Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Iris J. Broce, Chin Hong Tan, Chun Chieh Fan, Iris Jansen, Jeanne E. Savage, Aree Witoelar, Natalie Wen, Christopher P. Hess, William P. Dillon, Christine M. Glastonbury, Maria Glymour, Jennifer S. Yokoyama, Fanny M. Elahi, Gil D. Rabinovici, Bruce L. Miller, Elizabeth C. Mormino, Reisa A. Sperling, David A. Bennett, Linda K. McEvoy, James B. Brewer & 14 others Howard H. Feldman, Bradley T. Hyman, Margaret Pericak-Vance, Jonathan L. Haines, Lindsay A. Farrer, Richard Mayeux, Gerard D. Schellenberg, Kristine Yaffe, Leo P. Sugrue, Anders M. Dale, Danielle Posthuma, Ole A. Andreassen, Celeste M. Karch, Rahul S. Desikan

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
LanguageEnglish
Pages209-226
Number of pages18
JournalActa Neuropathologica
Volume137
Issue number2
Early online date2018
DOIs
Publication statusPublished - 11 Feb 2019

Cite this

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. https://doi.org/10.1007/s00401-018-1928-6
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. ; Posthuma, Danielle ; Andreassen, Ole A. ; Karch, Celeste M. ; Desikan, Rahul S. / Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease. In: Acta Neuropathologica. 2019 ; Vol. 137, No. 2. pp. 209-226.
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abstract = "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.",
author = "Broce, {Iris J.} and Tan, {Chin Hong} and Fan, {Chun Chieh} and Iris Jansen and Savage, {Jeanne E.} and Aree Witoelar and Natalie Wen and Hess, {Christopher P.} and Dillon, {William P.} and Glastonbury, {Christine M.} and Maria Glymour and Yokoyama, {Jennifer S.} and Elahi, {Fanny M.} and Rabinovici, {Gil D.} and Miller, {Bruce L.} and Mormino, {Elizabeth C.} and Sperling, {Reisa A.} and Bennett, {David A.} and McEvoy, {Linda K.} and Brewer, {James B.} and Feldman, {Howard H.} and Hyman, {Bradley T.} and Margaret Pericak-Vance and Haines, {Jonathan L.} and Farrer, {Lindsay A.} and Richard Mayeux and Schellenberg, {Gerard D.} and Kristine Yaffe and Sugrue, {Leo P.} and Dale, {Anders M.} and Danielle Posthuma and Andreassen, {Ole A.} and Karch, {Celeste M.} and Desikan, {Rahul S.}",
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Broce, IJ, Tan, CH, Fan, CC, Jansen, I, Savage, JE, Witoelar, A, Wen, N, Hess, CP, Dillon, WP, Glastonbury, CM, Glymour, M, Yokoyama, JS, Elahi, FM, Rabinovici, GD, Miller, BL, Mormino, EC, Sperling, RA, Bennett, DA, McEvoy, LK, Brewer, JB, Feldman, HH, Hyman, BT, Pericak-Vance, M, Haines, JL, Farrer, LA, Mayeux, R, Schellenberg, GD, Yaffe, K, Sugrue, LP, Dale, AM, Posthuma, D, Andreassen, OA, Karch, CM & Desikan, RS 2019, 'Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease', Acta Neuropathologica, vol. 137, no. 2, pp. 209-226. https://doi.org/10.1007/s00401-018-1928-6

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease. / 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.; Posthuma, Danielle; Andreassen, Ole A.; Karch, Celeste M.; Desikan, Rahul S.

In: Acta Neuropathologica, Vol. 137, No. 2, 11.02.2019, p. 209-226.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

AU - Broce, Iris J.

AU - Tan, Chin Hong

AU - Fan, Chun Chieh

AU - Jansen, Iris

AU - Savage, Jeanne E.

AU - Witoelar, Aree

AU - Wen, Natalie

AU - Hess, Christopher P.

AU - Dillon, William P.

AU - Glastonbury, Christine M.

AU - Glymour, Maria

AU - Yokoyama, Jennifer S.

AU - Elahi, Fanny M.

AU - Rabinovici, Gil D.

AU - Miller, Bruce L.

AU - Mormino, Elizabeth C.

AU - Sperling, Reisa A.

AU - Bennett, David A.

AU - McEvoy, Linda K.

AU - Brewer, James B.

AU - Feldman, Howard H.

AU - Hyman, Bradley T.

AU - Pericak-Vance, Margaret

AU - Haines, Jonathan L.

AU - Farrer, Lindsay A.

AU - Mayeux, Richard

AU - Schellenberg, Gerard D.

AU - Yaffe, Kristine

AU - Sugrue, Leo P.

AU - Dale, Anders M.

AU - Posthuma, Danielle

AU - Andreassen, Ole A.

AU - Karch, Celeste M.

AU - Desikan, Rahul S.

PY - 2019/2/11

Y1 - 2019/2/11

N2 - 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.

AB - 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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