mutation in familial hypercholesterolemia: Amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors. Cell 45: 15–24. doi: 10.1016/0092-8674(86)90533-7 3955657
24. 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
25. Peloso GM, Auer PL, Bis JC, Voorman A, Morrison AC, et al. (2014) Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks. Am J Hum Genet 94: 223–232. doi: 10.1016/j.ajhg.2014.01.009 24507774
26. Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, et al. (2013) Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet 45: 1160–1167. doi: 10.1038/ng.2745 23974870
27. Majithia AR, Flannick J, Shahinian P, Guo M, Bray MA, et al. (2014) Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. Proc Natl Acad Sci U S A 111: 13127–13132. doi: 10.1073/pnas.1410428111 25157153
28. Cohen JC, Stender S, Hobbs HH, (2014) APOC3, coronary disease, and complexities of mendelian randomization studies. Cell Metab 20: 387–389. doi: 10.1016/j.cmet.2014.08.007 25185943
29. Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, et al. (2013) Actionable, Pathogenic Incidental Findings in 1,000 Participants Exomes. Am J Hum Genet 93: 631–640. doi: 10.1016/j.ajhg.2013.08.006 24055113
30. Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, et al. (2013) Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 369: 1502. doi: 10.1056/NEJMoa1306555 24088041
31. Atherosclerosis-Thrombosis-and-Vascular-Biology-Italian-Study-Group (2003) No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age. Circulation 107: 1117–1122. doi: 10.1161/01.CIR.0000051465.94572.D0 12615788
32. Ardissino D, Berzuini C, Merlini PA, Mannuccio P, Surti A, et al. (2011) Influence of 9p21.3 genetic variants on clinical and angiographic outcomes in early-onset myocardial infarction. J Am Coll Card 58: 426–434. doi: 10.1016/j.jacc.2010.11.075
33. DeMott K, Nherera L, Humphries SE, Minhas R, Shaw EJ, et al. (2008) Clinical Guidelines and Evidence Review for Familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia. National Collaborating Centre for Primary Care and Royal College of General Practitioners (London).
34. Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, et al. (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337: 64–69. doi: 10.1126/science.1219240 22604720
35. Anderson RG, Goldstein JL, Brown MS, (1977) A mutation that impairs the ability of lipoprotein receptors to localise in coated pits on the cell surface of human fibroblasts. Nature 270: 695–699. doi: 10.1038/270695a0 201867
36. Villéger L, Abifadel M, Allard D, Rabès JP, Thiart R, et al. (2002) The UMD-LDLR database: additions to the software and 490 new entries to the database. Hum Mutat 20: 81–87. doi: 10.1002/humu.10102 12124988
37. Leigh SE, Foster AH, Whittall RA, Hubbart CS, Humphries SE, (2008) Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet 72: 485–498. doi: 10.1111/j.1469-1809.2008.00436.x 18325082
38. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, et al. (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42: D980–985. doi: 10.1093/nar/gkt1113 24234437
39. Cooper DN, Krawczak M, (1996) Human Gene Mutation Database. Hum Genet 98: 629. doi: 10.1007/s004390050272 8882888
40. Bertolini S, Cassanelli S, Garuti R, Ghisellini M, Simone ML, et al. (1999) Analysis of LDL Receptor Gene Mutations in Italian Patients With Homozygous Familial Hypercholesterolemia. Arterioscler Thromb Vasc Biol 19: 408–418. doi: 10.1161/01.ATV.19.2.408 9974426
41. 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
42. 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
43. Reva B, Antipin Y, Sander C, (2011) Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 39: e118. doi: 10.1093/nar/gkr407 21727090
44. Schwarz JM, Cooper DN, Schuelke M, Seelow D, (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11: 361–362. doi: 10.1038/nmeth.2890 24681721
45. Carpenter AE, Jones TR, Lamprecht MR, Clarke C, Kang IH, et al. (2006) CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol 7: R100–R100. doi: 10.1186/gb-2006-7-10-r100 17076895
46. Goldstein JL, Brown MS, Scriver C.R., Beaudet A.L., Sly W.S., Valle D., (1989) Familial hypercholesterolemia in The Metabolic and Molecular Basis of Inherited Disease eds. 1215–1250, McGraw Hill (New York).
47. Talmud PJ, Shah S, Whittall R, Futema M, Howard P, et al. (2013) Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 381: 1293–1301. doi: 10.1016/S0140-6736(12)62127-8 23433573
48. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, et al. (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466: 707–713. doi: 10.1038/nature09270 20686565
49. Erdmann J, Stark K, Esslinger UB, Rumpf PM, Koesling D, et al. (2013) Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature 504: 432–436. doi: 10.1038/nature12722 24213632