Translational Research
Volume 159, Issue 2 , Pages 64-79 , February 2012

Molecular genetic studies of complex phenotypes

  • Ali J. Marian

      Affiliations

    • Corresponding Author InformationReprint requests: Ali J. Marian, MD, Center for Cardiovascular Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Sciences Center, 6770 Bertner Street, Suite C900A, Houston, TX 77030.

Received 3 June 2011 ,Revised 3 August 2011 ,Accepted 4 August 2011.

References 

  1. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291:1304–1351
  2. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921
  3. Lander ES. Initial impact of the sequencing of the human genome. Nature. 2011;470:187–197
  4. Blaxter M. Revealing the dark matter of the genome. Science. 2010;330:1758–1759
  5. Levy S, Sutton G, Ng PC, et al. The diploid genome sequence of an individual human. PLoSBiol. 2007;5:e254
  6. Gunter C. Genomics: a picture worth 1000 Genomes. Nat Rev Genet. 2010;11:814
  7. Genomics Pennisi E. 1000 Genomes Project gives new map of genetic diversity. Science. 2010;330:574–575
  8. Gamazon ER, Zhang W, Dolan ME, Cox NJ. Comprehensive survey of SNPs in the Affymetrix exon array using the 1000 Genomes dataset. PLoS ONE. 2010;5:e9366
  9. Wang J, Wang W, Li R, et al. The diploid genome sequence of an Asian individual. Nature. 2008;456:60–65
  10. Wheeler DA, Srinivasan M, Egholm M, et al. The complete genome of an individual by massively parallel DNA sequencing. Nature. 2008;452:872–876
  11. Kim JI, Ju YS, Park H, et al. A highly annotated whole-genome sequence of a Korean individual. Nature. 2009;460:1011–1015
  12. Kidd JM, Cooper GM, Donahue WF, et al. Mapping and sequencing of structural variation from eight human genomes. Nature. 2008;453:56–64
  13. Sudmant PH, Kitzman JO, Antonacci F, et al. Diversity of human copy number variation and multicopy genes. Science. 2010;330:641–646
  14. Mills RE, Walter K, Stewart C, et al. Mapping copy number variation by population-scale genome sequencing. Nature. 2011;470:59–65
  15. Eichler EE, Flint J, Gibson G, et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet. 2010;11:446–450
  16. Durbin RM, Abecasis GR, Altshuler DL, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–1073
  17. Marian AJ, Belmont J. Strategic approaches to unraveling genetic causes of cardiovascular diseases. Circ Res. 2011;108:1252–1269
  18. Barabasi AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nat Rev Genet. 2011;12:56–68
  19. Romanoski CE, Che N, Yin F, et al. Network for activation of human endothelial cells by oxidized phospholipids: a critical role of heme oxygenase 1. Circ Res. 2011 Jul 7;[Epub ahead of print]
  20. Kathiresan S, Melander O, Guiducci C, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008;40:189–197
  21. Kathiresan S, Willer CJ, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56–65
  22. Debette S, Visvikis-Siest S, Chen MH, et al. Identification of cis- and trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels. Circ Res. 2011 Jul 14;[Epub ahead of print]
  23. Innocenti P, Morrow EH, Dowling DK. Experimental evidence supports a sex-specific selective sieve in mitochondrial genome evolution. Science. 2011;332:845–848
  24. Lemos B, Araripe LO, Hartl DL. Polymorphic Y chromosomes harbor cryptic variation with manifold functional consequences. Science. 2008;319:91–93
  25. Marian AJ. Nature's genetic gradients and the clinical phenotype. Circ Cardiovasc Genet. 2009;2:537–539
  26. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273:1516–1517
  27. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010;11:415–425
  28. Bodmer W, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet. 2008;40:695–701
  29. Pritchard JK. Are rare variants responsible for susceptibility to complex diseases?. AmJHumGenet. 2001;69:124–137
  30. Schork NJ, Murray SS, Frazer KA, Topol EJ. Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev. 2009;19:212–219
  31. Pritchard JK, Cox NJ. The allelic architecture of human disease genes: common disease-common variant…or not?. Hum Mol Genet. 2002;11:2417–2423
  32. Rodriguez G, Ueyama T, Ogata T, et al. Molecular Genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy. Circ Cardiovasc Genet. 2011 Jun 3;[Epub ahead of print]
  33. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB. Rare variants create synthetic genome-wide associations. PLoS Biol. 2010;8:e1000294
  34. McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008;9:356–369
  35. Gao X, Becker LC, Becker DM, Starmer JD, Province MA. Avoiding the high Bonferroni penalty in genome-wide association studies. Genet Epidemiol. 2010;34:100–105
  36. Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41:666–676
  37. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–713
  38. Sotoodehnia N, Isaacs A, de Bakker PI, et al. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet. 2010;42:1068–1076
  39. Harismendy O, Notani D, Song X, et al. 9p21 DNA variants associated with coronary artery disease impair interferon-gamma signalling response. Nature. 2011;470:264–268
  40. Arora P, Newton-Cheh C. Blood pressure and human genetic variation in the general population. Curr Opin Cardiol. 2010;25:229–237
  41. Kathiresan S, Manning AK, Demissie S, et al. A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study. BMC Med Genet. 2007;8:S17
  42. Pirruccello J, Kathiresan S. Genetics of lipid disorders. Curr Opin Cardiol. 2010;25:238–242
  43. Pfeufer A, Sanna S, Arking DE, et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet. 2009;41:407–414
  44. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385–389
