Whole-genome Sequence Analysis Revealed Novel Subjective Cognitive Decline-associated Genes in 10,763 Chinese
Mengying Wang, Liyang Sun, Xin Xu, Ruoqi Dai, Qilong Tan, Yun Zhu, Andi Xu, Weifang Zheng et al.. Genomics, proteomics & bioinformatics, 2025-10-28
Topic: Genetics and APOE
Subjective cognitive decline (SCD) is widely regarded as a potential preclinical stage of Alzheimer's disease (AD), yet its genetic basis remains poorly understood. To address this gap, we investigated genetic biomarkers associated with SCD using whole-genome sequencing (WGS) in 10,763 Chinese participants from the Healthy Zhejiang One Million People Cohort (HOPE Cohort). The discovery stage included 9284 samples, with 1479 samples used for validation. Using a two-stage design, we systematically investigated both common and rare variants associated with SCD. In rare variant analyses, we identified and replicated an association between the upstream region of SEPHS2 and SCD. SEPHS2 is involved in selenophosphate synthesis, and a Mendelian randomization analysis reveals that its expression levels in both blood and brain cerebellum are associated with AD. Additionally, we identified CLVS2, which encodes a protein primarily expressed in neuronal cells, as a potential regulator for SCD based on missense rare variants. Multi-omics evidence suggests that both SEPHS2 and CLVS2 may play roles in neurodegenerative diseases. For common variants, we validated 8 known loci related to cognitive decline, 3 of which originated from the only existing SCD genetic study conducted under a migraine background. Overall, our WGS-based study fills the gap in SCD research by providing vital genetic evidence from an East Asian population and offers insights into the pathogenic mechanisms of SCD.
Key findings
- To address this gap, we investigated genetic biomarkers associated with SCD using whole-genome sequencing (WGS) in 10,763 Chinese participants from the Healthy Zhejiang One Million People Cohort (HOPE Cohort).
- Using a two-stage design, we systematically investigated both common and rare variants associated with SCD.
- SEPHS2 is involved in selenophosphate synthesis, and a Mendelian randomization analysis reveals that its expression levels in both blood and brain cerebellum are associated with AD.
- Multi-omics evidence suggests that both SEPHS2 and CLVS2 may play roles in neurodegenerative diseases.
- Overall, our WGS-based study fills the gap in SCD research by providing vital genetic evidence from an East Asian population and offers insights into the pathogenic mechanisms of SCD.
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Study details
- Participants9,284
- Evidence strengthModerate
How this study scored 57/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 32 of the 56 points we could judge it on, which is 57 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Genomics, proteomics & bioinformatics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 3 / 4 | 9,284 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40728933) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 32 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 32 of the 56 points we could judge it on is 57 out of 100. |
| Total | 57 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Wang, M., Sun, L., Xu, X., Dai, R., Tan, Q., Zhu, Y., et al. (2025). Whole-genome Sequence Analysis Revealed Novel Subjective Cognitive Decline-associated Genes in 10,763 Chinese. Genomics, proteomics & bioinformatics. https://doi.org/10.1093/gpbjnl/qzaf063
Vancouver
Wang M, Sun L, Xu X, Dai R, Tan Q, Zhu Y, et al. Whole-genome Sequence Analysis Revealed Novel Subjective Cognitive Decline-associated Genes in 10,763 Chinese. Genomics, proteomics & bioinformatics. 2025. doi:10.1093/gpbjnl/qzaf063. PMID: 40728933.
BibTeX
@article{wang2025-40728933,
author = {Wang, Mengying and Sun, Liyang and Xu, Xin and Dai, Ruoqi and Tan, Qilong and Zhu, Yun and Xu, Andi and Zheng, Weifang and others},
title = {{Whole-genome Sequence Analysis Revealed Novel Subjective Cognitive Decline-associated Genes in 10,763 Chinese}},
journal = {Genomics, proteomics \& bioinformatics},
year = {2025},
doi = {10.1093/gpbjnl/qzaf063},
pmid = {40728933},
url = {https://doi.org/10.1093/gpbjnl/qzaf063}
}
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