Topic: Brain imaging, connectivity and assessment
Chronic pain and cognitive impairment are rising ageing-related burdens. Observational links between multisite chronic pain (MCP) and cognitive decline are confounded by reverse causation and comorbidity. We used bidirectional two-sample MR to assess the association of genetically predicted MCP with cognitive outcomes. MCP instruments (51 SNPs; P < 5×10⁻⁸) came from a UK Biobank GWAS (n = 387,649). Outcomes were cognitive performance (UKB-derived, n = 257,841), Alzheimer’s disease (IGAP ieu-a-297, n = 54,162) and all-cause dementia (FinnGen, n = 216,771). Genetically predicted MCP was associated with lower cognitive performance (IVW β=−0.361, 95% CI − 0.424 to − 0.299, p = 3.65×10⁻³⁰) with high heterogeneity (I²≈83.5%) and no directional pleiotropy. The Steiger test was non-significant (p = 0.23) and reverse MR significant (β=−0.171, p = 8.85×10⁻⁵⁸), so direction is uncertain. A non-UKB overlap-robustness re-interpretation (IGAP AD: β = 0.466, p = 0.008) corroborated the association independently of UK Biobank sample overlap. No mediator was significant. Genetic evidence is compatible with an MCP–lower-cognition association, but the direction is unresolved and the cognitive result is limited by UKB sample overlap. PREPRINT · VERSION 1 · NOT PEER-REVIEWED Posted on Research Square — a DOI will be assigned on posting. Preprint note. This is a preprint of a manuscript that has not undergone peer review; it is posted to solicit feedback. The China Health and Retirement Longitudinal Study (CHARLS) longitudinal validation component is ongoing and is marked [PENDING DATA] throughout: those sections describe planned analyses, not results. A revised version (version 2) will be posted when CHARLS data access is granted and incorporated, after which the manuscript will be submitted to a peer-reviewed journal (Scientific Reports, Nature Portfolio).
Key findings
- Genetically predicted MCP was associated with lower cognitive performance (IVW β=−0.361, 95% CI − 0.424 to − 0.299, p = 3.65×10⁻³⁰) with high heterogeneity (I²≈83.5%) and no directional pleiotropy.
- The Steiger test was non-significant (p = 0.23) and reverse MR significant (β=−0.171, p = 8.85×10⁻⁵⁸), so direction is uncertain.
- Genetic evidence is compatible with an MCP–lower-cognition association, but the direction is unresolved and the cognitive result is limited by UKB sample overlap.
- The China Health and Retirement Longitudinal Study (CHARLS) longitudinal validation component is ongoing and is marked [PENDING DATA] throughout: those sections describe planned analyses, not results.
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Study details
- Study designlongitudinal study
- Participants387,649
- Effect size83.5%
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 50 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for randomised / blinded because the record does not state it. We have no data on 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 and multi-centre collaboration, so those were left out: it earned 31 of the 62 points we could judge it on, which is 50 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 4 / 4 | 387,649 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 31 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 31 of the 62 points we could judge it on is 50 out of 100. |
| Total | 50 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. The record's author field reads “杨 永.”, which cannot be turned into a citation name, so it is left out. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Genetically predicted multisite chronic pain is associated with lower cognitive performance: a bidirectional Mendelian randomization study with NHANES contextual evidence. (2026). Research Square. https://doi.org/10.21203/rs.3.rs-11103914/v1
Vancouver
Genetically predicted multisite chronic pain is associated with lower cognitive performance: a bidirectional Mendelian randomization study with NHANES contextual evidence. Research Square. 2026. doi:10.21203/rs.3.rs-11103914/v1.
BibTeX
@article{study2026-a7ffdc0c,
title = {{Genetically predicted multisite chronic pain is associated with lower cognitive performance: a bidirectional Mendelian randomization study with NHANES contextual evidence}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11103914/v1},
url = {https://doi.org/10.21203/rs.3.rs-11103914/v1}
}
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