title: Towards a complete resolution of the genetic architecture of disease.
abstract: After years of linear gains in the genetic dissection of human disease we are now in a period of exponential discovery. This is particularly apparent for complex disease. Genome-wide association studies (GWAS) have provided myriad associations between common variability and disease, and have shown that common genetic variability is unlikely to explain the entire genetic predisposition to disease. Here we detail how one can expand on this success and systematically identify genetic risks that lead or predispose to disease using next-generation sequencing. Geneticists have had for many years a protocol to identify Mendelian disease. A similar set of tools is now available for the identification of rare moderate-risk loci and common low-risk variants. Whereas major challenges undoubtedly remain, particularly regarding data handling and the functional classification of variants, we suggest that these will be largely practical and not conceptual.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. singleta@mail.nih.gov
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000483:Alleles; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D012307:Risk Factors
references.citation: N Engl J Med. 2009 Oct 22;361(17):1651-61
references.pmid: 19846850
references.citation: Neuroepidemiology. 2009;33(3):276-9
references.pmid: 19696518
references.citation: Nature. 2009 Apr 23;458(7241):1039-42
references.pmid: 19242412
references.citation: Neuron. 2004 Nov 18;44(4):601-7
references.pmid: 15541309
references.citation: Nat Rev Genet. 2005 Feb;6(2):109-18
references.pmid: 15716907
references.citation: Science. 2001 Feb 16;291(5507):1304-51
references.pmid: 11181995
references.citation: Nature. 2001 Feb 15;409(6822):860-921
references.pmid: 11237011
references.citation: Cell. 1987 Jul 31;50(3):509-17
references.pmid: 3607877
references.citation: Science. 1989 Sep 8;245(4922):1073-80
references.pmid: 2570460
references.citation: PLoS Genet. 2007 Jun;3(6):e108
references.pmid: 17590087
references.citation: Science. 1989 Sep 8;245(4922):1066-73
references.pmid: 2475911
references.citation: Science. 2005 Apr 15;308(5720):419-21
references.pmid: 15761120
references.citation: Science. 2005 Apr 15;308(5720):385-9
references.pmid: 15761122
references.citation: Nature. 1991 Feb 21;349(6311):704-6
references.pmid: 1671712
references.citation: Nature. 2009 Sep 10;461(7261):272-6
references.pmid: 19684571
references.citation: Neurology. 2003 Aug 12;61(3):407-9
references.pmid: 12913211
references.citation: Nat Genet. 2009 Oct;41(10):1088-93
references.pmid: 19734902
references.citation: Int J Epidemiol. 2006 Jun;35(3):525-7
references.pmid: 16645027
references.citation: Curr Protoc Hum Genet. 2003 Aug;Chapter 7:Unit 7.13
references.pmid: 18428344
references.citation: Neuron. 2004 Nov 18;44(4):595-600
references.pmid: 15541308
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references.pmid: 19474294
references.citation: Nature. 1995 Aug 31;376(6543):775-8
references.pmid: 7651536
references.citation: Nat Genet. 2009 Dec;41(12):1308-12
references.pmid: 19915575
references.citation: Science. 1993 Aug 13;261(5123):921-3
references.pmid: 8346443
references.citation: Nat Genet. 2008 Aug;40(8):955-62
references.pmid: 18587394
references.citation: Eur J Hum Genet. 2006 Apr;14(4):426-37
references.pmid: 16479260
references.citation: Nat Genet. 2009 Dec;41(12):1303-7
references.pmid: 19915576
references.citation: Science. 1996 Oct 25;274(5287):536-9
references.pmid: 8928008
references.citation: N Engl J Med. 2004 Nov 4;351(19):1972-7
references.pmid: 15525722
references.citation: Cell. 1987 Dec 24;51(6):919-28
references.pmid: 3319190
references.citation: Science. 1989 Sep 8;245(4922):1059-65
references.pmid: 2772657
references.citation: Nat Genet. 2006 Sep;38(9):1049-54
references.pmid: 16936733
references.citation: N Engl J Med. 2007 Aug 2;357(5):436-9
references.pmid: 17634446
references.citation: PLoS Genet. 2006 Oct 6;2(10):e150
references.pmid: 17029559
references.citation: Lancet Neurol. 2008 Mar;7(3):207-15
references.pmid: 18243799
references.citation: Science. 2001 Sep 21;293(5538):2256-9
references.pmid: 11567139
references.citation: N Engl J Med. 2008 Feb 14;358(7):667-75
references.pmid: 18184952
references.citation: Nature. 2009 Aug 6;460(7256):748-52
references.pmid: 19571811
references.citation: Nat Rev Genet. 2008 May;9(5):356-69
references.pmid: 18398418
references.citation: N Engl J Med. 2009 Apr 23;360(17):1759-68
references.pmid: 19369657
references.citation: Science. 2005 Apr 15;308(5720):421-4
references.pmid: 15761121
references.citation: Nat Genet. 2010 Jan;42(1):30-5
references.pmid: 19915526
references.citation: Nature. 2009 Oct 8;461(7265):747-53
references.pmid: 19812666
references.citation: Science. 1988 Dec 9;242(4884):1427-30
references.pmid: 3201231
references.citation: Hum Mol Genet. 2008 Dec 15;17(24):3847-53
references.pmid: 18801880
references.citation: Nat Genet. 2009 Oct;41(10):1094-9
references.pmid: 19734903
references.citation: Nature. 1995 Jun 29;375(6534):754-60
references.pmid: 7596406