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

Alzheimer's Disease Genetics Consortium

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalAlzheimer's and Dementia
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • Alzheimer's disease
  • case-control studies
  • co-expression networks
  • differential gene expression
  • haplotype-stratified genome-wide association
  • MAPT

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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