title: Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs.
abstract: The utility of genotype imputation in genome-wide association studies is increasing as progressively larger reference panels are improved and expanded through whole-genome sequencing. Developing general guidelines for optimally cost-effective imputation, however, requires evaluation of performance issues that include the relative utility of study-specific compared with general/multipopulation reference panels; genotyping with various array scaffolds; effects of different ethnic backgrounds; and assessment of ranges of allele frequencies. Here we compared the effectiveness of study-specific reference panels to the commonly used 1000 Genomes Project (1000G) reference panels in the isolated Sardinian population and in cohorts of European ancestry including samples from Minnesota (USA). We also examined different combinations of genome-wide and custom arrays for baseline genotypes. In Sardinians, the study-specific reference panel provided better coverage and genotype imputation accuracy than the 1000G panels and other large European panels. In fact, even gene-centered custom arrays (interrogating ~200 000 variants) provided highly informative content across the entire genome. Gain in accuracy was also observed for Minnesotans using the study-specific reference panel, although the increase was smaller than in Sardinians, especially for rare variants. Notably, a combined panel including both study-specific and 1000G reference panels improved imputation accuracy only in the Minnesota sample, and only at rare sites. Finally, we found that when imputation is performed with a study-specific reference panel, cutoffs different from the standard thresholds of MACH-Rsq and IMPUTE-INFO metrics should be used to efficiently filter badly imputed rare variants. This study thus provides general guidelines for researchers planning large-scale genetic studies.
authors.affiliation: 1] Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy [2] Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA [3] Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pistis
authors.affiliation: 1] Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy [2] Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA [3] Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.affiliation: Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Vrieze
authors.affiliation: 1] Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy [2] Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA [3] Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sidore
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Steri
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Danjou
authors.affiliation: 1] Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy [2] Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Busonero
authors.affiliation: 1] Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy [2] Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zoledziewska
authors.affiliation: 1] Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy [2] Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Maschio
authors.affiliation: University of Michigan Sequencing Core, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Brennan
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lai
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Miller
authors.affiliation: CRS4, Parco tecnologico della Sardegna, Pula, Cagliari, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Marcelli
authors.affiliation: CRS4, Parco tecnologico della Sardegna, Pula, Cagliari, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Urru
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Pitzalis
authors.affiliation: University of Michigan Sequencing Core, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lyons
authors.affiliation: Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hyun M
authors.initials: HM
authors.lastname: Kang
authors.affiliation: CRS4, Parco tecnologico della Sardegna, Pula, Cagliari, Italy.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Jones
authors.affiliation: 1] Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy [2] University of Michigan Sequencing Core, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Iacono
authors.affiliation: Laboratory of Genetics, NIA, Baltimore, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: McGue
authors.affiliation: 1] Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy [2] Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.affiliation: Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
mesh_terms: D003362:Cost-Benefit Analysis; D005787:Gene Frequency; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000191:economics / Q000379:methods*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008910:Minnesota; D020641:Polymorphism, Single Nucleotide; D012107:Research Design; D017422:Sequence Analysis, DNA / Q000191:economics / Q000379:methods*; D044465:White People / Q000235:genetics