Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs

Pistis, Giorgio; Porcu, Eleonora; Vrieze, Scott; Sidore, Carlo; Steri, Maristella; Danjou, Fabrice; Busonero, Fabio; Mulas, Antonella; Żołędziewska, Magdalena; Maschio, Andrea; Brennan, Christine; Lai, Sandra; Miller, Michael B.; Marcelli, Marco; Urru, Maria Francesca; Pitzalis, Maristella; Lyons, Robert H.; Kang, Hyun Min; Jones, Chris; Angius, Andrea; Iacono, William G.; Schlessinger, David; McGue, Matt; Cucca, Francesco; Abecasis, Gonçalo R.; Sanna, Serena

doi:10.1038/ejhg.2014.216

Cited by 101 publications

(127 citation statements)

References 26 publications

(30 reference statements)

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…This is particularly noticeable when comparing with the gain in imputation quality of rare variants observed in other low-pass WGS projects, such as the Genome of the Netherlands and SardiNIA (Genome of the Netherlands 2014; Pistis et al 2015). One major difference between these efforts and our WGS project is the absence of related individuals among the French Canadians that were sequenced.…”

Section: Discussionmentioning

confidence: 84%

“…Motivated by recent reports that showed improvements in imputation quality when the target samples and reference haplotypes are from individuals of the same population (Genome of the Netherlands 2014; Pistis et al 2015), we tested the utility of our WGS-derived haplotypes to impute genotypes in French Canadians. For this analysis, we imputed genotypes in 731 independent French Canadians previously genotyped on the Illumina Omni2.5 M array.…”

Section: Imputationmentioning

confidence: 98%

See 1 more Smart Citation

Whole-genome sequencing in French Canadians from Quebec

Low‐Kam

Rhainds

et al. 2016

Hum Genet

View full text Add to dashboard Cite

Genome-wide association studies (GWAS) have had a tremendous success in the identification of common DNA sequence variants associated with complex human diseases and traits. However, because of their design, GWAS are largely inappropriate to characterize the role of rare and low-frequency DNA variants on human phenotypic variation. Rarer genetic variation is geographically more restricted, supporting the need for local whole-genome sequencing (WGS) efforts to study these variants in specific populations. Here, we present the first large-scale low-pass WGS of the French-Canadian population. Specifically, we sequenced at ~5.6× coverage the whole genome of 1970 French Canadians recruited by the Montreal Heart Institute Biobank and identified 29 million bi-allelic variants (31 % novel), including 19 million variants with a minor allele frequency (MAF) <0.5 %. Genotypes from the WGS data are highly concordant with genotypes obtained by exome array on the same individuals (99.8 %), even when restricting this analysis to rare variants (MAF <0.5, 99.9 %) or heterozygous sites (98.9 %). To further validate our data set, we showed that we can effectively use it to replicate several genetic associations with myocardial infarction risk and blood lipid levels. Furthermore, we analyze the utility of our WGS data set to generate a French-Canadian-specific imputation reference panel and to infer population structure in the Province of Quebec. Our results illustrate the value of low-pass WGS to study the genetics of human diseases in the founder French-Canadian population.

show abstract

Section: Discussionmentioning

confidence: 84%

Section: Imputationmentioning

confidence: 98%

Whole-genome sequencing in French Canadians from Quebec

Low‐Kam

Rhainds

et al. 2016

Hum Genet

View full text Add to dashboard Cite

show abstract

“…Imputation accuracy increases with the number of haplotypes in the reference panel of sequenced genomes 7–9 , particularly for rare (minor allele frequency (MAF) < 0.5%) and low-frequency (0.5% < MAF < 5%) variants. These rare and low-frequency variants include most loss-of-function alleles 10 and other high-impact variants that are key for genotype-based callback and focused studies of natural knockout alleles 11–13 .…”

mentioning

confidence: 99%

Next-generation genotype imputation service and methods

et al. 2016

Self Cite

View full text Add to dashboard Cite

Genotype imputation is a key component of genetic association studies, where it increases power, facilitates meta-analysis, and aids interpretation of signals. Genotype imputation is computationally demanding and, with current tools, typically requires access to a high-performance computing cluster and to a reference panel of sequenced genomes. Here we describe improvements to imputation machinery that reduce computational requirements by more than an order of magnitude with no loss of accuracy in comparison to standard imputation tools. We also describe a new web-based service for imputation that facilitates access to new reference panels and greatly improves user experience and productivity.

show abstract

“…This relationship is specific to low-frequency variants. Moreover, Pistis et al 15 found that the effectiveness of population-specific reference panels can be appreciable for other populations, but that effectiveness will vary depending on the size of the panels and the demographic history of the isolate.…”

Section: Gonl Reference Setmentioning

confidence: 99%

Population-specific genotype imputations using minimac or IMPUTE2

et al. 2015

View full text Add to dashboard Cite

In order to meaningfully analyze common and rare genetic variants, results from genome-wide association studies (GWass) of multiple cohorts need to be combined in a meta-analysis in order to obtain enough power. this requires all cohorts to have the same single-nucleotide polymorphisms (snps) in their GWass. to this end, genotypes that have not been measured in a given cohort can be imputed on the basis of a set of reference haplotypes. this protocol provides guidelines for performing imputations with two widely used tools: minimac and IMpute2. these guidelines were developed and used by the Genome of the netherlands (Gonl) consortium, which has created a population-specific reference panel for genetic imputations and used this reference to impute various Dutch biobanks. We also describe several factors that might influence the final imputation quality. this protocol, which has been used by the largest Dutch biobanks, should take approximately several days, depending on the sample size of the biobank and the computer resources available.

show abstract

Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs

Cited by 101 publications

References 26 publications

Whole-genome sequencing in French Canadians from Quebec

Whole-genome sequencing in French Canadians from Quebec

Next-generation genotype imputation service and methods

Population-specific genotype imputations using minimac or IMPUTE2

Contact Info

Product

Resources

About