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Distinct UNC13A Haplotype Blocks Define Disease Severity and Survival in Chinese Amyotrophic Lateral Sclerosis.

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Title: Distinct UNC13A Haplotype Blocks Define Disease Severity and Survival in Chinese Amyotrophic Lateral Sclerosis.
Authors: He, Cailin (AUTHOR), Liu, Ziqin (AUTHOR), Yuan, Yanchun (AUTHOR), Tang, Linxin (AUTHOR), Wang, Meirong (AUTHOR), Li, Yongchao (AUTHOR), Zhao, Qianqian (AUTHOR), Weng, Ling (AUTHOR), Du, Juan (AUTHOR), Wu, Hanjun (AUTHOR), Hu, Fan (AUTHOR), Xu, Renshi (AUTHOR), Guo, Jifeng (AUTHOR), Shen, Lu (AUTHOR), Tang, Beisha (AUTHOR), Wang, Junling (AUTHOR)
Source: European Journal of Neurology. Jun2026, Vol. 33 Issue 6, p1-13. 13p.
Subjects: Haplotypes, Disease progression, Survival analysis (Biometry), Amyotrophic lateral sclerosis, Prognosis, Genes, Chinese people, Genetic variation
Abstract: Background: UNC13A is a genetic modifier of amyotrophic lateral sclerosis (ALS) in European populations, but its role in Chinese patients remains incompletely characterized. We investigated the spectrum of UNC13A variation and its impact on disease risk and progression in a Chinese ALS cohort. Methods: We performed an integrated genetic analysis of 1,533 Chinese ALS patients and 1,405 controls, including rare variant burden testing, genome‐wide survival analysis, haplotype mapping, and conditional analyses. An integrated clinical‐genetic prognostic score was developed and validated. Results: Rare deleterious UNC13A variants were not associated with ALS risk. We identified two independent haplotype blocks with distinct clinical impacts. Block 1 (tagged by rs75421007) was associated with reduced baseline muscle strength (p = 0.030), while Block 2 (tagged by rs78549703), a brain‐specific splicing QTL, was the primary driver of survival heterogeneity. The European variant rs12608932 showed a survival association in single‐marker analysis (p = 0.024), but conditional analyses revealed its effect was not independent of Block 2. An integrated prognostic score combining clinical factors and Block 2 haplotype stratified patients into low‐, intermediate‐, and high‐risk groups (median survival: 52.6, 37.1, and 32.0 months; p < 0.001), with decision curve analysis confirming clinical utility. Conclusions: This study delineates UNC13A genetic architecture in Chinese ALS, identifying two independent haplotype blocks that differentially influence disease severity and survival. The Block 2 haplotype, which includes a brain sQTL, is a major determinant of survival heterogeneity and may inform patient stratification in future studies. [ABSTRACT FROM AUTHOR]
Copyright of European Journal of Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Distinct UNC13A Haplotype Blocks Define Disease Severity and Survival in Chinese Amyotrophic Lateral Sclerosis.
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  Data: &lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22He%2C+Cailin%22&quot;&gt;He, Cailin&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Liu%2C+Ziqin%22&quot;&gt;Liu, Ziqin&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Yuan%2C+Yanchun%22&quot;&gt;Yuan, Yanchun&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Tang%2C+Linxin%22&quot;&gt;Tang, Linxin&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Wang%2C+Meirong%22&quot;&gt;Wang, Meirong&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Li%2C+Yongchao%22&quot;&gt;Li, Yongchao&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Zhao%2C+Qianqian%22&quot;&gt;Zhao, Qianqian&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Weng%2C+Ling%22&quot;&gt;Weng, Ling&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Du%2C+Juan%22&quot;&gt;Du, Juan&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Wu%2C+Hanjun%22&quot;&gt;Wu, Hanjun&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Hu%2C+Fan%22&quot;&gt;Hu, Fan&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Xu%2C+Renshi%22&quot;&gt;Xu, Renshi&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Guo%2C+Jifeng%22&quot;&gt;Guo, Jifeng&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Shen%2C+Lu%22&quot;&gt;Shen, Lu&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Tang%2C+Beisha%22&quot;&gt;Tang, Beisha&lt;/searchLink&gt; (AUTHOR)&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Wang%2C+Junling%22&quot;&gt;Wang, Junling&lt;/searchLink&gt; (AUTHOR)
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  Data: &lt;searchLink fieldCode=&quot;JN&quot; term=&quot;%22European+Journal+of+Neurology%22&quot;&gt;European Journal of Neurology&lt;/searchLink&gt;. Jun2026, Vol. 33 Issue 6, p1-13. 13p.
