title: Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium.
abstract: Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.
authors.affiliation: School of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, USA. Megan.L.Grove@uth.tmc.edu
authors.forename: Megan L
authors.initials: ML
authors.lastname: Grove
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Cochran
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Mark
authors.initials: M
authors.lastname: Hansen
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Robert
authors.initials: R
authors.lastname: Kraaij
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Mosley
authors.forename: Gina M
authors.initials: GM
authors.lastname: Peloso
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.forename: Andre
authors.initials: A
authors.lastname: Uitterlinden
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
mesh_terms: D000375:Aging / Q000235:genetics*; D000483:Alleles; D016000:Cluster Analysis; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D023281:Genomics; D005838:Genotype; D006321:Heart / Q000502:physiology*; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044469:Racial Groups / Q000235:genetics; D018401:Sample Size; D057566:Self Report; D017422:Sequence Analysis, DNA