RT Journal Article
SR Electronic
T1 Imputation aware tag SNP selection to improve power for multi-ethnic association studies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 105551
DO 10.1101/105551
A1 Genevieve L. Wojcik
A1 Christian Fuchsberger
A1 Daniel Taliun
A1 Ryan Welch
A1 Alicia R Martin
A1 Suyash Shringarpure
A1 Christopher S. Carlson
A1 Goncalo Abecasis
A1 Hyun Min Kang
A1 Michael Boehnke
A1 Carlos D. Bustamante
A1 Christopher R. Gignoux
A1 Eimear E. Kenny
YR 2017
UL http://biorxiv.org/content/early/2017/02/03/105551.abstract
AB The emergence of very large cohorts in genomic research has facilitated a focus on genotype-imputation strategies to power rare variant association. Consequently, a new generation of genotyping arrays are being developed designed with tag single nucleotide polymorphisms (SNPs) to improve rare variant imputation. Selection of these tag SNPs poses several challenges as rare variants tend to be continentally-or even population-specific and reflect fine-scale linkage disequilibrium (LD) structure impacted by recent demographic events. To explore the landscape of tag-able variation and guide design considerations for large-cohort and biobank arrays, we developed a novel pipeline to select tag SNPs using the 26 population reference panel from Phase of the 1000 Genomes Project. We evaluate our approach using leave-one-out internal validation via standard imputation methods that allows the direct comparison of tag SNP performance by estimating the correlation of the imputed and real genotypes for each iteration of potential array sites. We show how this approach allows for an assessment of array design and performance that can take advantage of the development of deeper and more diverse sequenced reference panels. We quantify the impact of demography on tag SNP performance across populations and provide population-specific guidelines for tag SNP selection. We also examine array design strategies that target single populations versus multi-ethnic cohorts, and demonstrate a boost in performance for the latter can be obtained by prioritizing tag SNPs that contribute information across multiple populations simultaneously. Finally, we demonstrate the utility of improved array design to provide meaningful improvements in power, particularly in trans-ethnic studies. The unified framework presented will enable investigators to make informed decisions for the design of new arrays, and help empower the next phase of rare variant association for global health.