title: Rare variant association testing under low-coverage sequencing.
abstract: Deep sequencing technologies enable the study of the effects of rare variants in disease risk. While methods have been developed to increase statistical power for detection of such effects, detecting subtle associations requires studies with hundreds or thousands of individuals, which is prohibitively costly. Recently, low-coverage sequencing has been shown to effectively reduce the cost of genome-wide association studies, using current sequencing technologies. However, current methods for disease association testing on rare variants cannot be applied directly to low-coverage sequencing data, as they require individual genotype data, which may not be called correctly due to low-coverage and inherent sequencing errors. In this article, we propose two novel methods for detecting association of rare variants with disease risk, using low coverage, error-prone sequencing. We show by simulation that our methods outperform previous methods under both low- and high-coverage sequencing and under different disease architectures. We use real data and simulation studies to demonstrate that to maximize the power to detect associations for a fixed budget, it is desirable to include more samples while lowering coverage and to perform an analysis using our suggested methods.
authors: Molecular Microbiology and Biotechnology Department, Tel-Aviv University, Tel Aviv 69978, Israel.
authors: Oron
authors: O
authors: Navon
authors: Jae Hoon
authors: JH
authors: Sul
authors: Buhm
authors: B
authors: Han
authors: Lucia
authors: L
authors: Conde
authors: Paige M
authors: PM
authors: Bracci
authors: Jacques
authors: J
authors: Riby
authors: Christine F
authors: CF
authors: Skibola
authors: Eleazar
authors: E
authors: Eskin
authors: Eran
authors: E
authors: Halperin
mesh_terms: D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA
keywords: association test; low-coverage sequencing; pooling; rare variants; sequencing
references: Am J Hum Genet. 2008 Sep;83(3):311-21
references: 18691683
references: Am J Hum Genet. 2010 Jun 11;86(6):832-8
references: 20471002
references: Genome Res. 2008 Apr;18(4):653-60
references: 18353808
references: Am J Hum Genet. 2008 Jan;82(1):100-12
references: 18179889
references: Am J Hum Genet. 2007 Apr;80(4):779-91
references: 17357083
references: Hum Mol Genet. 2002 Oct 1;11(20):2417-23
references: 12351577
references: Nat Genet. 2012 Jun 03;44(7):808-11
references: 22660546
references: PLoS Genet. 2011 Mar;7(3):e1001322
references: 21408211
references: Nat Genet. 2011 Mar 06;43(4):333-8
references: 21378990
references: Science. 2004 Aug 6;305(5685):869-72
references: 15297675
references: J Comput Biol. 2011 Nov;18(11):1611-24
references: 21919745
references: Nat Genet. 2008 Jul;40(7):838-40
references: 18488026
references: Genome Res. 2009 Jul;19(7):1243-53
references: 19447965
references: Nat Genet. 2010 Aug;42(8):661-4
references: 20639881
references: Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
references: 12824425
references: Nature. 2010 Oct 28;467(7319):1061-73
references: 20981092
references: PLoS Genet. 2009 Feb;5(2):e1000384
references: 19214210
references: Nature. 2007 Jun 28;447(7148):1087-93
references: 17529967
references: Am J Hum Genet. 2011 Sep 9;89(3):354-67
references: 21885029
references: Am J Hum Genet. 2001 Jul;69(1):124-37
references: 11404818
references: Genome Biol. 2011 Nov 08;12(11):R112
references: 22067484
references: Diabetes. 2007 Apr;56(4):975-83
references: 17395743
references: Nature. 2007 Jun 7;447(7145):661-78
references: 17554300
references: Am J Hum Genet. 2007 Apr;80(4):727-39
references: 17357078
references: Nat Methods. 2010 Apr;7(4):248-9
references: 20354512
references: Genetics. 2011 May;188(1):181-8
references: 21368279
references: Nat Genet. 2009 Aug;41(8):873-5
references: 19620980
references: BMC Bioinformatics. 2011 Feb 15;12 Suppl 1:S53
references: 21342586
references: Nature. 2009 Oct 8;461(7265):747-53
references: 19812666