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

• Published in: Molecular psychiatry Vol. 21; no. 11; pp. 1608 - 1612
• Main Authors: Herold, C, Hooli, B V, Mullin, K, Liu, T, Roehr, J T, Mattheisen, M, Parrado, A R, Bertram, L, Lange, C, Tanzi, R E
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2016
• Subjects: Age; Age of Onset; Aged; Alleles; Alzheimer Disease - genetics; Alzheimer's disease; Apolipoprotein E; Apolipoproteins E - genetics; Carrier Proteins - genetics; Carrier Proteins - metabolism; Family; Female; Genes; Genetic Association Studies - methods; Genetic factors; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study - methods; Genomes; Genomics; Genotype; Heritability; Humans; Male; Meta-analysis; Middle Aged; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurodegenerative diseases; Phenotypes; 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; Single-nucleotide polymorphism; Systematic review; tRNA Methyltransferases - genetics; tRNA Methyltransferases - metabolism
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2015.218

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 ), rs1347297 in the gene OSBPL6 (P-value=4.53 × 10 ), and rs1513625 near PDCL3 (P-value=4.28 × 10 ). In addition, rs72953347 in OSBPL6 (P-value=6.36 × 10 ) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value=4.76 × 10 ; rs62400067, P-value=3.54 × 10 ). 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.