Format

Send to

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

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

Author information

1
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
2
Department of Biostatistics, Harvard T.H Chan School of Public Health, Boston, MA, USA.
3
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
4
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
5
Department of Biomedicine, Bartholins Allé 6, Aarhus, Denmark.
6
Computational Sciences, Janssen Research and Development, Pharmaceutical Company of Johnson and Johnson, Spring House, PA, USA.
7
School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London, UK.
8
Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.

Abstract

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.

PMID:
26830138
PMCID:
PMC4970971
DOI:
10.1038/mp.2015.218
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center