Rare variants discovery by extensive whole-genome sequencing of the Han Chinese population in Taiwan: applications to cardiovascular medicine

ABSTRACTPossession of a clinical or molecular disease label alters the context in which life-course events operate, but rarely explains the phenotypic variability observed by clinicians. Whole genome sequencing of unselected endothelial vasculopathy patients demonstrated more than a third had rare, likely deleterious variants in clinically-relevant genes unrelated to their vasculopathy (1 in 10 within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes). High erythrocyte membrane variant rates paralleled genomic damage and prevalence indices in the general population. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to their vasculopathy had more deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. We conclude that rare diseases can provide insights for medicine beyond their primary pathophysiology, and propose a framework based on rare variants to inform interpretative approaches to accelerate clinical impact from whole genome sequencing.

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NyuWa Genome Resource: Deep Whole Genome Sequencing Based Chinese Population Variation Profile and Reference Panel

10.1101/2020.11.10.376574 ◽

2020 ◽

Author(s):

Peng Zhang ◽

Huaxia Luo ◽

Yanyan Li ◽

You Wang ◽

Jiajia Wang ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Chinese Population ◽

Population Variation ◽

Reference Panel ◽

Specific Reference ◽

Whole Genome ◽

Loss Of Function ◽

Southern Chinese ◽

Novel Variants

AbstractThe lack of Chinese population specific haplotype reference panel and whole genome sequencing resources has greatly hindered the genetics studies in the world’s largest population. Here we presented the NyuWa genome resource of 71.1M SNPs and 8.2M indels based on deep (26.2X) sequencing of 2,999 Chinese individuals, and constructed NyuWa reference panel of 5,804 haplotypes and 19.3M variants, which is the first publicly available Chinese population specific reference panel with thousands of samples. There were 25.0M novel variants in NyuWa genome resource, and 3.2M specific variants in NyuWa reference panel. Compared with other panels, NyuWa reference panel reduces the Han Chinese imputation error rate by the range of 30% to 51%. Population structure and imputation simulation tests supported the applicability of one integrated reference panel for both northern and southern Chinese. In addition, a total of 22,504 loss-of-function variants in coding and noncoding genes were identified, including 11,493 novel variants. These results highlight the value of NyuWa genome resource to facilitate genetics research in Chinese and Asian populations.

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Whole-genome sequencing reveals new Alzheimer’s disease-associated rare variants in loci related to synaptic function and neuronal development

10.1101/2020.11.03.20225540 ◽

2020 ◽

Author(s):

Dmitry Prokopenko ◽

Sarah L. Morgan ◽

Kristina Mullin ◽

Oliver Hofmann ◽

Brad Chapman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Rare Variants ◽

Spatial Clustering ◽

Synaptic Function ◽

Genome Wide Association Studies ◽

Whole Genome ◽

Genome Wide

AbstractINTRODUCTIONGenome-wide association studies have led to numerous genetic loci associated with Alzheimer’s disease (AD). Whole-genome sequencing (WGS) now permit genome-wide analyses to identify rare variants contributing to AD risk.METHODSWe performed single-variant and spatial clustering-based testing on rare variants (minor allele frequency ≤1%) in a family-based WGS-based association study of 2,247 subjects from 605 multiplex AD families, followed by replication in 1,669 unrelated individuals.RESULTSWe identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, CLSTN2.DISCUSSIONDownstream analyses of these novel loci highlight synaptic function, in contrast to common AD-associated variants, which implicate innate immunity. These loci have not been previously associated with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of coding regions.

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Dynamic Scan Procedure for Detecting Rare-Variant Association Regions in Whole Genome Sequencing Studies

10.1101/552950 ◽

2019 ◽

Author(s):

Zilin Li ◽

Xihao Li ◽

Yaowu Liu ◽

Jincheng Shen ◽

Han Chen ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Rare Variant ◽

Type I Error ◽

Rare Variants ◽

Error Rates ◽

Type I ◽

Whole Genome ◽

Rare Variant Association ◽

Dynamic Scan

AbstractWhole genome sequencing (WGS) studies are being widely conducted to identify rare variants associated with human diseases and disease-related traits. Classical single-marker association analyses for rare variants have limited power, and variant-set based analyses are commonly used to analyze rare variants. However, existing variant-set based approaches need to pre-specify genetic regions for analysis, and hence are not directly applicable to WGS data due to the large number of intergenic and intron regions that consist of a massive number of non-coding variants. The commonly used sliding window method requires pre-specifying fixed window sizes, which are often unknown as a priori, are difficult to specify in practice and are subject to limitations given genetic association region sizes are likely to vary across the genome and phenotypes. We propose a computationally-efficient and dynamic scan statistic method (Scan the Genome (SCANG)) for analyzing WGS data that flexibly detects the sizes and the locations of rare-variants association regions without the need of specifying a prior fixed window size. The proposed method controls the genome-wise type I error rate and accounts for the linkage disequilibrium among genetic variants. It allows the detected rare variants association region sizes to vary across the genome. Through extensive simulated studies that consider a wide variety of scenarios, we show that SCANG substantially outperforms several alternative rare-variant association detection methods while controlling for the genome-wise type I error rates. We illustrate SCANG by analyzing the WGS lipids data from the Atherosclerosis Risk in Communities (ARIC) study.

