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Background <p>Progranulin is a molecular modifier of Alzheimer’s disease (AD). However, its <i>cis</i>-regulatory region remains under-characterized. Association studies of genetic variants in this region with AD have obtained conflicting results across different human populations.</p> Methods <p>We define the <i>cis</i>-regulatory region of the progranulin gene (<i>GRN</i>). Querying the genetically admixed Alzheimer’s Disease Sequencing Project whole-genome sequencing dataset (<i>n</i> = 9,416 cases; 13,603 controls), we conduct ancestry-specific analyses of AD association with <i>GRN</i> genetic variants.</p> Results <p>We report predicted impacts of genetic variation on transcription factor binding for 150 unique transcription factors across the <i>GRN cis</i>-regulatory region. We identify 99 common variants (MAF &gt; 0.005) in one or more superpopulations (African, Admixed American, East Asian, European, and South Asian). The common <i>GRN</i> variant rs5848 is significantly associated with AD only in East Asian ancestry.</p> Conclusions <p>Ancestry-specific effects may contribute to discordant findings in the literature. European-centric results in AD might not be generalizable to other populations.</p>

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Progranulin genetic variant rs5848 displays ancestry-specific associations with Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月13日

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  • Benjamin E. Life,
  • Erick I. Navarro-Delgado,
  • Oriol Fornes,
  • Jan M. Friedman,
  • Wyeth W. Wasserman,
  • Keegan Korthauer,
  • Blair R. Leavitt

摘要

Background

Progranulin is a molecular modifier of Alzheimer’s disease (AD). However, its cis-regulatory region remains under-characterized. Association studies of genetic variants in this region with AD have obtained conflicting results across different human populations.

Methods

We define the cis-regulatory region of the progranulin gene (GRN). Querying the genetically admixed Alzheimer’s Disease Sequencing Project whole-genome sequencing dataset (n = 9,416 cases; 13,603 controls), we conduct ancestry-specific analyses of AD association with GRN genetic variants.

Results

We report predicted impacts of genetic variation on transcription factor binding for 150 unique transcription factors across the GRN cis-regulatory region. We identify 99 common variants (MAF > 0.005) in one or more superpopulations (African, Admixed American, East Asian, European, and South Asian). The common GRN variant rs5848 is significantly associated with AD only in East Asian ancestry.

Conclusions

Ancestry-specific effects may contribute to discordant findings in the literature. European-centric results in AD might not be generalizable to other populations.