Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3

Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.


The genetic basis of Alzheimer's disease (AD) is complex and heterogeneous. Over 200 highly penetrant pathogenic variants in the genes APP, PSEN1, and PSEN2 cause a subset of early-onset familial AD. On the other hand, susceptibility to late-onset forms of AD (LOAD) is indisputably associated to the ɛ4 allele in the gene APOE, and more recently to variants in more than two-dozen additional genes identified in the large-scale genome-wide association studies (GWAS) and meta-analyses reports. Taken together however, although the heritability in AD is estimated to be as high as 80%, a large proportion of the underlying genetic factors still remain to be elucidated. In this study, we performed a systematic family-based genome-wide association and meta-analysis on close to 15 million imputed variants from three large collections of AD families (~3500 subjects from 1070 families). Using a multivariate phenotype combining affection status and onset age, meta-analysis of the association results revealed three single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with AD risk: rs7609954 in the gene PTPRG (P-value=3.98 × 10-8), rs1347297 in the gene OSBPL6 (P-value=4.53 × 10-8), and rs1513625 near PDCL3 (P-value=4.28 × 10-8). In addition, rs72953347 in OSBPL6 (P-value=6.36 × 10-7) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value=4.76 × 10-7; rs62400067, P-value=3.54 × 10-7). In summary, family-based GWAS meta-analysis of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6, and PDCL3 that influence risk for AD with genome-wide significance.

Publication types

  • Meta-Analysis

MeSH terms

  • Age of Onset
  • Aged
  • Alleles
  • Alzheimer Disease / genetics*
  • Apolipoproteins E / genetics
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Family
  • Female
  • Genetic Association Studies / methods
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods
  • Genomics
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Polymorphism, Single Nucleotide
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / genetics*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / metabolism
  • Receptors, Steroid / genetics*
  • Receptors, Steroid / metabolism
  • Risk Factors
  • tRNA Methyltransferases / genetics
  • tRNA Methyltransferases / metabolism


  • Apolipoproteins E
  • Carrier Proteins
  • Nerve Tissue Proteins
  • PDCL3 protein, human
  • Receptors, Steroid
  • oxysterol binding protein
  • tRNA Methyltransferases
  • CDKAL1 protein, human
  • PTPRG protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5