{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:37:20Z","timestamp":1768567040480,"version":"3.49.0"},"posted":{"date-parts":[[2024,2,27]]},"group-title":"Neurology","reference-count":31,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,2,28]]},"abstract":"Abstract<\/jats:title>\n \n Importance<\/jats:title>\n The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of \u03b1, \u03b2, and \u03b3 duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of \u03b1, \u03b2, and \u03b3 duplications, with the risk of PSP and\n MAPT<\/jats:italic>\n sub-haplotypes.\n <\/jats:p>\n <\/jats:sec>\n \n Design, setting, and participants<\/jats:title>\n Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of \u03b1, \u03b2, and \u03b3 duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer\u2019s Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023.<\/jats:p>\n <\/jats:sec>\n \n Main outcomes and measures<\/jats:title>\n The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The copy numbers of \u03b1 and \u03b2 were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of \u03b3 was independently associated with the increased risk of PSP. Each additional duplication of \u03b3 was associated with 1.10 (95% CI, 1.04-1.17;\n P<\/jats:italic>\n = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition \u03b3 duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33,\n P<\/jats:italic>\n = 5.47 \u00d7 10\n -5<\/jats:sup>\n ) for H1\u03b21\u03b31 to 1.29 (95%CI 1.16-1.43,\n P<\/jats:italic>\n = 1.35 \u00d7 10\n -6<\/jats:sup>\n ) for H1\u03b21\u03b32, 1.45 (95%CI 1.27-1.65,\n P<\/jats:italic>\n = 3.94 \u00d7 10\n -8<\/jats:sup>\n ) for H1\u03b21\u03b33, and 1.57 (95%CI 1.10-2.26,\n P<\/jats:italic>\n = 1.35 \u00d7 10\n -2<\/jats:sup>\n ) for H1\u03b21\u03b34. Moreover, H1\u03b21\u03b33 is in linkage disequilibrium with H1c (R\n 2<\/jats:sup>\n = 0.31), a widely recognized\n MAPT<\/jats:italic>\n sub-haplotype associated with increased risk of PSP. The proportion of\n MAPT<\/jats:italic>\n sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1\u03b21\u03b31 to 77% in H1\u03b21\u03b34.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and relevance<\/jats:title>\n \n This study revealed that the copy number of \u03b3 was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more \u03b3 duplications showed a higher odds ratio for PSP and were associated with\n MAPT<\/jats:italic>\n sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.\n <\/jats:p>\n <\/jats:sec>\n \n Key Points<\/jats:title>\n \n Question<\/jats:title>\n \n Do large copy number variations (i.e., \u03b1, \u03b2, and \u03b3) inside 17q21.31 contribute to the risk of progressive supranuclear palsy (PSP) independently from the H1 and H2 haplotypes? Do structural forms of 17q21.31, characterized by combinations of \u03b1, \u03b2, and \u03b3, present divergent risk to the development of PSP? Are structural forms of 17q21.31 associated with\n MAPT<\/jats:italic>\n sub-haplotypes, such as H1c?\n <\/jats:p>\n <\/jats:sec>\n \n Findings<\/jats:title>\n \n In this case-control study of 1,684 individuals with PSP and 2,392 control subjects, the copy number of \u03b3 duplication was independently associated with the risk of the disease. H1 haplotypes with more \u03b3 duplications (H1\u03b21\u03b32, H1\u03b21\u03b33, and H1\u03b21\u03b34) displayed a higher odds ratio for PSP when compared to H1\u03b21\u03b31. Notably, H1\u03b21\u03b33 was observed to be in linkage disequilibrium with H1c, a widely recognized\n MAPT<\/jats:italic>\n sub-haplotype associated with PSP.\n <\/jats:p>\n <\/jats:sec>\n \n Meaning<\/jats:title>\n The association between the H1 and H2 haplotypes and PSP involves multiple contributing factors, including the copy number of \u03b3 duplication.<\/jats:p>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.1101\/2024.02.26.24303379","type":"posted-content","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T16:15:16Z","timestamp":1709050516000},"source":"Crossref","is-referenced-by-count":0,"title":["Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and\n MAPT<\/i>\n 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