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P4-097: RARE VARIANTS IN FAMILIAL LATE-ONSET ALZHEIMER'S DISEASE IDENTIFIED FROM LARGE SCALE WHOLE GENOME SEQUENCING

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.3757 ◽

2019 ◽

Vol 15 ◽

pp. P1312-P1312

Author(s):

Badri N. Vardarajan ◽

James Jaworski ◽

Gary W. Beecham ◽

Sandra Barral ◽

Dolly Reyes-Dumeyer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Large Scale ◽

Rare Variants ◽

Late Onset ◽

Whole Genome

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Identification of genetic risk factors for Alzheimer's disease in the Chinese population by whole-genome sequencing

10.14711/thesis-991012654968703412 ◽

2018 ◽

Author(s):

Xiaopu Zhou

Keyword(s):

Risk Factors ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genetic Risk ◽

Chinese Population ◽

Genetic Risk Factors ◽

Whole Genome

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Identification of a novel heterozygous SPTB mutation by whole genome sequencing in a Chinese patient with hereditary spherocytosis and atrial septal defect: a case report

BMC Pediatrics ◽

10.1186/s12887-021-02771-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhanhui Du ◽

Gang Luo ◽

Kuiliang Wang ◽

Zhen Bing ◽

Silin Pan

Keyword(s):

Atrial Septal Defect ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Chinese Population ◽

Septal Defect ◽

Hereditary Spherocytosis ◽

Valuable Insight ◽

Whole Genome ◽

Biochemical Tests ◽

Chinese Girl

Abstract Background Hereditary spherocytosis (HS) is a common inherited red blood cell membrane disorder characterized by an abnormal increase of spherocytes in peripheral blood. SPTB gene mutation is one of the most common causes of HS; however, few cases of HS resulting from SPTB mutation in the Chinese population have been reported so far. Case presentation A 3-year-old Chinese girl presented to Qingdao Women and Children’s Hospital, Qingdao University, with atrial septal defect (ASD). Meanwhile, she was clinically diagnosed with HS. Whole genome sequencing (WGS) was performed for the proband and her parents for genetic molecular analysis. A novel SPTB mutation (c.1756delG) was detected by WGS and confirmed by Sanger sequencing in the proband. This mutation results in a frameshift with a premature termination codon in exon 12, leading to a nonsense mutation (p.Ala586Profs*7). Her parents had no similar symptoms, and blood routine and serum biochemical tests showed no significant abnormalities. The patient’s mother did not know of any relatives with HS-like symptoms. Percutaneous transcatheter closure was successfully performed for treating the ASD. Conclusion In this study, we identified a novel SPTB frameshift mutation in a Chinese girl with HS. This finding would expand the spectrum of SPTB mutations, provide a valuable insight into the genotyping of HS in the Chinese population, and contribute to the clinical management and genetic counseling in HS.

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Rare and common variant discovery by whole-genome sequencing of 101 Thoroughbred racehorses

Scientific Reports ◽

10.1038/s41598-021-95669-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Teruaki Tozaki ◽

Aoi Ohnuma ◽

Mio Kikuchi ◽

Taichiro Ishige ◽

Hironaga Kakoi ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Rare Variants ◽

Industrial Applications ◽

Whole Genome ◽

X Chromosomes ◽

Variant Discovery ◽

Functional Variants ◽

Thoroughbred Racehorses ◽

Using Data

AbstractThe Thoroughbred breed was formed by crossing Oriental horse breeds and British native horses and is currently used in horseracing worldwide. In this study, we constructed a single-nucleotide variant (SNV) database using data from 101 Thoroughbred racehorses. Whole genome sequencing (WGS) revealed 11,570,312 and 602,756 SNVs in autosomal (1–31) and X chromosomes, respectively, yielding a total of 12,173,068 SNVs. About 6.9% of identified SNVs were rare variants observed only in one allele in 101 horses. The number of SNVs detected in individual horses ranged from 4.8 to 5.3 million. Individual horses had a maximum of 25,554 rare variants; several of these were functional variants, such as non-synonymous substitutions, start-gained, start-lost, stop-gained, and stop-lost variants. Therefore, these rare variants may affect differences in traits and phenotypes among individuals. When observing the distribution of rare variants among horses, one breeding stallion had a smaller number of rare variants compared to other horses, suggesting that the frequency of rare variants in the Japanese Thoroughbred population increases through breeding. In addition, our variant database may provide useful basic information for industrial applications, such as the detection of genetically modified racehorses in gene-doping control and pedigree-registration of racehorses using SNVs as markers.

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