RT Journal
A1 van Bree, Elisabeth J.
A1 Guimarães, Rita L.F.P.
A1 Lundberg, Mischa
A1 Blujdea, 
Elena R.
A1 Rosenkrantz, Jimi L.
A1 White, Fred T.G.
A1 Poppinga, Josse
A1 Ferrer-Raventós, 
Paula
A1 Schneider, Anne-Fleur E.
A1 Clayton, Isabella
A1 Haussler, David
A1 Reinders, Marcel J.T.
A1 Holstege, Henne
A1 Ewing, Adam D.
A1 Moses, Colette
A1 Jacobs, Frank M.J.
T1 A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
JF Genome Research 
JO Genome Research 
YR 2022 
FD April 01 
VO 32 
IS 4 
SP 656 
OP 670 
DO 10.1101/gr.275515.121 
UL http://genome.cshlp.org/content/32/4/656.abstract 
AB 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.