TU74. A CO-SEGREGATION ANALYSIS OF ULTRA-RARE VARIANTS IN FAMILIES MULTIPLY AFFECTED BY SCHIZOPHRENIA USING WHOLE GENOME SEQUENCING

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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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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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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Whole Genome Rare-Variant Association Study of HIV-1 Progression in a Southern African Population

10.1101/2020.12.16.20248307 ◽

2020 ◽

Author(s):

Prisca K. Thami ◽

Wonderful Choga ◽

Delesa D. Mulisa ◽

Collet Dandara ◽

Andrey K. Shevchenko ◽

...

Keyword(s):

Functional Analysis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Rare Variant ◽

Rare Variants ◽

Variant Calling ◽

Analysis Tool ◽

Whole Genome ◽

Host Genetics ◽

Hiv 1

ABSTRACTDespite the high burden of HIV-1 in Botswana, the population of Botswana is significantly underrepresentation in host genetics studies of HIV-1. Furthermore, the bulk of previous genomics studies evaluated common human genetic variations, however, there is increasing evidence of the influence of rare variants in the outcome of diseases which may be uncovered by comprehensive complete and deep genome sequencing. This research aimed to evaluate the role of rare-variants in susceptibility to HIV-1 and progression through whole genome sequencing. Whole genome sequences (WGS) of 265 HIV-1 positive and 125 were HIV-1 negative unrelated individuals from Botswana were mapped to the human reference genome GRCh38. Population joint variant calling was performed using Genome Analysis Tool Kit (GATK) and BCFTools. Cumulative effects of rare variant sets on susceptibility to HIV-1 and progression (CD4+ T-cell decline) were determined with optimized Sequence Kernel Association Test (SKAT-O). In silico functional analysis of the prioritized variants was performed through gene-set enrichment using databases in GeneMANIA and Enrichr. Novel rare-variants within the ANKRD39 (8.48 × 10−8), LOC105378523 (7.45 × 10−7) and GTF3C3 (1.36 × 10−6) genes were significantly associated with HIV-1 progression. Functional analysis revealed that these genes are involved in viral translation and transcription. These findings highlight the significance of whole genome sequencing in pinpointing rare-variants of clinical relevance. The research contributes towards a deeper understanding of the host genetics HIV-1 and offers promise of population specific interventions against HIV-1.

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Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases

npj Genomic Medicine ◽

10.1038/s41525-021-00261-1 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Zeinab Fadaie ◽

Laura Whelan ◽

Tamar Ben-Yosef ◽

Adrian Dockery ◽

Zelia Corradi ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Rare Variants ◽

Genetic Diagnosis ◽

Whole Genome ◽

Retinal Diseases ◽

Structural Variants ◽

Pathogenic Variants ◽

Coding Variants

AbstractInherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was not found using whole-exome sequencing or targeted capture sequencing. We performed whole-genome sequencing (WGS) to identify causative variants in 100 unresolved cases. After initial prioritization, we performed an in-depth interrogation of all noncoding and structural variants in genes when one candidate variant was detected. In addition, functional analysis of putative splice-altering variants was performed using in vitro splice assays. We identified the genetic cause of the disease in 24 patients. Causative coding variants were observed in genes such as ATXN7, CEP78, EYS, FAM161A, and HGSNAT. Gene disrupting structural variants were also detected in ATXN7, PRPF31, and RPGRIP1. In 14 monoallelic cases, we prioritized candidate noncanonical splice sites or deep-intronic variants that were predicted to disrupt the splicing process based on in silico analyses. Of these, seven cases were resolved as they carried pathogenic splice defects. WGS is a powerful tool to identify causative variants residing outside coding regions or heterozygous structural variants. This approach was most efficient in cases with a distinct clinical diagnosis. In addition, in vitro splice assays provide important evidence of the pathogenicity of rare variants.

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Whole Genome Sequencing in Psychiatric Disorders: the WGSPD Consortium

10.1101/160499 ◽

2017 ◽

Author(s):

Stephan J. Sanders ◽

Benjamin M. Neale ◽

Hailiang Huang ◽

Donna M. Werling ◽

Joon-Yong An ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Psychiatric Disorders ◽

Genome Sequencing ◽

Rare Variants ◽

Autism Spectrum ◽

Whole Genome ◽

Complex Disorders ◽

Computationally Intensive ◽

Insight Into

AbstractAs technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls.

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