PMID- 33743587
OWN - NLM
STAT- MEDLINE
DCOM- 20210514
LR  - 20220531
IS  - 1471-2164 (Electronic)
IS  - 1471-2164 (Linking)
VI  - 22
IP  - 1
DP  - 2021 Mar 20
TI  - Comparing low-pass sequencing and genotyping for trait mapping in 
      pharmacogenetics.
PG  - 197
LID - 10.1186/s12864-021-07508-2 [doi]
LID - 197
AB  - BACKGROUND: Low pass sequencing has been proposed as a cost-effective alternative 
      to genotyping arrays to identify genetic variants that influence multifactorial 
      traits in humans. For common diseases this typically has required both large 
      sample sizes and comprehensive variant discovery. Genotyping arrays are also 
      routinely used to perform pharmacogenetic (PGx) experiments where sample sizes 
      are likely to be significantly smaller, but clinically relevant effect sizes 
      likely to be larger. RESULTS: To assess how low pass sequencing would compare to 
      array based genotyping for PGx we compared a low-pass assay (in which 1x coverage 
      or less of a target genome is sequenced) along with software for genotype 
      imputation to standard approaches. We sequenced 79 individuals to 1x genome 
      coverage and genotyped the same samples on the Affymetrix Axiom Biobank Precision 
      Medicine Research Array (PMRA). We then down-sampled the sequencing data to 0.8x, 
      0.6x, and 0.4x coverage, and performed imputation. Both the genotype data and the 
      sequencing data were further used to impute human leukocyte antigen (HLA) 
      genotypes for all samples. We compared the sequencing data and the genotyping 
      array data in terms of four metrics: overall concordance, concordance at single 
      nucleotide polymorphisms in pharmacogenetics-related genes, concordance in 
      imputed HLA genotypes, and imputation r(2). Overall concordance between the two 
      assays ranged from 98.2% (for 0.4x coverage sequencing) to 99.2% (for 1x coverage 
      sequencing), with qualitatively similar numbers for the subsets of variants most 
      important in pharmacogenetics. At common single nucleotide polymorphisms (SNPs), 
      the mean imputation r(2) from the genotyping array was 0.90, which was comparable 
      to the imputation r(2) from 0.4x coverage sequencing, while the mean imputation 
      r(2) from 1x sequencing data was 0.96. CONCLUSIONS: These results indicate that 
      low-pass sequencing to a depth above 0.4x coverage attains higher power for 
      association studies when compared to the PMRA and should be considered as a 
      competitive alternative to genotyping arrays for trait mapping in 
      pharmacogenetics.
FAU - Wasik, Kaja
AU  - Wasik K
AD  - Gencove, Inc., New York, NY, 10016, USA.
FAU - Berisa, Tomaz
AU  - Berisa T
AD  - Gencove, Inc., New York, NY, 10016, USA.
FAU - Pickrell, Joseph K
AU  - Pickrell JK
AD  - Gencove, Inc., New York, NY, 10016, USA.
FAU - Li, Jeremiah H
AU  - Li JH
AUID- ORCID: 0000-0002-9344-0237
AD  - Gencove, Inc., New York, NY, 10016, USA. jeremy@gencove.com.
FAU - Fraser, Dana J
AU  - Fraser DJ
AD  - PAREXEL Genomic Medicine, Durham, NC, 27713, USA.
FAU - King, Karen
AU  - King K
AD  - PAREXEL Genomic Medicine, Durham, NC, 27713, USA.
FAU - Cox, Charles
AU  - Cox C
AD  - GlaxoSmithKline, Stevenage, UK.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20210320
PL  - England
TA  - BMC Genomics
JT  - BMC genomics
JID - 100965258
SB  - IM
MH  - *Genome-Wide Association Study
MH  - Genotype
MH  - Genotyping Techniques
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - *Pharmacogenetics
MH  - Polymorphism, Single Nucleotide
PMC - PMC7981957
OTO - NOTNLM
OT  - Genotype imputation
OT  - Low-pass sequencing
OT  - Pharmacogenetics
OT  - Trait mapping
COIS- K. W., T.B., J.K.P., and J.H.L were employees of Gencove, Inc. at the time of 
      writing.
EDAT- 2021/03/22 06:00
MHDA- 2021/05/15 06:00
PMCR- 2021/03/20
CRDT- 2021/03/21 20:25
PHST- 2020/05/06 00:00 [received]
PHST- 2021/03/05 00:00 [accepted]
PHST- 2021/03/21 20:25 [entrez]
PHST- 2021/03/22 06:00 [pubmed]
PHST- 2021/05/15 06:00 [medline]
PHST- 2021/03/20 00:00 [pmc-release]
AID - 10.1186/s12864-021-07508-2 [pii]
AID - 7508 [pii]
AID - 10.1186/s12864-021-07508-2 [doi]
PST - epublish
SO  - BMC Genomics. 2021 Mar 20;22(1):197. doi: 10.1186/s12864-021-07508-2.