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Non-coding regions, typically covered by sparse off-target data, are often discarded by conventional WES analyses. Here, we develop a genotype calling pipeline named WEScall to analyse both target and off-target data. We leverage linkage disequilibrium shared within study samples and from an external reference panel to improve genotyping accuracy. In an application to WES of 2527 Chinese and Malays, WEScall can reduce the genotype discordance rate from 0.26% (SE=\u20096.4\u2009\u00d7\u200910\u22126) to 0.08% (SE\u2009=\u20093.6\u2009\u00d7\u200910\u22126) across 1.1 million single nucleotide polymorphisms (SNPs) in the deeply sequenced target regions. Furthermore, we obtain genotypes at 0.70% (SE\u2009=\u20093.0\u2009\u00d7\u200910\u22126) discordance rate across 5.2 million off-target SNPs, which had ~1.2\u00d7 mean sequencing depth. Using this dataset, we perform genome-wide association studies of 10 metabolic traits. Despite of our small sample size, we identify 10 loci at genome-wide significance (P\u2009&amp;lt;\u20095\u2009\u00d7\u200910\u22128), including eight well-established loci. The two novel loci, both associated with glycated haemoglobin levels, are GPATCH8-SLC4A1 (rs369762319, P\u2009=\u20092.56\u2009\u00d7\u200910\u221212) and ROR2 (rs1201042, P\u2009=\u20093.24\u2009\u00d7\u200910\u22128). Finally, using summary statistics from UK Biobank and Biobank Japan, we show that polygenic risk prediction can be significantly improved for six out of nine traits by incorporating off-target data (P\u2009&amp;lt;\u20090.01). These results demonstrate WEScall as a useful tool to facilitate WES studies with decent amounts of off-target data.<\/jats:p>","DOI":"10.1093\/bib\/bbaa084","type":"journal-article","created":{"date-parts":[[2020,4,22]],"date-time":"2020-04-22T11:12:23Z","timestamp":1587553943000},"source":"Crossref","is-referenced-by-count":11,"title":["Using off-target data from whole-exome sequencing to improve genotyping accuracy, association analysis and polygenic risk prediction"],"prefix":"10.1093","volume":"22","author":[{"given":"Jinzhuang","family":"Dou","sequence":"first","affiliation":[{"name":"School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2326-0468","authenticated-orcid":false,"given":"Degang","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Ding","sequence":"additional","affiliation":[{"name":"School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minghui","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoran","family":"Chai","sequence":"additional","affiliation":[{"name":"Singapore National Eye Centre, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dermot F","family":"Reilly","sequence":"additional","affiliation":[{"name":"Merck Research Laboratories, Kenilworth, NJ, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E Shyong","family":"Tai","sequence":"additional","affiliation":[{"name":"Saw Swee Hock School of Public Health, Duke-NUS Medical School, and Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianjun","family":"Liu","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore and a professor at Yong Loo Lin School of Medicine, National University of Singapore, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueling","family":"Sim","sequence":"additional","affiliation":[{"name":"Saw Swee Hock School of Public Health, National University of Singapore, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanshan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3945-1012","authenticated-orcid":false,"given":"Chaolong","family":"Wang","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,6,17]]},"reference":[{"key":"2021052109494545300_ref1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ajhg.2017.06.005","article-title":"10 years of GWAS 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