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.
N1 - Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
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.
KW - Alzheimer’s disease
KW - Cardiovascular
KW - Genetic pleiotropy
KW - Lipids
KW - Polygenic enrichment
UR - http://www.scopus.com/inward/record.url?scp=85056297318&partnerID=8YFLogxK
U2 - 10.1007/s00401-018-1928-6
DO - 10.1007/s00401-018-1928-6
M3 - Article
C2 - 30413934
AN - SCOPUS:85056297318
SN - 0001-6322
VL - 137
SP - 209
EP - 226
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -