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<p>Rare coding alleles have crucial roles in the molecular diagnosis of genetic diseases. However, the systematic identification of these alleles has been challenging due to their scarcity in the general population. Here we discovered and characterized rare coding alleles contributing to genetic dyslipidemia, a principal risk for coronary artery disease (CAD), among 1,158,017 multi-ancestral individuals. Testing 2,997,401 rare coding variants, we identified 800 exome-wide significant associations (176 predicted loss of function (pLoF) and 624 missense variants). Associated alleles are enriched in functional variant classes, show significant additive and recessive associations, exhibit similar effects across populations and resolve pathogenicity for variants of unknown significance. Furthermore, we identified five lipid-associated genes associated with CAD. Among them, silencing <i>RORC</i> represents a potential therapeutic target for lowering low-density lipoprotein cholesterol. This study provides resources and insights for understanding causal mechanisms, quantifying the expressivity of rare coding alleles and identifying new drug targets for dyslipidemia across diverse populations.</p>

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Exome-wide association study of blood lipids in 1,158,017 individuals from diverse populations

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月25日

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  • Satoshi Koyama,
  • Zhi Yu,
  • Seung Hoan Choi,
  • Sean J. Jurgens,
  • Margaret Sunitha Selvaraj,
  • Derek Klarin,
  • Jennifer E. Huffman,
  • Shoa L. Clarke,
  • Selena K. Zhang,
  • Michael N. Trinh,
  • Akshaya Ravi,
  • Jacqueline S. Dron,
  • Catherine Spinks,
  • Ida Surakka,
  • Aarushi Bhatnagar,
  • Kim Lannery,
  • Whitney Hornsby,
  • Scott M. Damrauer,
  • Kyong-Mi Chang,
  • Julie A. Lynch,
  • Themistocles L. Assimes,
  • Philip S. Tsao,
  • Daniel J. Rader,
  • Kelly Cho,
  • Gina M. Peloso,
  • Patrick T. Ellinor,
  • Yan V. Sun,
  • Peter W. F. Wilson,
  • Pradeep Natarajan

摘要

Rare coding alleles have crucial roles in the molecular diagnosis of genetic diseases. However, the systematic identification of these alleles has been challenging due to their scarcity in the general population. Here we discovered and characterized rare coding alleles contributing to genetic dyslipidemia, a principal risk for coronary artery disease (CAD), among 1,158,017 multi-ancestral individuals. Testing 2,997,401 rare coding variants, we identified 800 exome-wide significant associations (176 predicted loss of function (pLoF) and 624 missense variants). Associated alleles are enriched in functional variant classes, show significant additive and recessive associations, exhibit similar effects across populations and resolve pathogenicity for variants of unknown significance. Furthermore, we identified five lipid-associated genes associated with CAD. Among them, silencing RORC represents a potential therapeutic target for lowering low-density lipoprotein cholesterol. This study provides resources and insights for understanding causal mechanisms, quantifying the expressivity of rare coding alleles and identifying new drug targets for dyslipidemia across diverse populations.