A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci

被引：14

作者：

van Bree, Elisabeth J. ^{[1
]}

Guimaraes, Rita L. F. P. ^{[1
,2
,3
]}

Lundberg, Mischa ^{[4
]}

Blujdea, Elena R. ^{[1
]}

Rosenkrantz, Jimi L. ^{[1
]}

White, Fred T. G. ^{[1
]}

Poppinga, Josse ^{[1
]}

Ferrer-Raventos, Paula ^{[1
]}

Schneider, Anne-Fleur E. ^{[1
]}

Clayton, Isabella ^{[1
]}

Haussler, David ^{[5
]}

Reinders, Marcel J. T. ^{[6
]}

Holstege, Henne ^{[2
,3
,6
,7
]}

Ewing, Adam D. ^{[4
]}

Moses, Colette ^{[1
]}

Jacobs, Frank M. J. ^{[1
,7
]}

机构：

[1] Univ Amsterdam, Swammerdam Inst Life Sci, Evolutionary Neurogen, NL-1098 XH Amsterdam, Netherlands

[2] Vrije Univ Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam Neurosci,Genom Neurodegenerat Dis & Agi, NL-1081 HV Amsterdam, Netherlands

[3] Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam UMC,Amsterdam Neurosci, NL-1081 HV Amsterdam, Netherlands

[4] Univ Queensland, Mater Res Inst, Woolloongabba, Qld 4102, Australia

[5] UC Santa Cruz, Howard Hughes Med Inst, Genom Inst, Santa Cruz, CA 95064 USA

[6] Delft Univ Technol, Delft Bioinformat Lab, NL-2628 XE Delft, Netherlands

[7] Univ Amsterdam, Amsterdam Neurosci, Complex Trait Genet, Amsterdam, Netherlands

来源：

GENOME RESEARCH | 2022年 / 32卷 / 04期

基金：

欧洲研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; AMYOTROPHIC-LATERAL-SCLEROSIS; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; FUS GENE; RETROTRANSPOSONS; METAANALYSIS; EXPRESSION; IDENTIFICATION; VARIANTS;

D O I：

10.1101/gr.275515.121

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SINE-VNTR-Alu (SVA) elements, a class of great ape-specific transposable elements with gene-regulatory roles, which represents a major source of structural variability in the human population. We highlight the presence of structurally variable SVAs (SV-SVAs) in neurological disease-associated loci, and we further associate SV-SVAs to disease-associated SNPs and differential gene expression using luciferase assays and expression quantitative trait loci data. Finally, we genetically deleted SV-SVAs in the BIN1 and CD2AP Alzheimer's disease-associated risk loci and in the BCKDK Parkinson's disease-associated risk locus and assessed multiple aspects of their gene-regulatory influence in a human neuronal context. Together, this study reveals a novel layer of genetic variation in transposable elements that may contribute to identification of the structural variants that are the actual drivers of disease associations of GWAS loci.

引用

页码：656 / 670

页数：15