Detection of trait-associated structural variations using short-read sequencing

Shunichi Kosugi; Yoichiro Kamatani; Katsutoshi Harada; Kohei Tomizuka; Yukihide Momozawa; Takayuki Morisaki; BioBank Japan Project; Chikashi Terao

doi:10.1016/j.xgen.2023.100328

Detection of trait-associated structural variations using short-read sequencing

Cell Genom. 2023 May 18;3(6):100328. doi: 10.1016/j.xgen.2023.100328. eCollection 2023 Jun 14.

Authors

Shunichi Kosugi^{1

2}, Yoichiro Kamatani³, Katsutoshi Harada¹, Kohei Tomizuka¹, Yukihide Momozawa⁴, Takayuki Morisaki⁵; BioBank Japan Project; Chikashi Terao^{1

2

6}

Affiliations

¹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
² Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
³ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5, Kashiwanoha, Kashiwa-shi, Chiba 277-8562, Japan.
⁴ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan.
⁵ Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
⁶ The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

Abstract

Genomic structural variation (SV) affects genetic and phenotypic characteristics in diverse organisms, but the lack of reliable methods to detect SV has hindered genetic analysis. We developed a computational algorithm (MOPline) that includes missing call recovery combined with high-confidence SV call selection and genotyping using short-read whole-genome sequencing (WGS) data. Using 3,672 high-coverage WGS datasets, MOPline stably detected ∼16,000 SVs per individual, which is over ∼1.7-3.3-fold higher than previous large-scale projects while exhibiting a comparable level of statistical quality metrics. We imputed SVs from 181,622 Japanese individuals for 42 diseases and 60 quantitative traits. A genome-wide association study with the imputed SVs revealed 41 top-ranked or nearly top-ranked genome-wide significant SVs, including 8 exonic SVs with 5 novel associations and enriched mobile element insertions. This study demonstrates that short-read WGS data can be used to identify rare and common SVs associated with a variety of traits.

Keywords: CNV; GWAS; MOPline; SV; WGS; imputation; short read; structural variant; structural variation; whole-genome sequencing.