Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease
Broce IJ, Tan CH, Fan CC, Jansen I, Savage JE, Witoelar A, Wen N, Hess CP et al.. Acta neuropathologica, 2018-11-09
Topic: Amyloid, tau and blood-test diagnosis
Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10 -9 ), MINK1 (chromosome 17, meta-p = 1.98 × 10 -7 ) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10 -7 and closest gene = MYBPC3, meta-p = 5.62 × 10 -8 ). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.
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APA 7th
Broce, I. J., Tan, C. H., Fan, C. C., Jansen, I., Savage, J. E., Witoelar, A., et al. (2019). Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta neuropathologica. https://doi.org/10.1007/s00401-018-1928-6
Vancouver
Broce IJ, Tan CH, Fan CC, Jansen I, Savage JE, Witoelar A, et al. Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta neuropathologica. 2019. doi:10.1007/s00401-018-1928-6. PMID: 30413934.
BibTeX
@article{broce2019-30413934,
author = {Broce, I. J. and Tan, C. H. and Fan, C. C. and Jansen, I. and Savage, J. E. and Witoelar, A. and Wen, N. and Hess, C. P. and others},
title = {{Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease}},
journal = {Acta neuropathologica},
year = {2019},
doi = {10.1007/s00401-018-1928-6},
pmid = {30413934},
url = {https://doi.org/10.1007/s00401-018-1928-6}
}
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Key findings
- Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL).
- In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR.
- Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes.
- In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10 -9 ), MINK1 (chromosome 17, meta-p = 1.98 × 10 -7 ) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10 -7 and closest gene = MYBPC3, meta-p = 5.62 × 10 -8 ).
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Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 69/100
Published in a leading specialty journal, and it is a meta-analysis pooling many studies. Scored zero for sample size, effect reported and studied in people 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 and multi-centre collaboration, so those were left out: it earned 40 of the 58 points we could judge it on, which is 69 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2019 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| 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 30413934) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 40 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 40 of the 58 points we could judge it on is 69 out of 100. |
| Total | 69 / 100 | — |
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