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  Data: &lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Haplotypes%22&quot;&gt;Haplotypes&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Disease+progression%22&quot;&gt;Disease progression&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Survival+analysis+%28Biometry%29%22&quot;&gt;Survival analysis (Biometry)&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Amyotrophic+lateral+sclerosis%22&quot;&gt;Amyotrophic lateral sclerosis&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Prognosis%22&quot;&gt;Prognosis&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Genes%22&quot;&gt;Genes&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Chinese+people%22&quot;&gt;Chinese people&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;DE&quot; term=&quot;%22Genetic+variation%22&quot;&gt;Genetic variation&lt;/searchLink&gt;
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background: UNC13A is a genetic modifier of amyotrophic lateral sclerosis (ALS) in European populations, but its role in Chinese patients remains incompletely characterized. We investigated the spectrum of UNC13A variation and its impact on disease risk and progression in a Chinese ALS cohort. Methods: We performed an integrated genetic analysis of 1,533 Chinese ALS patients and 1,405 controls, including rare variant burden testing, genome‐wide survival analysis, haplotype mapping, and conditional analyses. An integrated clinical‐genetic prognostic score was developed and validated. Results: Rare deleterious UNC13A variants were not associated with ALS risk. We identified two independent haplotype blocks with distinct clinical impacts. Block 1 (tagged by rs75421007) was associated with reduced baseline muscle strength (p = 0.030), while Block 2 (tagged by rs78549703), a brain‐specific splicing QTL, was the primary driver of survival heterogeneity. The European variant rs12608932 showed a survival association in single‐marker analysis (p = 0.024), but conditional analyses revealed its effect was not independent of Block 2. An integrated prognostic score combining clinical factors and Block 2 haplotype stratified patients into low‐, intermediate‐, and high‐risk groups (median survival: 52.6, 37.1, and 32.0 months; p &lt; 0.001), with decision curve analysis confirming clinical utility. Conclusions: This study delineates UNC13A genetic architecture in Chinese ALS, identifying two independent haplotype blocks that differentially influence disease severity and survival. The Block 2 haplotype, which includes a brain sQTL, is a major determinant of survival heterogeneity and may inform patient stratification in future studies. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: &lt;i&gt;Copyright of European Journal of Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder&#39;s express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.&lt;/i&gt; (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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    Identifiers:
      – Type: doi
        Value: 10.1111/ene.70653
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 13
        StartPage: 1
    Subjects:
      – SubjectFull: Haplotypes
        Type: general
      – SubjectFull: Disease progression
        Type: general
      – SubjectFull: Survival analysis (Biometry)
        Type: general
      – SubjectFull: Amyotrophic lateral sclerosis
        Type: general
      – SubjectFull: Prognosis
        Type: general
      – SubjectFull: Genes
        Type: general
      – SubjectFull: Chinese people
        Type: general
      – SubjectFull: Genetic variation
        Type: general
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      – TitleFull: Distinct UNC13A Haplotype Blocks Define Disease Severity and Survival in Chinese Amyotrophic Lateral Sclerosis.
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            – D: 01
              M: 06
              Text: Jun2026
              Type: published
              Y: 2026
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