Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease

Studies of the genetics of Alzheimer’s disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, most of the disease heritability has yet to be uncovered, suggesting that there is substantial genetic risk conferred by other forms of genetic variation. There are over one million short tandem repeats (STRs) in the genome, and their link to AD risk has not been assessed. As pathogenic expansions of STR cause over 30 neurologic diseases, it is important to ascertain whether STRs may also be implicated in AD risk. Here, we genotype 312,731 polymorphic STR tracts genome-wide using PCR-free whole genome sequencing data from 2981 individuals (1489 AD case and 1492 control individuals). We implement an approach to identify STR expansions as STRs with tract lengths that are outliers from the population. We then test for differences in aggregate burden of expansions in case versus control individuals. AD patients harbor a 1.19-fold increase of STR expansions compared to healthy elderly controls (p = 8.27×10-3, two-sided Mann-Whitney test). Individuals carrying >30 STR expansions have a 3.69-fold higher odds of having AD and have more severe AD neuropathology. AD STR expansions are highly enriched within active promoters in post-mortem hippocampal brain tissues and particularly within SINE-VNTR-Alu (SVA) retrotransposons. Together, these results demonstrate that expanded STRs within active promoter regions of the genome associate with risk of AD.