| Title: | Whole exome sequencing analyses identified novel genes for Alzheimer's disease and related dementia |
| Journal: | Alzheimer's & Dementia |
| Published: | 11 Aug 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39129223/ |
| DOI: | https://doi.org/10.1002/alz.14181 |
Publication 12994
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Abstract
INTRODUCTION: The heritability of Alzheimer's disease (AD) is estimated to be 58%-79%. However, known genes can only partially explain the heritability.</p>
METHODS: Here, we conducted gene-based exome-wide association study (ExWAS) of rare variants and single-variant ExWAS of common variants, utilizing data of 54,569 clinically diagnosed/proxy AD and related dementia (ADRD) and 295,421 controls from the UK Biobank.</p>
RESULTS: Gene-based ExWAS identified 11 genes predicting a higher ADRD risk, including five novel ones, namely FRMD8, DDX1, DNMT3L, MORC1, and TGM2, along with six previously reported ones, SORL1, GRN, PSEN1, ABCA7, GBA, and ADAM10. Single-variant ExWAS identified two ADRD-associated novel genes, SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-β process pathways, microglia, and brain regions like hippocampus. The druggability evidence suggests that DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets.</p>
DISCUSSION: Our study contributes to the current body of evidence on the genetic etiology of ADRD.</p>
HIGHLIGHTS: Gene-based analyses of rare variants identified five novel genes for Alzheimer's disease and related dementia (ADRD), including FRMD8, DDX1, DNMT3L, MORC1, and TGM2. Single-variant analyses of common variants identified two novel genes for ADRD, including SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-β process pathways, microglia, and brain regions like hippocampus. DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets.</p>
12 Authors
- Ya-Ru Zhang
- Bang-Sheng Wu
- Shi-Dong Chen
- Liu Yang
- Yue-Ting Deng
- Yu Guo
- Xin-Rui Wu
- Wei-Shi Liu
- Ju-Jiao Kang
- Jian-Feng Feng
- Wei Cheng
- Jin-Tai Yu
1 Application
| Application ID | Title |
|---|---|
| 19542 | Identifying multi-level biomarkers and disease mechanisms for major mental disorders |
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