TY - JOUR
T1 - MAPT haplotype–stratified GWAS reveals differential association for AD risk variants
AU - Strickland, Samantha L.
AU - Reddy, Joseph S.
AU - Allen, Mariet
AU - N'songo, Aurelie
AU - Burgess, Jeremy D.
AU - Corda, Morgane M.
AU - Ballard, Travis
AU - Wang, Xue
AU - Carrasquillo, Minerva M.
AU - Biernacka, Joanna M.
AU - Jenkins, Gregory D.
AU - Mukherjee, Shubhabrata
AU - Boehme, Kevin
AU - Crane, Paul
AU - Kauwe, John S.
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
For samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona and utilized in the brain expression studies: The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05‐901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research.
Funding Information:
This work was supported by National Institute on Aging [RF AG051504; U01 AG046139; R01 AG061796 to NET]; and the National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET].
Funding Information:
We thank the patients and their families for their participation, without which these studies would not have been possible. This work was supported by National Institute on Aging [RF AG051504; U01 AG046139; R01 AG061796 to NET]; and the National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET]. For samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona and utilized in the brain expression studies: The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01?AG032984, RC2?AG036528; NACC, U01?AG016976; NCRAD, U24?AG021886; NIA LOAD, U24?AG026395, U24?AG026390; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1?HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG0016574, U01?AG006786; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133,?AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England [HEFCE], Alzheimer's Research Trust [ART], BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stichting Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01?AG024904, RC2?AG036535, K01 AG030514. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research.
Publisher Copyright:
© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Introduction: MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD). Methods: Using Alzheimer's Disease Genetics Consortium (ADGC) genome-wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype–stratified association to discover MAPT haplotype–specific AD risk loci. Results: We identified 11 loci—5 in H2-non-carriers and 6 in H2-carriers—although none of the MAPT haplotype–specific associations achieved genome-wide significance. The most significant H2 non-carrier–specific association was with a NECTIN2 intronic (P = 1.33E-07) variant, and that for H2 carriers was near NKX6-1 (P = 1.99E-06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E-06). Eight of the 12 genes at these loci had transcriptome-wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co-expression network implicated in “synaptic transmission” (P = 9.85E-59), which is also enriched for neuronal genes (P = 1.0E-164), including MAPT. Discussion: This stratified GWAS identified loci that may confer AD risk in a MAPT haplotype–specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission.
AB - Introduction: MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD). Methods: Using Alzheimer's Disease Genetics Consortium (ADGC) genome-wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype–stratified association to discover MAPT haplotype–specific AD risk loci. Results: We identified 11 loci—5 in H2-non-carriers and 6 in H2-carriers—although none of the MAPT haplotype–specific associations achieved genome-wide significance. The most significant H2 non-carrier–specific association was with a NECTIN2 intronic (P = 1.33E-07) variant, and that for H2 carriers was near NKX6-1 (P = 1.99E-06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E-06). Eight of the 12 genes at these loci had transcriptome-wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co-expression network implicated in “synaptic transmission” (P = 9.85E-59), which is also enriched for neuronal genes (P = 1.0E-164), including MAPT. Discussion: This stratified GWAS identified loci that may confer AD risk in a MAPT haplotype–specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission.
KW - Alzheimer's disease
KW - MAPT
KW - case-control studies
KW - co-expression networks
KW - differential gene expression
KW - haplotype-stratified genome-wide association
UR - http://www.scopus.com/inward/record.url?scp=85084419555&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85084419555&partnerID=8YFLogxK
U2 - 10.1002/alz.12099
DO - 10.1002/alz.12099
M3 - Article
C2 - 32400971
AN - SCOPUS:85084419555
SN - 1552-5260
VL - 16
SP - 983
EP - 1002
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 7
ER -