MAPT haplotype-stratified GWAS reveals differential association for AD risk variants

Alzheimers Dement. 2020 Jul;16(7):983-1002. doi: 10.1002/alz.12099. Epub 2020 May 13.

Abstract

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.

Keywords: MAPT; Alzheimer's disease; case-control studies; co-expression networks; differential gene expression; haplotype-stratified genome-wide association.

MeSH terms

  • Alzheimer Disease / genetics*
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotype
  • Haplotypes*
  • Humans
  • Polymorphism, Single Nucleotide*
  • tau Proteins / genetics*

Substances

  • MAPT protein, human
  • tau Proteins

Grant support