Dataset Information

Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals.

ABSTRACT: The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4 × on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions. We also catalogue structural variants, including 3.4 million insertions and deletions, and 25,923 genic copy-number variants. The 1KJPN was effective for imputing genotypes of the Japanese population genome wide. These data demonstrate the value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele frequency ?0.1%, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association studies.

SUBMITTER: Nagasaki M

PROVIDER: S-EPMC4560751 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals.

Nagasaki Masao M Yasuda Jun J Katsuoka Fumiki F Nariai Naoki N Kojima Kaname K Kawai Yosuke Y Yamaguchi-Kabata Yumi Y Yokozawa Junji J Danjoh Inaho I Saito Sakae S Sato Yukuto Y Mimori Takahiro T Tsuda Kaoru K Saito Rumiko R Pan Xiaoqing X Nishikawa Satoshi S Ito Shin S Kuroki Yoko Y Tanabe Osamu O Fuse Nobuo N Kuriyama Shinichi S Kiyomoto Hideyasu H Hozawa Atsushi A Minegishi Naoko N Douglas Engel James J Kinoshita Kengo K Kure Shigeo S Yaegashi Nobuo N Yamamoto Masayuki M

Nature communications 20150821

The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4 × on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions. We ...[more]

PMID: 26292667

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Project description:Essential tremor (ET) is one of the most common movement disorders. The etiology of ET remains largely unexplained. Whole genome sequencing (WGS) is likely to be of value in understanding a large proportion of ET with Mendelian and complex disease inheritance patterns. In ET families with Mendelian inheritance patterns, WGS may lead to gene identification where WES analysis failed to identify the causative single nucleotide variant (SNV) or indel due to incomplete coverage of the entire coding region of the genome, in addition to accurate detection of larger structural variants (SVs) and copy number variants (CNVs). Alternatively, in ET families with complex disease inheritance patterns with gene x gene and gene x environment interactions enrichment of functional rare coding and non-coding variants may explain the heritability of ET. We performed WGS in eight ET families (n = 40 individuals) enrolled in the Family Study of Essential Tremor. The analysis included filtering WGS data based on allele frequency in population databases, rare SNV and indel classification and association testing using the Mixed-Model Kernel Based Adaptive Cluster (MM-KBAC) test. A separate analysis of rare SV and CNVs segregating within ET families was also performed. Prioritization of candidate genes identified within families was performed using phenolyzer. WGS analysis identified candidate genes for ET in 5/8 (62.5%) of the families analyzed. WES analysis in a subset of these families in our previously published study failed to identify candidate genes. In one family, we identified a deleterious and damaging variant (c.1367G>A, p.(Arg456Gln)) in the candidate gene, CACNA1G, which encodes the pore forming subunit of T-type Ca(2+) channels, CaV3.1, and is expressed in various motor pathways and has been previously implicated in neuronal autorhythmicity and ET. Other candidate genes identified include SLIT3 which encodes an axon guidance molecule and in three families, phenolyzer prioritized genes that are associated with hereditary neuropathies (family A, KARS, family B, KIF5A and family F, NTRK1). Functional studies of CACNA1G and SLIT3 suggest a role for these genes in ET disease pathogenesis.

Dataset Information

Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals.

Publications

Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals.

Similar Datasets

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