Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease
Abstract 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 var...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56400-0 |
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| author | Michael H. Guo Wan-Ping Lee Badri Vardarajan Gerard D. Schellenberg Jennifer E. Phillips-Cremins |
| author_facet | Michael H. Guo Wan-Ping Lee Badri Vardarajan Gerard D. Schellenberg Jennifer E. Phillips-Cremins |
| author_sort | Michael H. Guo |
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| description | Abstract 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. |
| format | Article |
| id | doaj-art-b8646e2e78b24050b8fc0bb8f4a93663 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-b8646e2e78b24050b8fc0bb8f4a936632025-02-02T12:32:23ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-025-56400-0Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s diseaseMichael H. Guo0Wan-Ping Lee1Badri Vardarajan2Gerard D. Schellenberg3Jennifer E. Phillips-Cremins4Department of Genetics, Perelman School of Medicine, University of PennsylvaniaDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurology, College of Physicians and Surgeons, Columbia UniversityDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Genetics, Perelman School of Medicine, University of PennsylvaniaAbstract 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.https://doi.org/10.1038/s41467-025-56400-0 |
| spellingShingle | Michael H. Guo Wan-Ping Lee Badri Vardarajan Gerard D. Schellenberg Jennifer E. Phillips-Cremins Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease Nature Communications |
| title | Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease |
| title_full | Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease |
| title_fullStr | Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease |
| title_full_unstemmed | Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease |
| title_short | Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease |
| title_sort | polygenic burden of short tandem repeat expansions promotes risk for alzheimer s disease |
| url | https://doi.org/10.1038/s41467-025-56400-0 |
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