Non-coding variants in MYH11, FZD3, and SORCS3 are associated with dementia in women

Alzheimers Dement. 2021 Feb;17(2):215-225. doi: 10.1002/alz.12181. Epub 2020 Sep 23.

Abstract

Introduction: Recent studies suggest that both sex-specific genetic risk factors and those shared between dementia and stroke are involved in dementia pathogenesis.

Methods: We performed both single-variant and gene-based genome-wide association studies of >11,000 whole genome sequences from the Women's Health Initiative cohort to discover loci associated with dementia, with adjustment for age, ethnicity, stroke, and venous thromboembolism status. Evidence for prior evidence of association and differential gene expression in dementia-related tissues and samples was gathered for each locus.

Results: Our multiethnic studies identified significant associations between variants within APOE, MYH11, FZD3, SORCS3, and GOLGA8B and risk of dementia. Ten genes implicated by these loci, including MYH11, FZD3, SORCS3, and GOLGA8B, were differentially expressed in the context of Alzheimer's disease.

Discussion: Our association of MYH11, FZD3, SORCS3, and GOLGA8B with dementia is supported by independent functional studies in human subjects, model systems, and associations with shared risk factors for stroke and dementia.

Keywords: dementia; sex-specific; stroke; whole-genome sequence; women.

MeSH terms

  • Alzheimer Disease / ethnology
  • Alzheimer Disease / genetics*
  • Cohort Studies
  • Female
  • Frizzled Receptors / genetics*
  • Genome-Wide Association Study*
  • Humans
  • Middle Aged
  • Myosin Heavy Chains / genetics*
  • Nerve Tissue Proteins / genetics*
  • Receptors, Cell Surface / genetics*
  • Risk Factors

Substances

  • FZD3 protein, human
  • Frizzled Receptors
  • MYH11 protein, human
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • SorCS3 protein, human
  • Myosin Heavy Chains