Key result
A MAPT haplotype-stratified GWAS identified 11 potential Alzheimer's disease risk loci (5 in H2-non-carriers, 6 in H2-carriers), though none achieved genome-wide significance.
Why the study?
The MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer disease, but MAPT haplotype-specific AD risk loci remain to be identified.
Observational (n=18,841)
Yes
Stratified GWAS identified loci that may confer Alzheimer's disease risk in a MAPT haplotype-specific manner, potentially enriching for neuronal genes implicated in synaptic transmission.
No MAPT haplotype-specific AD loci reach genome-wide significance; leaves open potential subtype-specific risk variants pending larger studies.
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.
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Strickland et al. (2020) conducted an observational in Alzheimer's disease (n=18,841). MAPT H1/H2 haplotype vs. H2-carriers vs H2-non-carriers was evaluated on MAPT haplotype-specific AD risk loci. A MAPT haplotype-stratified GWAS identified 11 potential Alzheimer's disease risk loci (5 in H2-non-carriers, 6 in H2-carriers), though none achieved genome-wide significance.
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