Two-stage Bayesian GWAS of 9576 individuals identifies SNP regions that are targeted by miRNAs inversely expressed in Alzheimer's and cancer

Alzheimers Dement. 2020 Jan;16(1):162-177. doi: 10.1002/alz.12003.

Abstract

Introduction: We compared genetic variants between Alzheimer's disease (AD) and two age-related cancers-breast and prostate -to identify single-nucleotide polymorphisms (SNPs) that are associated with inverse comorbidity of AD and cancer.

Methods: Bayesian multinomial regression was used to compare sex-stratified cases (AD and cancer) against controls in a two-stage study. A ±500 KB region around each replicated hit was imputed and analyzed after merging individuals from the two stages. The microRNAs (miRNAs) that target the genes involving these SNPs were analyzed for miRNA family enrichment.

Results: We identified 137 variants with inverse odds ratios for AD and cancer located on chromosomes 19, 4, and 5. The mapped miRNAs within the network were enriched for miR-17 and miR-515 families.

Discussion: The identified SNPs were rs4298154 (intergenic), within TOMM40/APOE/APOC1, MARK4, CLPTM1, and near the VDAC1/FSTL4 locus. The miRNAs identified in our network have been previously reported to have inverse expression in AD and cancer.

Keywords: Alzheimer's; CLPTM1; FSTL4; GWAS; MARK4; VDAC1; aging; cancer; genetic risk; inverse association; two-stage Bayesian.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / genetics*
  • Bayes Theorem
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Membrane Proteins / genetics
  • MicroRNAs / genetics*
  • Neoplasms / genetics*
  • Polymorphism, Single Nucleotide

Substances

  • CLPTM1 protein, human
  • Membrane Proteins
  • MicroRNAs