Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs

• Published in: Nature genetics Vol. 40; no. 10; pp. 1253 - 1260
• Main Authors: Korn, Joshua M, Kuruvilla, Finny G, McCarroll, Steven A, Wysoker, Alec, Nemesh, James, Cawley, Simon, Hubbell, Earl, Veitch, Jim, Collins, Patrick J, Darvishi, Katayoon, Lee, Charles, Nizzari, Marcia M, Gabriel, Stacey B, Purcell, Shaun, Daly, Mark J, Altshuler, David
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2008; Nature Publishing Group
• Subjects: Agriculture; Algorithms; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromosomes, Human - genetics; Chromosomes, Human, Pair 4 - genetics; DNA - genetics; DNA microarrays; Female; Fundamental and applied biological sciences. Psychology; Gene Dosage - genetics; Gene Function; Genetic algorithms; Genetic diversity; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genotype; Genotype & phenotype; Genotypes; Haplotypes - genetics; Human Genetics; Humans; Life sciences; Male; Markov Chains; Models, Statistical; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Research methodology; Single nucleotide polymorphisms; Software; technical-report; United States; Genotype; Association; Single nucleotide polymorphism; Copy number
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.237

David Altshuler and colleagues describe analysis for integrating genotype calling of SNPs, common copy number polymorphisms and rare CNVs, implemented in a suite of software programs collectively named Birdsuite. Accurate and complete measurement of single nucleotide (SNP) and copy number (CNV) variants, both common and rare, will be required to understand the role of genetic variation in disease. We present Birdsuite, a four-stage analytical framework instantiated in software for deriving integrated and mutually consistent copy number and SNP genotypes. The method sequentially assigns copy number across regions of common copy number polymorphisms (CNPs), calls genotypes of SNPs, identifies rare CNVs via a hidden Markov model (HMM), and generates an integrated sequence and copy number genotype at every locus (for example, including genotypes such as A-null, AAB and BBB in addition to AA, AB and BB calls). Such genotypes more accurately depict the underlying sequence of each individual, reducing the rate of apparent mendelian inconsistencies. The Birdsuite software is applied here to data from the Affymetrix SNP 6.0 array. Additionally, we describe a method, implemented in PLINK, to utilize these combined SNP and CNV genotypes for association testing with a phenotype.