Integrating whole-genome sequencing with multi-omic data reveals the impact of structural variants on gene regulation in the human brain

Vialle, Ricardo Assunção; Lopes, Kátia de Paiva; Bennett, David A.; Crary, John F.; Raj, Towfique

doi:10.1038/s41593-022-01031-7

Cited by 47 publications

(43 citation statements)

References 94 publications

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“…We used the genotype and RNA-seq data in brain cortex tissue from seven cohorts, namely BrainGVEX, the Lieber Institute for Brain Development, the CommonMind Consortium and the CommonMind Consortium’s National Institute of Mental Health Human Brain Collection Core, Mount Sinai Brain Bank (including four cortex regions: BM10, BM22, BM36 and BM44), Mayo Clinic and ROSMAP. Data generation has been detailed elsewhere 43 , 44 , 73 . RNA-seq data from the Mount Sinai Brain Bank cohort were from four brain cortex regions: BM10 (Brodmann area 10; part of the frontopolar prefrontal cortex); BM22 (Brodmann area 22; part of the superior temporal gyrus); BM36 (Brodmann area 36; part of the fusiform gyrus); and BM44 (Brodmann area 44; opercular part of the inferior frontal gyrus).…”

Section: Methodsmentioning

confidence: 99%

Genetic control of RNA splicing and its distinct role in complex trait variation

Fang

et al. 2022

Nat Genet

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Most genetic variants identified from genome-wide association studies (GWAS) in humans are noncoding, indicating their role in gene regulation. Previous studies have shown considerable links of GWAS signals to expression quantitative trait loci (eQTLs) but the links to other genetic regulatory mechanisms, such as splicing QTLs (sQTLs), are underexplored. Here, we introduce an sQTL mapping method, testing for heterogeneity between isoform-eQTLeffects (THISTLE), with improved power over competing methods. Applying THISTLE together with a complementary sQTL mapping strategy to brain transcriptomic (n = 2,865) and genotype data, we identified 12,794 genes with cis-sQTLs at P < 5 × 10−8, approximately 61% of which were distinct from eQTLs. Integrating the sQTL data into GWAS for 12 brain-related complex traits (including diseases), we identified 244 genes associated with the traits through cis-sQTLs, approximately 61% of which could not be discovered using the corresponding eQTL data. Our study demonstrates the distinct role of most sQTLs in the genetic regulation of transcription and complex trait variation.

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Section: Methodsmentioning

confidence: 99%

Genetic control of RNA splicing and its distinct role in complex trait variation

Fang

et al. 2022

Nat Genet

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“…Currently, no large-scale association studies in ALS have been reported (yet) with long-read WGS. Studies have utilized long reads, however, to identify many structural variants in a small number of subjects [144], and been used to resolve complex regions that harbor known polymorphisms [145][146][147][148] or to validate structural variants that have been determined by other methods [149,150].…”

Section: Long-read Sequencing Applicationsmentioning

confidence: 99%

Advances in sequencing technologies for amyotrophic lateral sclerosis research

Udine

Jain

Blitterswijk

2023

Mol Neurodegeneration

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Amyotrophic lateral sclerosis (ALS) is caused by upper and lower motor neuron loss and has a fairly rapid disease progression, leading to fatality in an average of 2-5 years after symptom onset. Numerous genes have been implicated in this disease; however, many cases remain unexplained. Several technologies are being used to identify regions of interest and investigate candidate genes. Initial approaches to detect ALS genes include, among others, linkage analysis, Sanger sequencing, and genome-wide association studies. More recently, next-generation sequencing methods, such as whole-exome and whole-genome sequencing, have been introduced. While those methods have been particularly useful in discovering new ALS-linked genes, methodological advances are becoming increasingly important, especially given the complex genetics of ALS. Novel sequencing technologies, like long-read sequencing, are beginning to be used to uncover the contribution of repeat expansions and other types of structural variation, which may help explain missing heritability in ALS. In this review, we discuss how popular and/or upcoming methods are being used to discover ALS genes, highlighting emerging long-read sequencing platforms and their role in aiding our understanding of this challenging disease.

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“…These novel findings in genomic, transcriptomic, proteomics and epigenomic studies of the brain highlight the potential of stored brain tissue to advance our understanding of significant scientific and clinical questions (Allen et al, 2012;Colantuoni et al, 2011;Ertekin-Taner, 2010;Hollingworth et al, 2011; H. U. Klein et al, 2019;Lopes et al, 2022;Naj et al, 2011;Nativio et al, 2020;Panitch et al, 2021;Qi et al, 2022;Toker et al, 2018;Vialle et al, 2022;Xiong, Ge, & Ma, 2019;Zou et al, 2012). With the application of new technologies such as single-cell RNA sequencing, the application potential of human brain tissue stored in brain banks will be further enhanced.…”

Section: Discussionmentioning

confidence: 99%

“…Using 1,760 whole genomes from aged and AD individuals, 170,996 SVs were discovered. Quantitative trait locus (SV-xQTL) analyses revealed that more than 3,200 SVs were associated with at least one molecular phenotype in postmortem brain tissues, such as histone modifications, gene expression, splicing and protein abundance (Vialle et al, 2022).…”

Section: Brain Bank Advancing Neuropsychiatric Disease Studiesmentioning

confidence: 99%

Human Brain Banking as a Convergence Platform of Neuroscience and Neuropsychiatric Research

Liu

Yin²,

Cong³

et al. 2022

Human Brain

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Neuropsychiatric disorders affect hundreds of millions of people and their families worldwide. Many studies have used human postmortem brain samples to decipher the molecular framework of these diseases. These studies uncovered brain-specific genetic and epigenetic patterns using high-throughput sequencing techniques. Therefore, determining the best way to collect human postmortem brain samples, analysing such a large amount of sequencing data, and interpreting these results is critical to advancing the field of neuropsychiatric sciences. By collecting postmortem/biopsied neural tissues and information about the diseases and life of donors, human brain banks support the observation and research of human brain sciences. Furthermore, the construction of large-scale brain banks has promoted the exploration of human brain morphology and function, development and ageing, as well as the mechanism of many neuropsychiatric diseases, which progressively reveal the normal mechanism of human brain activities and lead the direction of the prevention and treatment of neurological diseases. This article introduces the significance of human brain tissue bank construction and the current situation of the human brain tissue bank worldwide, as well as an overview of neurology or neuroscience advanced by using human brain samples.

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Integrating whole-genome sequencing with multi-omic data reveals the impact of structural variants on gene regulation in the human brain

Cited by 47 publications

References 94 publications

Genetic control of RNA splicing and its distinct role in complex trait variation

Genetic control of RNA splicing and its distinct role in complex trait variation

Advances in sequencing technologies for amyotrophic lateral sclerosis research

Human Brain Banking as a Convergence Platform of Neuroscience and Neuropsychiatric Research

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