The impact of genomic structural variation on the transcriptome, chromatin, and proteome in the human brain

ABSTRACT Structural variants (SVs), defined as any genomic rearrangements of 50 or more bp, are an important source of genetic diversity and have been linked to many diseases. However, their contribution to molecular traits in the brain and impact on neurodegenerative diseases remains unknown. Here, we report 170,996 SVs which were constructed using 1,760 short-read whole genomes from aging and Alzheimer’s disease subjects. We quantified the impact of cis -acting SVs on several molecular traits including histone modification, gene expression, mRNA splicing, and protein abundance in post-mortem brain tissues. More than 3,800 genes were associated with at least one molecular phenotype, and 712 (18%) with more than one phenotype, with a significant positive correlation in the direction of effect between RNA, histone peaks, and protein levels. SV associations with RNA and protein levels shared the same direction of effect in more than 87% of SV-gene pairs. We found reproducibility of SV-eQTLs across three groups of samples and multiple brain regions ranging from 81 to 98%, including the innate immune system related genes ERAP2 and GBP3 . Additionally, associations of SVs with progressive supranuclear palsy, an amyloid-independent primary tauopathy, identified previously known and novel SVs at the 17q.21.31 MAPT locus and several other novel suggestive associations. Our study provides a comprehensive view of the mechanisms linking structural variation to gene regulation and provides a valuable resource for understanding the functional impact of SVs in the aged human brain.