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 - 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
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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 -