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MAPT haplotype–stratified GWAS reveals differential association for AD risk variants
Author(s) -
Strickland Samantha L.,
Reddy Joseph S.,
Allen Mariet,
N'songo Aurelie,
Burgess Jeremy D.,
Corda Morgane M.,
Ballard Travis,
Wang Xue,
Carrasquillo Minerva M.,
Biernacka Joanna M.,
Jenkins Gregory D.,
Mukherjee Shubhabrata,
Boehme Kevin,
Crane Paul,
Kauwe John S.,
ErtekinTaner Nilüfer
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12099
Subject(s) - haplotype , genome wide association study , biology , genetics , genetic association , locus (genetics) , alzheimer's disease , gene , disease , allele , single nucleotide polymorphism , medicine , genotype , pathology
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.