Herold, ChristineHooli, Basavaraj V.Mullin, KristinaLiu, TianRoehr, Johannes TMattheisen, ManuelParrado, Antonio R.Bertram, LarsLange, ChristophTanzi, Rudolph2016-10-112015Herold, Christine, Basavaraj V. Hooli, Kristina Mullin, Tian Liu, Johannes T Roehr, Manuel Mattheisen, Antonio R. Parrado, Lars Bertram, Christoph Lange, and Rudolph E. Tanzi. 2015. “Family-based Association Analyses of Imputed Genotypes Reveal Genome-Wide Significant Association of Alzheimer’s disease with OSBPL6, PTPRG and PDCL3.” Molecular psychiatry :10.1038/mp.2015.218. doi:10.1038/mp.2015.218. http://dx.doi.org/10.1038/mp.2015.218.1359-4184http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002716The 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 Alzheimer's disease (EOFAD). On the other hand, susceptibility to late-onset forms of AD (LOAD) is indisputably associated to the ε4 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 (~3,500 subjects from 1,070 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 = 3.98·10−08), rs1347297 in the gene OSBPL6 (P-value = 4.53·10−08), and rs1513625 near PDCL3 (P-value = 4.28·10−08). In addition, rs72953347 in OSBPL6 (P-value = 6.36·10−07) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value: 4.76·10−07; rs62400067, P-value: 3.54·10−07). 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.en-USJournal Article2016-10-1110.1038/mp.2015.218