Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans

Alzheimers Dement. 2017 Feb;13(2):119-129. doi: 10.1016/j.jalz.2016.09.002. Epub 2016 Oct 20.

Abstract

Introduction: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power.

Methods: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs.

Results: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability.

Discussion: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.

Keywords: ABCA7; APOE; African Americans; Age; Alzheimer's disease; COBL; Diabetes; Education; Genome-wide association study (GWAS); Informed conditioning on clinical covariates; Resveratrol; SLC10A2; Sex differences; Smoking.

Publication types

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

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • African Americans / genetics*
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / ethnology*
  • Alzheimer Disease / genetics*
  • Apolipoproteins E / genetics
  • Diabetes Complications / ethnology
  • Diabetes Complications / genetics
  • Educational Status
  • Female
  • Genetic Loci*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Male
  • Microfilament Proteins / genetics*
  • Organic Anion Transporters, Sodium-Dependent / genetics*
  • Polymorphism, Single Nucleotide*
  • Prevalence
  • Smoking / ethnology
  • Smoking / genetics
  • Symporters / genetics*

Substances

  • ABCA7 protein, human
  • ATP-Binding Cassette Transporters
  • Apolipoproteins E
  • Cobl protein, human
  • Microfilament Proteins
  • Organic Anion Transporters, Sodium-Dependent
  • Symporters
  • sodium-bile acid cotransporter

Grant support