ScholarLink (思领科)
错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2024年6月29日

查看全文
  • Tess D. Pottinger,
  • Joshua E. Motelow,
  • Gundula Povysil,
  • Cristiane A. Martins Moreno,
  • Zhong Ren,
  • Hemali Phatnani,
  • Matthew B. Harms,
  • Justin Kwan,
  • Dhruv Sareen,
  • Han-I. Wang,
  • James R. Broach,
  • Zachary Simmons,
  • Ximena Arcila-Londono,
  • Steve Parrott,
  • Edward B. Lee,
  • Steve Parrott,
  • Vivianna M. Van Deerlin,
  • Ernest Fraenkel,
  • Lyle W. Ostrow,
  • Frank Baas,
  • Noah Zaitlen,
  • James D. Berry,
  • Andrea Malaspina,
  • Pietro Fratta,
  • Gregory A. Cox,
  • Leslie M. Thompson,
  • Steve Finkbeiner,
  • Efthimios Dardiotis,
  • Timothy M. Miller,
  • Siddharthan Chandran,
  • Steve Parrott,
  • Suvankar Pal,
  • Eran Hornstein,
  • Daniel J. MacGowan,
  • Terry Heiman-Patterson,
  • Molly G. Hammell,
  • Nikolaos A. Patsopoulos,
  • Joshua Dubnau,
  • Avindra Nath,
  • Timothy J. Aitman,
  • Javier Santoyo-Lopez,
  • Nicola Williams,
  • Jonathan Berg,
  • Ruth McGowan,
  • Zosia Miedzybrodzka,
  • Mary Porteous,
  • Edward Tobias,
  • Hiroshi Mitsumoto,
  • Pam Factor-Litvak,
  • Regina Santella,
  • Howard Andrews,
  • Daragh Heitzman,
  • Richard S. Bedlack,
  • Jonathan S. Katz,
  • Robert Miller,
  • Steve Parrott,
  • Dallas Forshew,
  • Richard J. Barohn,
  • Eric J. Sorenson,
  • Bjorn E. Oskarsson,
  • Edward J. Kasarskis,
  • Steve Parrott,
  • Catherine Lomen-Hoerth,
  • Jennifer Murphy,
  • Yvonne D. Rollins,
  • Tahseen Mozaffar,
  • J. Americo M. Fernandes,
  • Andrea J. Swenson,
  • Sharon P. Nations,
  • Jeremy M. Shefner,
  • Jinsy A. Andrews,
  • Agnes Koczon-Jaremko,
  • Peter L. Nagy,
  • Pam Factor-Litvak,
  • Rejina Santella,
  • Howard Andrews,
  • Raymond Goetz,
  • Chris Gennings,
  • Jennifer Murphy,
  • Mary Kay Floeter,
  • Richard J. Barohn,
  • Sharon Nations,
  • Christen Shoesmith,
  • Edward Kasarskis,
  • Matthew B. Harms,
  • Stanley Appel,
  • Robert Baloh,
  • Richard Bedlack,
  • Siddharthan Chandran,
  • Laura Foster,
  • Stephen Goutman,
  • Ericka Greene,
  • Chafic Karam,
  • David Lacomis,
  • George Manousakis,
  • Timothy Miller,
  • Suvankar Pals,
  • Dhruv Sareen,
  • Alex Sherman,
  • Zachary Simmons,
  • Leo Wang,
  • George Manousakis,
  • David B. Goldstein,
  • Matthew B. Harms

摘要

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.

Methods

Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.

Results

A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10–39; OR = 4.73, p = 2 × 10–10; OR = 2.3, p = 7.49 × 10–9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10–7), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10–16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10–6).

Conclusions

In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.