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

Samantha L. Strickland, Joseph S. Reddy, Mariet Allen, Aurelie N'songo, Jeremy D. Burgess, Morgane M. Corda, Travis Ballard, Xue Wang, Minerva M. Carrasquillo, Joanna M. Biernacka, Gregory D. Jenkins, Shubhabrata Mukherjee, Kevin Boehme, Paul Crane, John S. Kauwe, Nilüfer Ertekin-Taner

Research output: Contribution to journalArticlepeer-review

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)
Pages (from-to)983-1002
Number of pages20
JournalAlzheimer's and Dementia
Volume16
Issue number7
DOIs
StatePublished - Jul 1 2020

Keywords

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

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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