  45. Maller J, George S, Purcell S, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nature Genetics. 2006;38:1055–1059
  46. Manolio TA. Genomewide association studies and assessment of the risk of disease. New Engl J Med. 2010;363:166–176
  47. Jakobsdottir J, Gorin MB, Conley YP, Ferrell RE, Weeks DE. Interpretation of genetic association studies: markers with replicated highly significant odds ratios may be poor classifiers. PLoS genetics. 2009;5:e1000337
  48. Margulies M, Egholm M, Altman WE, et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature. 2005;437:376–380
  49. Nielsen R, Paul JS, Albrechtsen A, Song YS. Genotype and SNP calling from next-generation sequencing data. Nat Rev Genet. 2011;12:443–451
  50. Ansorge WJ. Next-generation DNA sequencing techniques. N Biotechnol. 2009;25:195–203
  51. Hedges DJ, Guettouche T, Yang S, et al. Comparison of three targeted enrichment strategies on the SOLiD sequencing platform. PLoS ONE. 2011;6:e18595
  52. Meder B, Haas J, Keller A, et al. Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circ Cardiovasc Genet. 2011 Apr;4:110–122
  53. Vermeer S, Hoischen A, Meijer RP, et al. Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia. Am J Hum Genet. 2010;87:813–819
  54. Rehman AU, Morell RJ, Belyantseva IA, et al. Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79. Am J Hum Genet. 2010;86:378–388
  55. Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010;42:30–35
  56. Ng SB, Bigham AW, Buckingham KJ, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42:790–793
  57. Choi M, Scholl UI, Ji W, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009;106:19096–19101
  58. Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331:768–772
  59. Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–667
  60. Klassen T, Davis C, Goldman A, et al. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell. 2011;145:1036–1048
  61. Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–249
  62. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–1081
  63. Roach JC, Glusman G, Smit AF, et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science. 2010;328:636–639
  64. Sobreira NL, Cirulli ET, Avramopoulos D, et al. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS genetics. 2010;6:e1000991
  65. Holm H, Gudbjartsson DF, Sulem P, et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat Geneti. 2011;43:316–320
  66. Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265:2037–2048
  67. Dawson E, Abecasis GR, Bumpstead S, et al. A first-generation linkage disequilibrium map of human chromosome 22. Nature. 2002;418:544–548
  68. Ardlie KG, Kruglyak L, Seielstad M. Patterns of linkage disequilibrium in the human genome. NatRevGenet. 2002;3:299–309
  69. Reich DE, Cargill M, Bolk S, et al. Linkage disequilibrium in the human genome. Nature. 2001;411:199–204
  70. Pritchard JK, Przeworski M. Linkage disequilibrium in humans: models and data. Am J Hum Genet. 2001;69:1–14
  71. Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491–1493
  72. McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316:1488–1491
  73. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678
  74. Visel A, Zhu Y, May D, et al. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature. 2010;464:409–412
  75. Daw EW, Chen SN, Czernuszewicz G, et al. Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy. Hum Mol Genet. 2007;16:2463–2471
  76. Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association expert panel on familial hypercholesterolemia. J Clin Lipidol. 2011;5:S9–17
  77. Guey LT, Kravic J, Melander O, et al. Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants. Genet Epidemiol. 2011 Feb 9;[Epub ahead of print]
  78. O’Roak BJ, Deriziotis P, Lee C, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43:585–589
  79. Malkin I, Ginsburg E, Elston RC. Increase in power of transmission-disequilibrium tests for quantitative traits. Genet Epidemiol. 2002;23:234–244
  80. Samani NJ, Raitakari OT, Sipila K, et al. Coronary artery disease-associated locus on chromosome 9p21 and Early markers of atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28:1679–1683
  81. Spencer CC, Su Z, Donnelly P, Marchini J. Designing genome-wide association studies: sample size, power, imputation, and the choice of genotyping chip. PLoS Genetics. 2009;5:e1000477
  82. Laan M, Paabo S. Mapping genes by drift-generated linkage disequilibrium. Am J Hum Genet. 1998;63:654–656
  83. Terwilliger JD, Zollner S, Laan M, Paabo S. Mapping genes through the use of linkage disequilibrium generated by genetic drift: "drift mapping" in small populations with no demographic expansion. Human Hered. 1998;48:138–154
  84. Novembre J, Johnson T, Bryc K, et al. Genes mirror geography within Europe. Nature. 2008;456:98–101
  85. Tishkoff SA, Reed FA, Friedlaender FR, et al. The genetic structure and history of Africans and African Americans. Science. 2009;324:1035–1044
  86. Marian AJ. Hypertrophic cardiomyopathy: from genetics to treatment. Eur J Clin Invest. 2010;40:360–369
  87. Li M, Wang IX, Li Y, et al. Widespread RNA and DNA sequence differences in the human transcriptome. Science. 2011;333:53–58

 Supported by Grant R01-088498 from NHLBI, Grant R21 AG038597-01 from NIA, Burroughs Wellcome Award in Translational Research #1005907, the TexGen Fund from Greater Houston Community Foundation and George and Mary Josephine Hamman Foundation.

PII: S1931-5244(11)00261-1

doi: 10.1016/j.trsl.2011.08.001

Translational Research
Volume 159, Issue 2 , Pages 64-79 , February 2012

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