Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease

Alzheimers Dement. 2016 Aug;12(8):862-71. doi: 10.1016/j.jalz.2016.01.010. Epub 2016 Mar 15.

Abstract

Introduction: The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.

Methods: We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study.

Results: We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]).

Discussion: We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

Keywords: APOE; Alzheimer's disease; GWAS; Genetics; Posterior cortical atrophy; Selective vulnerability.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aged
  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics*
  • Apolipoproteins E / genetics
  • Atrophy / etiology
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Cerebral Cortex / pathology*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Male
  • Membrane Transport Proteins / genetics
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Proteins / genetics*
  • Receptors, Complement 3b / genetics
  • Risk Factors
  • Semaphorins / genetics*

Substances

  • Apolipoproteins E
  • CNTNAP5 protein, human
  • CR1 protein, human
  • Cell Adhesion Molecules, Neuronal
  • FAM46A protein, human
  • Membrane Transport Proteins
  • Proteins
  • Receptors, Complement 3b
  • Sema3C protein, human
  • Semaphorins
  • TOMM40 protein, human