Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease
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...
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| Format: | Journal Article |
| Language: | English |
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2019
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| Online Access: | https://hdl.handle.net/10356/82843 http://hdl.handle.net/10220/50292 |
| _version_ | 1811685594676330496 |
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| author | Posthuma, Danielle Andreassen, Ole A. Karch, Celeste M. Desikan, Rahul S. Broce, Iris J. Tan, Chin Hong Fan, Chun Chieh Jansen, Iris Savage, Jeanne E. Witoelar, Aree Wen, Natalie Hess, Christopher P. Dillon, William P. Glastonbury, Christine M. Glymour, Maria Yokoyama, Jennifer S. Elahi, Fanny M. Rabinovici, Gil D. Miller, Bruce L. Mormino, Elizabeth C. Sperling, Reisa A. Bennett, David A. McEvoy, Linda K. Brewer, James B. Feldman, Howard H. Hyman, Bradley T. Pericak-Vance, Margaret Haines, Jonathan L. Farrer, Lindsay A. Mayeux, Richard Schellenberg, Gerard D. Yaffe, Kristine Sugrue, Leo P. Dale, Anders M. |
| author2 | School of Social Sciences |
| author_facet | School of Social Sciences Posthuma, Danielle Andreassen, Ole A. Karch, Celeste M. Desikan, Rahul S. Broce, Iris J. Tan, Chin Hong Fan, Chun Chieh Jansen, Iris Savage, Jeanne E. Witoelar, Aree Wen, Natalie Hess, Christopher P. Dillon, William P. Glastonbury, Christine M. Glymour, Maria Yokoyama, Jennifer S. Elahi, Fanny M. Rabinovici, Gil D. Miller, Bruce L. Mormino, Elizabeth C. Sperling, Reisa A. Bennett, David A. McEvoy, Linda K. Brewer, James B. Feldman, Howard H. Hyman, Bradley T. Pericak-Vance, Margaret Haines, Jonathan L. Farrer, Lindsay A. Mayeux, Richard Schellenberg, Gerard D. Yaffe, Kristine Sugrue, Leo P. Dale, Anders M. |
| author_sort | Posthuma, Danielle |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T04:47:01Z |
| format | Journal Article |
| id | ntu-10356/82843 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:47:01Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/828432020-03-07T13:00:26Z Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease Posthuma, Danielle Andreassen, Ole A. Karch, Celeste M. Desikan, Rahul S. Broce, Iris J. Tan, Chin Hong Fan, Chun Chieh Jansen, Iris Savage, Jeanne E. Witoelar, Aree Wen, Natalie Hess, Christopher P. Dillon, William P. Glastonbury, Christine M. Glymour, Maria Yokoyama, Jennifer S. Elahi, Fanny M. Rabinovici, Gil D. Miller, Bruce L. Mormino, Elizabeth C. Sperling, Reisa A. Bennett, David A. McEvoy, Linda K. Brewer, James B. Feldman, Howard H. Hyman, Bradley T. Pericak-Vance, Margaret Haines, Jonathan L. Farrer, Lindsay A. Mayeux, Richard Schellenberg, Gerard D. Yaffe, Kristine Sugrue, Leo P. Dale, Anders M. School of Social Sciences Polygenic Enrichment Social sciences::Psychology Lipids 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. Accepted version 2019-10-30T09:14:12Z 2019-12-06T15:06:43Z 2019-10-30T09:14:12Z 2019-12-06T15:06:43Z 2018 Journal Article Broce, I. J., Tan, C. H., Fan, C. C., Jansen, I., Savage, J. E., Witoelar, A., . . . Desikan, R. S. (2019). Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease. Acta Neuropathologica, 137(2), 209-226. doi:10.1007/s00401-018-1928-6 0001-6322 https://hdl.handle.net/10356/82843 http://hdl.handle.net/10220/50292 10.1007/s00401-018-1928-6 en Acta Neuropathologica © 2018 Springer-Verlag GmbH Germany, part of Springer Nature. All rights reserved. This paper was published in Acta Neuropathologica and is made available with permission of Springer-Verlag GmbH Germany, part of Springer Nature. 30 p. application/pdf |
| spellingShingle | Polygenic Enrichment Social sciences::Psychology Lipids Posthuma, Danielle Andreassen, Ole A. Karch, Celeste M. Desikan, Rahul S. Broce, Iris J. Tan, Chin Hong Fan, Chun Chieh Jansen, Iris Savage, Jeanne E. Witoelar, Aree Wen, Natalie Hess, Christopher P. Dillon, William P. Glastonbury, Christine M. Glymour, Maria Yokoyama, Jennifer S. Elahi, Fanny M. Rabinovici, Gil D. Miller, Bruce L. Mormino, Elizabeth C. Sperling, Reisa A. Bennett, David A. McEvoy, Linda K. Brewer, James B. Feldman, Howard H. Hyman, Bradley T. Pericak-Vance, Margaret Haines, Jonathan L. Farrer, Lindsay A. Mayeux, Richard Schellenberg, Gerard D. Yaffe, Kristine Sugrue, Leo P. Dale, Anders M. Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease |
| title | Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease |
| title_full | Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease |
| title_fullStr | Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease |
| title_full_unstemmed | Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease |
| title_short | Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease |
| title_sort | dissecting the genetic relationship between cardiovascular risk factors and alzheimer s disease |
| topic | Polygenic Enrichment Social sciences::Psychology Lipids |
| url | https://hdl.handle.net/10356/82843 http://hdl.handle.net/10220/50292 |
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