Technical Report abstract

Nature Genetics 40, 1253 - 1260 (2008)
Published online: 7 September 2008 | doi:10.1038/ng.237

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

Joshua M Korn1,2,3,4,5,10, Finny G Kuruvilla1,4,5,6,10, Steven A McCarroll1,4,5, Alec Wysoker1, James Nemesh1, Simon Cawley7, Earl Hubbell7, Jim Veitch7, Patrick J Collins7, Katayoon Darvishi8, Charles Lee8, Marcia M Nizzari1, Stacey B Gabriel1, Shaun Purcell1,5, Mark J Daly1,5,9 & David Altshuler1,4,5,9

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.

  1. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
  2. Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA.
  3. Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts 02138, USA.
  4. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  5. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  6. Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts 02115, USA.
  7. Affymetrix, Inc., Santa Clara, California 95051, USA.
  8. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  9. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
  10. These authors contributed equally to this work.

Correspondence to: Joshua M Korn1,2,3,4,5,10 e-mail:

Correspondence to: David Altshuler1,4,5,9 e-mail: