■染色体17q21.31区域,包含定义H1和H2单倍型的900Kb反转,代表进行性核上性麻痹(PSP)中最强的遗传风险位点。除了H1和H2外,17q21.31的各种结构形式,其特征在于α的拷贝数,β,和γ复制,已被确认。然而,在大型队列研究中从未评估过每种结构形式对PSP风险的具体影响.
■为了评估由α的拷贝数定义的17q.21.31的不同结构形式的关联,β,和γ复制,具有PSP和MAPT亚单倍型的风险。
■利用1,684(1,386尸检确认)PSP个体和2,392名对照受试者的全基因组测序数据,进行了病例对照研究,以调查α的拷贝数的关联,β,和具有PSP风险的17q21.31的γ重复和结构形式。所有研究对象选自阿尔茨海默病测序项目(ADSP)伞NG00067。V7.数据在2022年3月至2023年11月之间进行了分析。
■主要结果是95%CI的PSP风险(比值比[OR])。PSP的风险通过逻辑回归模型进行评估。
■α和β的拷贝数仅由于它们与H1和H2的相关性而与PSP的风险相关,而γ的拷贝数与PSP的风险增加独立相关。当调节H1和H2时,γ的每个额外重复与PSP风险增加1.10倍(95%CI,1.04-1.17;P=0.0018)相关。对于H1单倍型,额外的γ重复显示PSP的优势比更高:优势比从H1β1γ1的1.21(95CI1.10-1.33,P=5.47×10-5)增加到1.29(95CI1.16-1.43,P=1.35×10-6)对于H1β1γ2,1.45(95CI1.27-1.65,P=3.94×10-8)对于H1β3,对于H1β2此外,H1β1γ3与H1c处于连锁不平衡状态(R2=0.31),与PSP风险增加相关的广泛认可的MAPT亚单倍型。与PSP风险增加相关的MAPT亚单倍型的比例(即,H1c,H1d,H1g,H1o,和H1h)从H1β1γ1中的34%增加到H1β1γ4中的77%。
■这项研究表明,γ的拷贝数与H1和H2独立地与PSP的风险有关。具有更多γ重复的H1单倍型显示更高的PSP优势比,并且与具有增加的PSP风险的MAPT亚单倍型相关。这些发现扩大了我们对17q21.31的复杂结构如何影响PSP风险的理解。
■问题:进行大量拷贝数变化(即,α,β,andγ)inside17q21.31contributetotheriskofprogressivelypupanucarparsysy(PSP)independentlyfromtheH1andH2haplotype?Dostructuralformsof17q21.31,characterizedbycombinationsofα,β,和γ,presentdivergentrisktothedevelopmentofPSP?Arestructuralformsof17q21.31associatedwithMAPTsub-suplotypes,例如H1c?研究结果:在本病例对照研究中,1,684名PSP患者和2,392名对照受试者,γ重复拷贝数与疾病风险独立相关.与H1β1γ1相比,具有更多γ重复的H1单倍型(H1β1γ2,H1β1γ3和H1β1γ4)显示出更高的PSP优势比。值得注意的是,观察到H1β1γ3与H1c处于连锁不平衡状态,与PSP相关的广泛认可的MAPT亚单倍型。意义:H1和H2单倍型与PSP之间的关联涉及多个影响因素,包括γ复制的拷贝数。
UNASSIGNED: 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 α, β, and γ 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.
UNASSIGNED: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, β, and γ duplications, with the risk of PSP and MAPT sub-haplotypes.
UNASSIGNED: 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 α, β, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer\'s Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023.
UNASSIGNED: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models.
UNASSIGNED: The copy numbers of α and β were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1β1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1β1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1β1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1β1γ4. Moreover, H1β1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1β1γ1 to 77% in H1β1γ4.
UNASSIGNED: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT 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.